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Missling. Document filed by Kenneth Downing. 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Regarding Document No. 21 MOTION for Stephen G. Topetzes to Appear Pro Hac Vice . Filing fee $ 200.00, receipt number ANYSDC-29796431. Motion and supporting papers to be reviewed by Clerk's Office staff.. The document has been reviewed and there are no deficiencies. 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MISSLING,\n\n Defendants.\n-------------------------------x\n\n\n Pursuant to Rule 7.1 of the Federal Rules of Civil Procedure, Defendant Anavex Life\n\nSciences Corporation, by its attorneys K&L Gates LLP, hereby discloses and certifies as follows:\n\n Anavex Life Sciences Corporation has no parent corporation, and no publicly held\n\ncorporation owns 10% or more of its stock.\n\n\n\n Dated: August 23, 2024 Respectfully submitted,\n\n\n /s/ Theodore L. Kornobis\n Theodore L. Kornobis\n Stephen G. Topetzes (pro hac vice pending)\n K&L Gates LLP\n 1601 K Street NW\n Washington, DC 20006-1600\n Phone: (202) 778-9000\n Email: ted.kornobis@klgates.com\n stephen.topetzes@klgates.com\n\n Attorneys for Defendant Anavex Life Sciences\n Corporation and Christopher U. Missling\n\n\n\n\n319897561.1\n\f","ocr_status":2,"date_upload":"2024-08-23T20:53:01.974568-07:00","document_number":"25","attachment_number":null,"pacer_doc_id":"127036039551","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Rule 7.1 Corporate Disclosure Statement","acms_document_guid":""}],"date_created":"2024-08-23T20:48:28.152073-07:00","date_modified":"2025-12-22T08:34:03.562713-08:00","date_filed":"2024-08-23","time_filed":"23:46:03","entry_number":25,"recap_sequence_number":"2024-08-23.005","pacer_sequence_number":110,"description":"RULE 7.1 CORPORATE DISCLOSURE STATEMENT. No Corporate Parent. Document filed by Anavex Life Sciences Corporation..(Kornobis, Theodore) (Entered: 08/23/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/400348517/","id":400348517,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579211/","id":409579211,"tags":[],"absolute_url":"/docket/68511120/24/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:48:28.132903-07:00","date_modified":"2025-12-22T08:34:03.532575-08:00","sha1":"fcac68df6f93498a09ef9ed9621b5ec38a525c15","page_count":23,"file_size":243153,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.24.0_1.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.24.0.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":" Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 1 of 23\n\n\n\n\nUNITED STATES DISTRICT COURT\nSOUTHERN DISTRICT OF NEW YORK\n\n\nKENNETH DOWNING, individually and on\n Case No. 1:24-cv-03529-CM\nbehalf of all others similarly situated,\n\n Plaintiff,\n\n v.\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n\n\n\n\n DEFENDANTS\u2019 MEMORANDUM OF LAW\n IN SUPPORT OF THEIR\n MOTION TO DISMISS THE COMPLAINT\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 2 of 23\n\n\n\n\n TABLE OF CONTENTS\n Page\nPRELIMINARY STATEMENT .....................................................................................................1\n\nBACKGROUND .............................................................................................................................2\n\nI. Anavex and Its Rett Syndrome Studies ...............................................................................2\n\n A. The U.S. Phase 2 Study (ANAVEX\u00ae2-73-RS-001) ...............................................2\n\n B. The Avatar Study (ANAVEX\u00ae2-73-RS-002).........................................................3\n\n C. The Excellence Study (ANAVEX\u00ae2-73-RS-003) ..................................................4\n\nII. Plaintiff\u2019s Alleged False Statements and Alleged \u201cCorrective Disclosures\u201d ......................6\n\nIII. Procedural History ...............................................................................................................8\n\nSTANDARD OF REVIEW .............................................................................................................9\n\nARGUMENT ...................................................................................................................................9\n\nI. Plaintiff Utterly Fails to Meet the High Burden Established to Plead Scienter in\n Securities Fraud Cases. ........................................................................................................9\n\nII. The Intra-Class Period Disclosure of the Excellence Endpoints Negates Plaintiff\u2019s\n Claims of False or Misleading Statements.........................................................................12\n\nIII. Loss Causation Is Negated by the Intra-Class Period Disclosures of Endpoints ...............13\n\nIV. The Complaint Does Not Allege Any False or Misleading Statement or Omission\n of Material Fact with the Required Particularity ...............................................................14\n\n A. The Complaint Fails to Adequately Identify and Explain the Allegedly\n False or Misleading Statements .............................................................................14\n\n B. Several of the Statements At Issue Do Not Involve Any Cognizable Fraud .........15\n\n C. Any Remaining Criticisms of the Choice of Endpoints Do Not State a\n Claim ......................................................................................................................16\n\nV. Claims as to Avatar Are Time-Barred and Divorced from the Corrective\n Disclosure ..........................................................................................................................16\n\nCONCLUSION ..............................................................................................................................18\n\n\n\n\n i\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 3 of 23\n\n\n\n\n TABLE OF AUTHORITIES\n\n Page(s)\n\nCases\n\nAbely v. Aeterna Zentaris Inc.,\n No. 12 CIV. 4711, 2013 WL 2399869 (S.D.N.Y. May 29, 2013)...........................................16\n\nATSI Commc\u2019ns, Inc. v. Shaar Fund, Ltd.,\n 493 F.3d 87 (2d Cir. 2007)...............................................................................................2, 9, 10\n\nBettis v. Aixtron SE,\n No. 16 CIV. 00025 (CM), 2016 WL 7468194 (S.D.N.Y. Dec. 20, 2016)...............................12\n\nCity of Brockton Ret. Sys. v. Shaw Group Inc.,\n 540 F. Supp. 2d 464 (S.D.N.Y. 2008) (McMahon, J.) .............................................................11\n\nECA & Local 134 IBEW Joint Pension Trust of Chicago v. JP Morgan Chase Co.,\n 553 F.3d 187 (2d Cir. 2009).......................................................................................................9\n\nFort Worth Emps. Ret. Fund v. Biovail Corp.,\n 615 F. Supp. 2d 218 (S.D.N.Y. 2009)......................................................................................13\n\nGamm v. Sanderson Farms, Inc.,\n 944 F.3d 455 (2d Cir. 2019).....................................................................................................15\n\nGanino v. Citizens Utils. Co.,\n 228 F.3d 154 (2d Cir. 2000).....................................................................................................13\n\nIn re AstraZeneca plc Sec. Litig.,\n No. 21-cv-722, 2022 WL 4133258 (S.D.N.Y. Sept. 12, 2022),\n aff\u2019d sub nom. Nandkumar v. AstraZeneca PLC, No. 22-2704-CV,\n 2023 WL 3477164 (2d Cir. May 16, 2023) .............................................................................14\n\nKalnit v. Eichler,\n 264 F.3d 131 (2d Cir. 2001).....................................................................................................10\n\nKleinman v. Elan Corp.,plc,\n 706 F.3d 145 (2d Cir. 2013)...........................................................................................9, 14, 16\n\nKoplyay v. Cirrus Logic, Inc.,\n No. 13-cv-790 (CM), 2013 WL 6233908 (S.D.N.Y. Dec. 2, 2013) ................................4, 9, 11\n\nIn re Lululemon Sec. Litig.,\n 14 F. Supp. 3d 553 (S.D.N.Y. 2014), aff\u2019d, 604 F. App\u2019x 62 (2d Cir. 2015)..............10, 14, 15\n\nIn re MBIA Inc.,\n No. 05-cv-3514, 2007 WL 473708 (S.D.N.Y. Feb. 14, 2007) ................................................17\n\n\n ii\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 4 of 23\n\n\n\n\nMerck & Co. v. Reynolds,\n 559 U.S. 633 (2010) .................................................................................................................17\n\nMills v. Polar Molecular Corp.,\n 12 F.3d 1170 (2d Cir. 1993).....................................................................................................11\n\nIn re New Energy Sys. Sec. Litig.,\n 66 F. Supp. 3d 401 (S.D.N.Y. 2014)........................................................................................13\n\nNovak v. Kasaks,\n 216 F.3d 300 (2d Cir. 2000).....................................................................................................10\n\nOkla. Firefighters Pension & Ret. Sys. v. Student Loan Corp.,\n 951 F. Supp. 2d 479 (S.D.N.Y. 2013)..........................................................................11, 12, 13\n\nPolar Int\u2019l Brokerage Corp. v. Reeve,\n 108 F. Supp. 2d 225 (S.D.N.Y. 2000)......................................................................................15\n\nIn re Progress Energy, Inc.,\n 371 F. Supp. 2d 548 (S.D.N.Y.2005).................................................................................12, 16\n\nStaehr v. Hartford Fin. Servs. Grp., Inc.,\n 547 F.3d 406 (2d Cir. 2008).......................................................................................................5\n\nIn re Sanofi Sec. Litig.,\n 87 F. Supp. 3d 510 (S.D.N.Y. 2015), aff\u2019d sub nom.\n Tongue v. Sanofi, 816 F.3d 199 (2d Cir. 2016) .........................................................................6\n\nIn re Sanofi-Aventis Sec. Litig.,\n 774 F. Supp. 2d 549 (S.D.N.Y.2011).......................................................................................16\n\nShetty v. Trivago N.V.,\n 796 F. App\u2019x 31 (2d Cir. 2019) ...............................................................................................11\n\nIn re Signet Jewelers Ltd. Sec. Litig.,\n No. 16-cv-6728 (CM), 2019 WL 3001084 (S.D.N.Y. July 10, 2019) .....................................13\n\nTellabs, Inc. v. Makor Issues & Rts., Ltd.,\n 551 U.S. 308 (2007) .............................................................................................................9, 10\n\nStatutes\n\n28 U.S.C. \u00a7 1658(b) .......................................................................................................................17\n\n\n\n\n iii\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 5 of 23\n\n\n\n\n TABLE OF DEFINED TERMS\n\nAnavex Anavex Life Sciences Corporation\n\nClass Period June 21, 2021 to January 1, 2024, inclusive\n\nCGI-I Clinical Global Impression of Improvement Scale\n\nFDA U.S. Food and Drug Administration\n\nMMRM Mixed-effects models for repeated measures\n\nPSLRA Private Securities Litigation Reform Act of 1995\n\nRSBQ Rett Syndrome Behavioural Questionnaire\n\nRSBQ AUC Rett Syndrome Behavioural Questionnaire (RSBQ) Area Under\n the Curve (AUC)\n\n\n\n\n iv\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 6 of 23\n\n\n\n\n PRELIMINARY STATEMENT\n\n This is a prototypical strike suit. It is a copycat of another class action lawsuit, filed mere\n\ndays before the closing of the PSLRA period as part of an (unsuccessful) effort to cause\n\nMr. Downing to be appointed as lead plaintiff. The Complaint\u2019s inadequacies are striking and\n\nnumerous, revealing seemingly no effort to undertake basic due diligence or develop the\n\nallegations in a manner that could come close to surviving dismissal, let alone satisfy the\n\nheightened standards applicable to securities fraud lawsuits. Indeed, the central premise of the\n\nsuit\u2014that the endpoints for the Excellence study were not revealed until the end of the Class\n\nPeriod\u2014is demonstrably false, as such matters were disclosed, directly and explicitly, on multiple\n\noccasions. It is no surprise, then, that the allegations overall lack particularity and fail to muster\n\nanything more than boilerplate to support scienter\u2014there is nothing for Plaintiff to have pled in\n\nsupport of such unfounded and unsupportable claims.\n\n Plaintiff alleges that Defendant Anavex Life Sciences Corporation (\u201cAnavex\u201d or the\n\n\u201cCompany\u201d) and its CEO, Dr. Christopher U. Missling, misled investors because the \u201cendpoints\u201d\n\nin two studies changed between the study announcement and release of the results. What Plaintiff\n\nfails to allege, however, is fraud. As explained below, beyond a handful of conclusory sentences,\n\nthere are no allegations to support that Defendants acted with fraudulent intent. The absence of\n\neven a passing effort to meet this fundamental pleading burden is alone fatal to the case. And clear\n\nintra-Class Period disclosures of the allegedly non-disclosed facts further illustrate a lack of\n\ninvestigation and support for these claims. Such disclosure undermines the elements of falsity and\n\nloss causation. It is therefore unsurprising that the allegations as to the purportedly misleading\n\nstatements also lack particularity and in some cases are demonstrably untrue. Finally, indicative\n\nof the purely tactical nature of this lawsuit, many of the alleged misstatements are clearly time-\n\n\n\n\n 1\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 7 of 23\n\n\n\n\nbarred and appear to have been included solely to aid in getting Mr. Downing appointed as lead\n\nplaintiff.\n\n For all of these reasons the Complaint should be dismissed with prejudice.\n\n BACKGROUND1\n\nI. Anavex and Its Rett Syndrome Studies\n\n Anavex is a biopharmaceutical company working to develop treatments for certain nervous\n\nsystem diseases, including ANAVEX 2-73. Compl. \u00b6 2.2 Anavex engaged in several clinical trials\n\nfor this drug, including a U.S. Phase 2 study (results announced December 2020); the Avatar study\n\n(results announced February 1, 2022); and the Excellence study (results announced January 2,\n\n2024). Compl. \u00b6\u00b6 6-7, 56. These studies each had \u201cendpoints,\u201d i.e., measures used to determine\n\nsuccess relative to Rett Syndrome. Endpoints for Rett Syndrome include the Rett Syndrome\n\nBehaviour Questionnaire (\u201cRSBQ\u201d), which is measured by the patient\u2019s caregiver, and the Clinical\n\nGlobal Impression Improvement Scale (\u201cCGI-I\u201d), which is physician measured. Compl. \u00b6 29. As\n\nis typical in the biopharmaceutical industry, each study was double-blinded (i.e., the Company did\n\nnot know who received treatment and who received placebos). Ex. 1 (2023 Form 10-K) at 10.\n\n A. The U.S. Phase 2 Study (ANAVEX\u00ae2-73-RS-001)\n\n Anavex commenced a U.S.-Based Phase 2 trial in March 2019. See Ex. 2 (2022 Form 10-\n\nK) at 9. The primary endpoint of the trial was safety; secondary efficacy endpoints were measured\n\n\n\n1\n This section accepts as true the non-conclusory allegations in the Complaint and cites materials\nthe Court can properly consider, including \u201cstatements or documents incorporated into the\ncomplaint by reference, legally required public disclosure documents filed with the SEC, and\ndocuments possessed by or known to the plaintiff and upon which it relied in bringing the suit.\u201d\nATSI Commc\u2019ns, Inc. v. Shaar Fund, Ltd., 493 F.3d 87, 98 (2d Cir. 2007). Such materials are\nprovided as exhibits to the Declaration of Theodore L. Kornobis, referred to herein as \u201cEx. __\u201d.\n2\n As one example of demonstrably false \u201cfactual\u201d allegations, Plaintiff mistakenly alleges Anavex\nis a Delaware corporation (Compl. \u00b6 16) when it is in fact incorporated in Nevada. Ex. 1.\n\n\n\n 2\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 8 of 23\n\n\n\n\nusing RSBQ and CGI-I. Id. On December 15, 2020, Anavex announced that the U.S.-Based Phase\n\n2 trial met the primary and secondary endpoints. Id. Approximately six months later, Anavex\n\nannounced further results from the same trial; specifically, that predictive biomarker data\n\ncorrelated with the improvements seen in the two primary clinical efficacy endpoints of RSBQ\n\nand CGI-I. Ex. 3 (June 21, 2021 press release) at 3.\n\n B. The Avatar Study (ANAVEX\u00ae2-73-RS-002)\n\n While the U.S.-Based Phase 2 study was underway, Anavex commenced the Avatar study.\n\nCompl. \u00b6 20. Information about the study was posted on ClinicalTrials.gov, including identified\n\nendpoints. Compl. \u00b6\u00b6 20-21.\n\n When Anavex announced results of the Avatar study on February 1, 2022, it reported the\n\nresults using an endpoint method referred to as RSBQ AUC. Compl. \u00b6 43. In describing it,\n\nDr. Missling noted known limitations with RSBQ as a stand-alone endpoint based on its propensity\n\nfor error as a caregiver-measured score, and explained:\n\n The FDA hence recommended, and it\u2019s also provided in the guidelines from the\n FDA, and recommended specifically in these cases, because you don\u2019t have many\n choices of endpoints to pick from which have been validated for rare diseases like\n Rett Syndrome, to use instead the RSBQ with an anchor. That\u2019s called anchor-based\n responder method, which links the score from one clinical outcome assessment, the\n RSBQ in this case, with scores from a simple reference anchor, which is the outcome\n assessment with a clinically meaningful threshold, which is the CGI-I, and that\n facilitates the interpretation of what constitutes a meaningful within and between\n patient change in clinical outcome assessment. And so this RSBQ AUC was born.\n\nEx. 4 (Feb. 1, 2022 transcript) at 4. In explaining the choice of endpoint, the presentation slides\n\nreiterated that the FDA recommended an \u201canchor-based responder method,\u201d citing a guidance\n\ndocument issued by the agency. See Ex. 5 (presentation) at 4; Ex. 6 (FDA Guidance) at 29.3 The\n\nslide identified RSBQ AUC as an example of such method.\n\n\n3\n The slide presentation is referenced in the transcript and attached to a Form 8-K the Company\nfiled with the SEC. When \u201cthe Complaint quotes and relies upon statements made in press releases\n\n\n 3\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 9 of 23\n\n\n\n\n After releasing the Avatar results, Anavex issued a press release providing additional\n\ninformation regarding the change in endpoints. Compl. \u00b6 56. A few days later, during an analyst\n\ncall, Dr. Missling made clear that ClinicalTrials.gov should not be relied upon as the most updated\n\nsource of information:\n\n And in regards to ClinicalTrials.gov, I would like to make, again, a statement here\n that the ClinicalTrials.gov is not what we refer to as company communication. It\n will be updated eventually. So I\u2019d like you to \u2013 you to be aware of that. So the\n company communication is \u2013 has priority over ClinicalTrials.gov, but it will be\n updated when we have finalized the study outcome. And then we will also update\n the ClinicalTrials.gov. Right now, it might not be completely up to date. So I want\n to make sure people understand that.\n\nCompl. \u00b6 58; Ex. 7 (Feb. 9, 2022 transcript) at 8.\n\n C. The Excellence Study (ANAVEX\u00ae2-73-RS-003)\n\n The Excellence study commenced in late 2019 and was underway when the Avatar results\n\nwere released. Compl. \u00b6 24. The Company initially disclosed its intention to also use RSBQ AUC\n\nas an endpoint in Excellence. Compl. \u00b6 53. This first occurred during the same February 1, 2022,\n\nconference call that revealed the Avatar results and the use of RSBQ AUC for that study. In\n\nresponse to a question regarding whether Excellence will also use RSBQ AUC, Dr. Missling\n\nresponded by referring back to his earlier discussion about the FDA guidance to use an anchor-\n\nbased methodology: \u201cSo that\u2019s right, the Excellence study will use the same endpoint because as\n\njust described, it is just the preference of the FDA.\u201d Ex. 4 (Feb. 1, 2022 transcript) at 13.\n\n Partway through the Class Period, however, the Company announced that, after further\n\nconsultation with the FDA, it would (unlike Avatar) not use RSBQ AUC. On February 7, 2023,\n\nduring an earnings call, Dr. Missling had an exchange with an analyst in which he explicitly said\n\n\n\nand investor calls, the Court may properly consider the complete referenced press releases, the full\ntranscripts of those calls, and any the SEC filings referenced and incorporated therein\u2026.\u201d Koplyay\nv. Cirrus Logic, Inc., No. 13-cv-790 (CM), 2013 WL 6233908, *4 (S.D.N.Y. Dec. 2, 2013).\n\n\n\n 4\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 10 of 23\n\n\n\n\nthat the endpoint would not be RSBQ AUC, would thus differ from Avatar, and that instead the\n\nplan for the primary endpoint was RSBQ with CGI-I as key secondary endpoint:\n\n Yun Zhong\n Okay. And then switching to the Rett syndrome study, I believe the press release\n announcing over enrollment had the language that was the FDA\u2019s input. You are\n using the primary endpoint. So I wanted to confirm that the primary endpoint is\n RSBQ AUC, similar to or the same to the one used in the AVATAR study. And\n so has the FDA agreed that the AUC, the modified RSBQ scale can be an\n appropriate endpoint for Rett syndrome study?\n\n Christopher U. Missling\n We have it described in clinicaltrials.gov, and it was also never changed in\n clinicaltrials.gov for the EXCELLENCE study. It is - the RSBQ is primary\n endpoint and the CGI-I is key secondary endpoint. This is over the course of the\n trial.\n\n Yun Zhong\n Is that the same endpoint that was used in the AVATAR study?\n\n Christopher U. Missling\n It\u2019s slightly different. So it\u2019s actually the measurement over time from beginning\n to end of trial.\n\n Yun Zhong\n Not AUC?\n\n Christopher U. Missling\n Not AUC.\n\n Yun Zhong\n Not AUC.\n\n Christopher U. Missling\n Exactly, yes. Because the study is large enough that it can carry the signal by\n itself without AUC.\n\n Yun Zhong\n Okay, great.\n\nEx. 8 (Feb. 7, 2023 transcript) at 5-6.4 Then, on June 6, 2023, the Company issued a press release\n\nthat said:\n\n\n4\n The Court can properly consider documents for the fact that information was publicly available\nand previously disclosed. See Staehr v. Hartford Fin. Servs. Grp., Inc., 547 F.3d 406, 425 (2d Cir.\n\n\n 5\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 11 of 23\n\n\n\n\n In communication with the FDA, the Company received the Agency\u2019s input on the\n study endpoints, which were utilized in this clinical study. The [RSBQ] total score\n and [CGI-I] score are co-primary endpoints in the statistical analysis plan with\n specified linear mixed-effects models for repeated measures (MMRM) as the\n primary analysis methods.\n\nEx. 9 (June 6, 2023 press release) at 2. Later press releases further confirmed these endpoints.\n\nExs. 10 (June 12, 2023 press release) at 2; Ex. 11 (Aug. 8, 2023 press release) at 3.\n\nII. Plaintiff\u2019s Alleged False Statements and Alleged \u201cCorrective Disclosures\u201d\n\n The Complaint does not clearly set out what statements it alleges are false or misleading.\n\nIn a section titled \u201cDefendants\u2019 False and/or Misleading Statements and Omissions During the\n\nClass Period,\u201d Plaintiff cites the following:\n\n \u2022 A June 21, 2021, press release that (Plaintiff alleges) announced data for the Avatar\n\n study and identified endpoints different than what was shown on ClinicalTrials.gov.\n\n Compl. \u00b6\u00b6 28-29. However, as explained further below and as the document itself\n\n makes clear, this press release related to the U.S.-Based Phase 2 study, not Avatar.\n\n \u2022 A handful of disclosures, including a Form 8-K, prospectus supplement, Form 10-Q,\n\n Form S-3, prospectus, and earnings call statement. Compl. \u00b6\u00b6 30, 33, 35. Plaintiff does\n\n not identify anything in these statements that were false or materially misleading but\n\n alleges that none of them referenced any changes to the primary or secondary outcome\n\n measures for Avatar or Excellence. Compl. \u00b6\u00b6 31-33, 36.\n\n \u2022 Two answers to analyst questions, Compl. \u00b6\u00b6 37-38, and two updates to\n\n ClinicalTrials.gov, Compl. \u00b6\u00b6 34, 40, though the Complaint does not identify if or how\n\n these were allegedly false or misleading.\n\n\n\n\n2008); In re Sanofi Sec. Litig., 87 F. Supp. 3d 510, 539 n.13 (S.D.N.Y. 2015), aff\u2019d sub nom.\nTongue v. Sanofi, 816 F.3d 199 (2d Cir. 2016).\n\n\n\n 6\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 12 of 23\n\n\n\n\n The Complaint also includes a section titled \u201cInvestors First Learn the Truth,\u201d in which\n\nPlaintiff recites various other statements by the Company or third parties from February 1, 2022,\n\nthrough January 2, 2024. Compl. \u00b6\u00b6 42-61.5 He does not identify whether or how any of these\n\nstatements is misleading. The closest he comes is to assert that a presentation filed on February 1,\n\n2022, did not repeat a prior disclosure (Compl. \u00b6 47) or explain why the Avatar endpoints were\n\nchosen (Compl. \u00b6 49).\n\n The Complaint also alleges broadly that Defendants\u2019 misled investors by \u201csuggest[ing]\u201d\n\nand/or \u201cpromis[ing]\u201d that it would use particular endpoints, Compl. \u00b6 61, and that in fact different\n\nendpoints were used in the Avatar and Excellence studies, as follows:\n\n \u2022 As to the Avatar study, Plaintiff alleges that the true endpoint (RSBQ AUC) was\n\n revealed for the first time on February 1, 2022. Compl. \u00b6\u00b6 42-43.\n\n \u2022 As to Excellence, he alleges that the incorrect endpoint (RSBQ AUC) was first\n\n communicated on February 1, 2022, and that the correct endpoints (RSBQ and CGI-I\n\n as co-primary endpoints) and measurement method (MMRM) were revealed on\n\n January 2, 2024, the day after the Class Period ended. Compl. \u00b6\u00b6 62-67.\n\n On January 2, 2024, Anavex announced the results of the Excellence study. Compl. \u00b6 62.\n\nThe results were disappointing in that the study met one of the co-primary endpoints (RSBQ) but\n\nnot the other (CGI-I). Compl. \u00b6 63. Plaintiff alleges that analysts responded negatively to the\n\nannouncement of the results and the Company\u2019s explanation of potential causes for those results\n\n\n5\n The statements in this time period were all made within the class period for the action captioned\nHuey v. Anavex Life Sciences Corporation, No. 24-cv-1910, which Mr. Downing moved\n(unsuccessfully) to have consolidated with this action and moved (unsuccessfully) to be appointed\nlead plaintiff. In denying those motions, the Court made clear that if Mr. Downing continued with\nthe present case, he could not represent a class of persons who are also members of the class in\nHuey. It is therefore unclear to what extent (if any) Mr. Downing can pursue liability based on\nstatements made after February 1, 2022.\n\n\n\n 7\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 13 of 23\n\n\n\n\n(Compl. \u00b6 70), but Plaintiff does not allege that any analyst commented or reacted in any way with\n\nrespect to the choice of endpoints.6 Plaintiff alleges that shares of Anavex stock tumbled after the\n\nCompany released the Excellence results. Compl. \u00b6 71.\n\nIII. Procedural History\n\n Prior to this lawsuit being filed, another Anavex investor, Jonathan Blum, filed a lawsuit\n\n(No. 1:24-cv-1910-CM) with similar allegations covering a shorter class period: February 1, 2022,\n\nthrough January 2, 2024 (i.e., the period from the release of the Avatar results until the release of\n\nthe Excellence results). Counsel for the plaintiff in that case issued the required PSLRA notice,\n\nbeginning the 60-day period for class members to seek to be named lead plaintiff. On May 8,\n\n2024, five days before that PSLRA notice period expired, the Plaintiff filed this lawsuit. On May\n\n13, 2024, Mr. Downing filed a motion for consolidation with the Blum case and also sought to be\n\nappointed lead plaintiff.\n\n The Court held a hearing on June 13, 2024, in which it denied the motion to consolidate,\n\ndenied Mr. Downing\u2019s motion to be appointed lead plaintiff in the previously-named Blum action,\n\nand appointed Quintessa Huey as the lead plaintiff in that case (now captioned Huey v. Anavex\n\nLife Sciences Corp., No. 1:24-cv-1910-CM). In its ruling, the Court explained that Mr. Downing\n\ncould proceed with his separate case, but that any class he represents could not include members\n\nof the class in the Huey case. No. 24-cv-1910, ECF No. 32 at 6:6-8.\n\n Mr. Downing elected not to amend the Complaint. No motion for lead plaintiff has been\n\nfiled in the present action and no lead plaintiff has been appointed.\n\n\n\n\n6\n Plaintiff also makes passing criticisms of the way in which Excellence data was presented on\nJanuary 2, 2024, but none of these statements is alleged to be misleading \u2013 this is the alleged\ncorrective disclosure.\n\n\n\n 8\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 14 of 23\n\n\n\n\n STANDARD OF REVIEW\n\n \u201cTo survive dismissal, the plaintiff must provide the grounds upon which his claim rests\n\nthrough factual allegations sufficient \u2018to raise a right to relief above the speculative level.\u2019\u201d ATSI,\n\n493 F.3d at 98 (citation omitted). \u201cAllegations that are conclusory or unsupported by factual\n\nassertions are insufficient.\u201d Id. at 99. \u201cA securities fraud complaint must also meet the heightened\n\npleading standards of [Rule] 9(b) and the [PSLRA].\u201d Kleinman v. Elan Corp., plc, 706 F.3d 145,\n\n152 (2d Cir. 2013). The \u201ccircumstances constituting fraud\u201d must be \u201cstate[d] with particularity,\u201d\n\nincluding the reasons why a statement is misleading. Id.\n\n ARGUMENT\n\n As shown below, the Complaint fails to establish nearly all of the required elements of a\n\nSection 10(b) and Rule 10b-5 claim, i.e., misstatements or omissions of material fact, made with\n\nscienter, in connection with the purchase or sale of securities, upon which the plaintiff relied, and\n\nproximate causation of injury. Koplyay, 2013 WL 6233908, at *4 (citing Lentell v. Merrill Lynch\n\n& Co., Inc., 396 F.3d 161, 172 (2d Cir. 2005)). Much of the claim is also time-barred. As such,\n\nboth Count I and Count II (which is derivative of Count I) should be dismissed.\n\nI. Plaintiff Utterly Fails to Meet the High Burden Established to Plead Scienter in\n Securities Fraud Cases.\n\n The Complaint is striking for the almost non-existent effort undertaken to plead scienter.\n\nA plaintiff must \u201cstate with particularity facts giving rise to a strong inference that the defendant\n\nacted with the required state of mind,\u201d i.e., an \u201cintention \u2018to deceive, manipulate, or defraud.\u2019\u201d\n\nTellabs, Inc. v. Makor Issues & Rts., Ltd., 551 U.S. 308, 313-14 (2007) (citations omitted); see\n\nalso ECA & Local 134 IBEW Joint Pension Tr. of Chicago v. JP Morgan Chase Co., 553 F.3d\n\n187, 198 (2d Cir. 2009). It amounts to deliberate, illegal behavior or conduct constituting \u201can\n\nextreme departure from the standards of ordinary care to the extent that the danger was either\n\n\n\n 9\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 15 of 23\n\n\n\n\nknown to the defendant or so obvious that the defendant must have been aware of it.\u201d In re\n\nLululemon Sec. Litig., 14 F. Supp. 3d 553, 573 (S.D.N.Y. 2014), aff\u2019d, 604 F. App\u2019x 62 (2d Cir.\n\n2015) (citation omitted). In assessing whether a plaintiff has adequately pled scienter, the \u201ccourt\n\nmust consider plausible, nonculpable explanations for the defendant\u2019s conduct.\u201d Tellabs, 551 U.S.\n\nat 324. For an inference of scienter to be strong, \u201ca reasonable person [must] deem [it] cogent and\n\nat least as compelling as any opposing inference one could draw from the facts alleged.\u201d Id.\n\n(emphasis added).\n\n The Complaint contains a single paragraph regarding scienter, and it consists entirely of\n\nconclusory statements that merely parrot the two avenues for pleading scienter in the Second\n\nCircuit. Compl. \u00b6 72. See ATSI, 493 F.3d at 99 (describing motive and opportunity or strong\n\ncircumstantial evidence of conscious misbehavior or recklessness). This is clearly insufficient to\n\nestablish scienter in a securities fraud case.\n\n First, Plaintiff does not allege any particular motive, i.e., no allegation that Defendants\n\n\u201cbenefitted in some concrete and personal way from the purported fraud.\u201d Novak v. Kasaks, 216\n\nF.3d 300, 307-08 (2d Cir. 2000). A simple recitation that there was \u201cmotive and opportunity\u201d does\n\nnot satisfy the pleading burden.\n\n Next, Plaintiff similarly does not allege anything to support his conclusory allegation that\n\nDefendants \u201chad actual knowledge of the misleading nature of the statements they made or acted\n\nin reckless disregard of the true information known to them at the time.\u201d Compl. \u00b6 72; see also\n\nCompl. \u00b6\u00b6 81, 89. The standard to plead conscious misbehavior or recklessness is high (and even\n\ngreater absent allegations of motive). Kalnit v. Eichler, 264 F.3d 131, 143 (2d Cir. 2001). A\n\nplaintiff \u201cmust specifically identify the reports or statements\u201d from which defendants learned facts\n\ncontrary to the public representations. Novak, 216 F.3d at 309. A plaintiff\u2019s \u201cfailure to do so is\n\n\n\n\n 10\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 16 of 23\n\n\n\n\nsufficient to end the inquiry.\u201d Shetty v. Trivago N.V., 796 F. App\u2019x 31, 35 (2d Cir. 2019)\n\n(summary order); see also Koplyay, 2013 WL 6233908, at *7 (dismissing complaint that \u201cnever\n\nmakes reference to any internal reports, statements by confidential witnesses, or other specific\n\nfacts showing that Defendants had access to\u201d the allegedly undisclosed contrary data).\n\n Plaintiff does not cite any internal document, describe any internal meeting, or quote a\n\nsingle witness (let alone a credible one). Instead, he relies only on his own conclusory statements\n\nand naked inference that Dr. Missling must have known certain asserted facts due to his corporate\n\nposition, an allegation routinely dismissed as insufficient. Compl. \u00b6\u00b6 18, 72, 81, 89. See City of\n\nBrockton Ret. Sys. v. Shaw Grp. Inc., 540 F. Supp. 2d 464, 473 (S.D.N.Y. 2008) (McMahon, J.)\n\n(rejecting general allegation that defendants must have known accounting improprieties due to\n\ninvolvement in daily operations, absent factual allegations supporting inference of knowledge such\n\nas \u201caccess to particular, identified internal reports that would have alerted them\u201d); Okla.\n\nFirefighters Pension & Ret. Sys. v. Student Loan Corp., 951 F. Supp. 2d 479, 497-98 (S.D.N.Y.\n\n2013).\n\n In fact, the Complaint does not even allege that, at the time any statement about endpoints\n\nwas made, Defendants knew that the endpoints would be different than what was disclosed.\n\nInstead, Plaintiff alleges merely that the endpoints changed after the Company \u201csuggested\u201d or\n\n\u201cpromised\u201d that they would not. Compl. \u00b6 61; see also Compl. \u00b6 7 (\u201cAnavex used different\n\noutcomes\u201d). But a breach of promise does not amount to a securities fraud claim. Mills v. Polar\n\nMolecular Corp., 12 F.3d 1170, 1176 (2d Cir. 1993).\n\n In contrast to Plaintiff\u2019s rote recitation of the scienter standards and conclusory assertions,\n\nthe alleged facts instead present a more compelling and supported non-fraudulent alternative: that\n\nAnavex, based on FDA guidance, decided to anchor CGI-I to RSBQ, and did so using the RSBQ\n\n\n\n\n 11\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 17 of 23\n\n\n\n\nAUC measure. Anavex also intended to use that endpoint for Excellence as it communicated\n\npublicly, but partway through the Class Period Anavex met further with the FDA and, based in\n\npart on those discussions, decided to instead use RSBQ and CGI-I as co-primary endpoints.\n\nAnavex disclosed this after the change was decided, on multiple occasions during the Class Period.\n\nWhen Anavex announced somewhat disappointing Excellence results in January 2024, the\n\nnegative market reaction was due to that, not the (already disclosed) endpoints. This is all\n\nconsistent with the Company\u2019s disclosures.\n\nII. The Intra-Class Period Disclosure of the Excellence Endpoints Negates Plaintiff\u2019s\n Claims of False or Misleading Statements\n\n The several, clear intra-Class Period disclosures about the actual Excellence endpoints\n\nentirely undercut Plaintiff\u2019s case. His theory is that Defendants knowingly did not reveal the\n\nExcellence endpoints until the end of the Class Period. Compl. \u00b6 9. That is demonstrably false.\n\nOn February 7, 2023, Defendants explicitly disclosed that (unlike Avatar) the Excellence endpoint\n\nwould not involve RSBQ AUC. Ex. 8 at 5-6. On June 6, 2023, the Company further disclosed\n\nthat the Excellence study would have co-primary endpoints of RSBQ and CGI-I, and would use\n\nthe MMRM method to analyze results. Ex. 9 at 2. This was repeated on June 12, 2023, and August\n\n8, 2023. Exs. 10 at 2; Ex. 11 at 3.\n\n Nothing regarding a change of endpoints was disclosed on January 2, 2024. The only new\n\ninformation released that day was the Excellence study results. Thus, there can be no liability, as\n\nthe Complaint fails to allege omission of material fact that was not disclosed until after the Class\n\nPeriod. See In re Progress Energy, Inc., 371 F. Supp. 2d 548, 552 (S.D.N.Y. 2005) (\u201c[I]t is\n\nindisputable that there can be no omission where the allegedly omitted facts are disclosed.\u201d); Okla.\n\nFirefighters, 951 F. Supp. 2d at 500 (\u201c[D]efendants disclosed precisely the type of information\n\nplaintiffs claim was withheld.\u201d); Bettis v. Aixtron SE, No. 16 CIV. 00025 (CM), 2016 WL\n\n\n\n 12\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 18 of 23\n\n\n\n\n7468194, at *11 (S.D.N.Y. Dec. 20, 2016) (\u201c[O]n several occasions, [the company] made exactly\n\nthe disclosures that Plaintiff claims were withheld from investors.\u201d); Ganino v. Citizens Utils. Co.,\n\n228 F.3d 154, 167 (2d Cir. 2000) (\u201c[A] misrepresentation is immaterial if the information is already\n\nknown to the market because the misrepresentation cannot then defraud the market.\u201d).\n\nIII. Loss Causation Is Negated by the Intra-Class Period Disclosures of Endpoints\n\n The prior disclosures of the actual study endpoints also negate loss causation.\n\n First, as to Avatar, Plaintiff admits that the actual endpoint of RSBQ AUC was disclosed\n\non February 1, 2022. Compl. \u00b6\u00b6 42-43. None of the market movement on January 2, 2024, could\n\nproperly be ascribed to the disclosure of the Avatar endpoint. In re New Energy Sys. Sec. Litig.,\n\n66 F. Supp. 3d 401, 405 (S.D.N.Y. 2014) (\u201c[T]o establish loss causation, \u2018a plaintiff must allege\n\n... that the subject of the fraudulent statement or omission was the cause of the actual loss\n\nsuffered.\u2019\u201d (citation omitted)). Although Plaintiff alleges the market declined on the day the\n\nAvatar results were released, Compl. \u00b6 54, his loss causation allegations exclusively relate to\n\nJanuary 2, 2024. Compl. \u00b6\u00b6 73-76.\n\n Second, as to Excellence, any decline in stock price on January 2, 2024, cannot plausibly\n\nbe understood as attributable to disclosure of anything with respect to endpoints. As explained in\n\nthe prior section, the endpoints were previously disclosed and the announcement on January 2,\n\n2024, did not reveal anything about endpoints that was unknown up to that point. See Okla.\n\nFirefighters, 951 F. Supp. 2d at 503 (citing Lentell, 396 F.3d at 173); Fort Worth Emps. Ret. Fund\n\nv. Biovail Corp., 615 F. Supp. 2d 218, 229 (S.D.N.Y. 2009) (\u201cThe all-but-inevitable decline in the\n\nprice of Biovail\u2019s stock price following the company\u2019s announcement that the FDA had not\n\napproved the [drug application] was caused by the agency\u2019s failure to approve the drug\u2014not by\n\nany \u2018corrective\u2019 disclosure of some prior untruth.\u201d); see also In re Signet Jewelers Ltd. Sec. Litig.,\n\n\n\n\n 13\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 19 of 23\n\n\n\n\nNo. 16-cv-6728 (CM), 2019 WL 3001084, at *19 (S.D.N.Y. July 10, 2019) (\u201c[C]ourts are required\n\nto cut off the class period on the date of a statement or event that cures the market.\u201d).\n\nIV. The Complaint Does Not Allege Any False or Misleading Statement or Omission of\n Material Fact with the Required Particularity\n\n Plaintiff\u2019s haphazard recitation of various statements made by Defendants during the Class\n\nPeriod does not satisfy the heightened pleading standards that apply to securities fraud cases.\n\n\u201cUntrue statements must be identified and, if applicable, so must the omitted facts that are\n\n\u2018necessary in order to make the statements made, in the light of the circumstances in which they\n\nwere made, not misleading.\u2019\u201d Kleinman, 706 F.3d at 152 (quoting 15 U.S.C. \u00a7 78u-4). \u201cThe\n\nSecond Circuit has repeatedly stated that plaintiffs must do more than simply assert that a statement\n\nis false\u2014\u2019they must demonstrate with specificity why that is so.\u2019\u201d In re Lululemon, 14 F. Supp.\n\n3d at 571 (quoting Rombach v. Chang, 355 F.3d 164, 174 (2d Cir. 2004)); see also In re\n\nAstraZeneca plc Sec. Litig., No. 21-cv-722, 2022 WL 4133258 (S.D.N.Y. Sept. 12, 2022) (\u201c[T]he\n\nPSLRA obligates the plaintiff to \u2018demonstrate with specificity why and how\u2019 each statement is\n\nmaterially false or misleading.\u201d (citation omitted)), aff\u2019d sub nom. Nandkumar v. AstraZeneca\n\nPLC, No. 22-2704-CV, 2023 WL 3477164 (2d Cir. May 16, 2023).\n\n A. The Complaint Fails to Adequately Identify and Explain the Allegedly False\n or Misleading Statements\n\n It is unclear from the Complaint what statements (or parts thereof) are even alleged to be\n\nmisleading. As noted above, Plaintiff recites a series of statements without explaining why they\n\nare misleading. Plaintiff merely says that the statements did not specifically disclose changes to\n\nendpoints. \u201cSuch allegations do not specify why and how each statement is misleading because\n\nthey do not specify what understanding each statement left investors, and how that understanding\n\nwas inconsistent with alleged omissions.\u201d In re AstraZeneca, 2022 WL 4133258, at *6. To plead\n\nan actionable omission, a plaintiff must describe with particularity what statement was made\n\n\n 14\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 20 of 23\n\n\n\n\nmaterially misleading due to the omitted fact, including why it was misleading. See Polar Int\u2019l\n\nBrokerage Corp. v. Reeve, 108 F. Supp. 2d 225, 241 (S.D.N.Y. 2000); Lululemon, 14 F. Supp. 3d\n\nat 571; see also Gamm v. Sanderson Farms, Inc., 944 F.3d 455, 463 (2d Cir. 2019) (\u201cUnder Rule\n\n9(b) and the PSLRA, the circumstances of a fraud include \u2018the basis\u2019 for that contention.\u201d).\n\nPlaintiff has not done that here. Even more crucially, Plaintiff has not alleged any facts to support\n\nthat, at the time the statement was made, the endpoints had in fact changed. A statement of future\n\nintent is not false unless the speaker did not honestly believe it at the time. See In re Lululemon,\n\n14 F. Supp. 3d at 571.\n\n B. Several of the Statements At Issue Do Not Involve Any Cognizable Fraud\n\n Plaintiff measures the start of his Class Period based on a June 21, 2021, press release that\n\nhe describes as where \u201cAnavex announced \u2018convincing biomarker correlating efficacy data\u2019 for\n\nthe AVATAR study.\u201d Compl. \u00b6 28. In addition to not adequately alleging what about this was\n\nfalse or misleading, this allegation suffers from an even more fundamental flaw: this press release\n\nhas nothing to do with Avatar, and instead relates to an entirely different study. Even a cursory\n\nreview of the press release makes clear that it relates to the U.S.-Based Phase 2 study. Ex. 3 (June\n\n21, 2021 press release). Indeed, it says it in the first paragraph. The press release also explicitly\n\ndistinguishes Avatar and Excellence as \u201ctwo other ongoing late-stage placebo-controlled clinical\n\nstudies.\u201d Id. (emphasis added). Accordingly, even had Plaintiff alleged something misleading\n\nabout this press release, it would not present a plausible claim.\n\n The Complaint also faults the February 1, 2022, disclosure for two things: it \u201cfailed to\n\nnote\u201d other information the Company previously disclosed (Compl. \u00b6 47) and it failed to explain\n\nwhy the Company decided to use CGI-I as an anchor despite previously saying it \u201c[did]n\u2019t want\n\nto overemphasize\u201d that score (Compl. \u00b6 49). Neither criticism supports a claim for securities fraud.\n\nThe first criticism attacks Defendants for not repeating again a disclosure the Company had already\n\n\n 15\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 21 of 23\n\n\n\n\nmade. Plaintiff therefore admits the information was already disclosed. In re Progress Energy,\n\nInc., 371 F. Supp. 2d 548, 552 (S.D.N.Y. 2005) (\u201c[I]t is indisputable that there can be no omission\n\nwhere the allegedly omitted facts are disclosed.\u201d). As to the second item, Plaintiff fails to allege\n\nwhy it was misleading for the Company not to address Plaintiff\u2019s own subjective criticism of the\n\ndata presentation. It also ignores the lengthy passages in the analyst call transcript where the\n\nCompany explained why it was using the RSBQ AUC metric anchored to CGI-I. See Ex. 4 (Feb.\n\n1 2022 transcript) at 4.\n\n C. Any Remaining Criticisms of the Choice of Endpoints Do Not State a Claim\n\n To the extent the Complaint can otherwise be read as making general criticisms of\n\nAnavex\u2019s choice of endpoints or design of the clinical trial, such quibbles do not state a securities\n\nfraud claim. Numerous cases reject claims against biopharmaceutical companies that second-\n\nguess how data is presented. See, e.g., Kleinman, 706 F.3d at 154\u201355 (dismissing a complaint that\n\nargued that the company\u2019s changing of measures to present data in a different format must have\n\nbeen misleading, explaining defendants had no obligation to present results in any particular\n\nformat); In re Sanofi-Aventis Sec. Litig., 774 F. Supp. 2d 549, 567 (S.D.N.Y.2011) (\u201cPlaintiffs\n\ncannot premise a fraud claim upon a mere disagreement with how Sanofi chose to interpret the\n\nresults.\u201d); Abely v. Aeterna Zentaris Inc., No. 12 CIV. 4711, 2013 WL 2399869, at *2-3, 6-9\n\n(S.D.N.Y. May 29, 2013) (\u201cThe Second Circuit and other tribunals have concluded that the\n\nsecurities laws do not recognize a fraud claim premised on criticisms of a drug trial\u2019s methodology,\n\nso long as the methodology was not misleadingly described to investors.\u201d).\n\nV. Claims as to Avatar Are Time-Barred and Divorced from the Corrective Disclosure\n\n All of Plaintiff\u2019s claims fail for the reasons explained above, i.e., the utter absence of\n\nscienter allegations, earlier intra-Class Period disclosure, and failure to plead with particularity.\n\nPlaintiff\u2019s allegations as to the Avatar study fail for the additional reason that they are time-barred.\n\n\n 16\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 22 of 23\n\n\n\n\n A claim under Section 10(b) and Rule 10b-5 must be filed within two years after discovery\n\nof the facts constituting the violation. 28 U.S.C. \u00a7 1658(b). The limitations period \u201cbegins to run\n\nonce the plaintiff actually discovered or a reasonably diligent plaintiff would have \u2018discover[ed]\n\nthe facts constituting the violation\u2019\u2014whichever comes first.\u201d Merck & Co. v. Reynolds, 559 U.S.\n\n633 (2010) (quoting 28 U.S.C \u00a7 1658(b)(1)). The same limitations period applies to Count II under\n\nSection 20(a), which is derivative of Count I. In re MBIA Inc., No. 05-cv-3514, 2007 WL 473708,\n\nat *9 (S.D.N.Y. Feb. 14, 2007).\n\n As the Complaint makes clear, the final Avatar endpoints were publicly disclosed on\n\nFebruary 1, 2022. Compl. \u00b6\u00b6 6, 42-46. At that time, analysts \u201ccritiqued\u201d and \u201cchided\u201d the\n\nCompany for the changes and lowered the target on Anavex shares. Compl. \u00b6\u00b6 6, 50-52. The\n\nannouncement of the endpoint change was accompanied by negative market reaction. Compl.\n\n\u00b6 54. In other words, all of the allegedly concealed information was fully disclosed as of February\n\n1, 2022, and that is when Plaintiff allegedly experienced a loss associated with the Avatar-related\n\ndisclosure. Any claim would have fully accrued at that point. Plaintiff filed the Complaint on\n\nMay 8, 2024\u2014two years, three months, and one week later. Accordingly, claims regarding the\n\nalleged failure to disclose the change of endpoints as to the Avatar study are time-barred.7\n\n\n\n\n7\n Indeed, Plaintiff\u2019s decision to start his Class Period in June 2021 appears derived entirely from a\ndesire to show the largest market loss so as to be appointed lead plaintiff in the Huey matter.\nLooking only within the statute of limitations period, Mr. Downing has no losses using a last-in-\nfirst-out analysis. He purchased and sold 1,000 shares at a realized gain and then\u2014less than six\nweeks before the end of the Class Period and well after disclosure of the Excellence endpoints\u2014\nhe purchased another 1,000 shares. See ECF No. 15-2. Per Plaintiff\u2019s own calculations, this results\nin a net gain (inclusive of the recognized value for his retained shares) of $2,355.99. Id.\n\n\n\n 17\n\f Case 1:24-cv-03529-CM Document 24 Filed 08/23/24 Page 23 of 23\n\n\n\n\n CONCLUSION\n\n For all of the reasons outlined above, the Court should dismiss the Complaint.\n\nDate: August 23, 2024 Respectfully submitted,\n\n /s/ Theodore L. Kornobis\n Stephen G. Topetzes (pro hac vice pending)\n Theodore L. Kornobis\n K&L GATES LLP\n 1601 K Street, NW\n Washington, DC 20006\n Phone: (202) 778-9000\n Fax: (202) 778-9100\n stephen.topetzes@klgates.com\n ted.kornobis@klgates.com\n\n Attorneys for Defendants Anavex Life Sciences\n Corporation and Christopher U. Missling\n\n\n\n\n 18\n\f","ocr_status":2,"date_upload":"2024-08-26T06:04:36.657459-07:00","document_number":"24","attachment_number":null,"pacer_doc_id":"127036039537","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Memorandum of Law in Support of Motion","acms_document_guid":""}],"date_created":"2024-08-23T20:48:28.114949-07:00","date_modified":"2025-12-22T08:34:03.509851-08:00","date_filed":"2024-08-23","time_filed":"23:43:46","entry_number":24,"recap_sequence_number":"2024-08-23.004","pacer_sequence_number":107,"description":"MEMORANDUM OF LAW in Support re: 22 MOTION to Dismiss . . Document filed by Anavex Life Sciences Corporation, Christopher U. Missling..(Kornobis, Theodore) (Entered: 08/23/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/400348516/","id":400348516,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579210/","id":409579210,"tags":[],"absolute_url":"/docket/68511120/23/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:48:28.095126-07:00","date_modified":"2025-12-22T08:34:03.488306-08:00","sha1":"12362abf0deb9db9f087ccbca2540ccaff555840","page_count":3,"file_size":119793,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.0.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.0.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":" Case 1:24-cv-03529-CM Document 23 Filed 08/23/24 Page 1 of 3\n\n\n\n\nUNITED STATES DISTRICT COURT\nSOUTHERN DISTRICT OF NEW YORK\n\n\nKENNETH DOWNING, individually and on\n Case No. 1:24-cv-03529-CM\nbehalf of all others similarly situated,\n\n Plaintiff,\n\n v.\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n\n\n\n DECLARATION OF THEODORE L. KORNOBIS IN SUPPORT OF\n DEFENDANTS\u2019 MOTION TO DISMISS\n\n I, Theodore L. Kornobis, hereby declare pursuant to 28 U.S.C. \u00a7 1746, that the following\n\nis true and correct.\n\n 1. I am admitted to the Bars of the State of New York and the District of Columbia,\n\nand I am admitted to this Court.\n\n 2. I am a partner with the law firm of K&L GATES LLP, attorneys for Defendants\n\nAnavex Life Sciences Corporation (\u201cAnavex\u201d) and Christopher Missling (\u201cMr. Missling\u201d)\n\n(collectively, \u201cDefendants\u201d) in the above-captioned action.\n\n 3. I submit this Declaration based on my personal knowledge in support of\n\nDefendants\u2019 Motion for Summary Judgment, filed August 23, 2024.\n\n 4. Annexed hereto as Exhibit 1 is a true and correct excerpt of the Form 10-K filed by\n\nAnavex with the Securities and Exchange Commission (\u201cSEC\u201d) for the fiscal year ended\n\nSeptember 30, 2023, a full copy of which is publicly filed and available on the SEC website.\n\n\n\n\n303202452 v1\n\f Case 1:24-cv-03529-CM Document 23 Filed 08/23/24 Page 2 of 3\n\n\n\n\n 5. Annexed hereto as Exhibit 2 is a true and correct excerpt of the Form 10-K filed by\n\nAnavex with the SEC for the fiscal year ended September 30, 2022, a full copy of which is publicly\n\nfiled and available on the SEC website.\n\n 6. Annexed hereto as Exhibit 3 is a true and correct copy of a press release issued by\n\nAnavex on June 21, 2021, titled \u201cAnavex Life Sciences Announces ANAVEX\u00ae2-73Biomarker\n\nCorrelated with Efficacy Endpoint in Trial.\u201d\n\n 7. Annexed hereto as Exhibit 4 is a true and correct copy of a transcript of the Anavex\n\nManagement Discussion held on February 1, 2022, titled \u201cANAVEX 2-73 (Blarcamesine)\n\nAVATAR Phase 3 Trial met Primary and Secondary Endpoints for the Treatment of Adult Patients\n\nwith Rett Syndrome,\u201d as prepared from audio by BIG Language Solutions.\n\n 8. Annexed hereto as Exhibit 5 is a true and correct copy of the presentation slide deck\n\ntitled \u201cAVATAR Phase 3 RS-002 Rett Syndrome Top-Line Clinical Trial Data ANAVEX\u00ae2-73\n\n(blarcamesine),\u201d which is attached to Anavex\u2019s Form 8-K, filed February 2, 2022, a full copy of\n\nwhich is publicly filed and available on the SEC website.\n\n 9. Annexed hereto as Exhibit 6 is a true and correct copy of a document issued by the\n\nU.S. Food and Drug Administration (FDA) titled, \u201cGuidance for Industry Patient-Reported\n\nOutcome Measures: Use in Medical Product Development to Support Labeling Claims,\u201d dated\n\nDecember 2009.\n\n 10. Annexed hereto as Exhibit 7 is a true and correct copy of a transcript of the Anavex\n\nFirst Quarter 2022 Earnings Conference Call, held on February 9, 2022, as provided by S&P\n\nGlobal Market Intelligence.\n\n\n\n\n 2\n\f Case 1:24-cv-03529-CM Document 23 Filed 08/23/24 Page 3 of 3\n\n\n\n\n 11. Annexed hereto as Exhibit 8 is a true and correct copy of a transcript of the Anavex\n\nFirst Quarter 2023 Earnings Conference Call, held on February 7, 2023, as prepared from audio\n\nby BIG Language Solutions.\n\n 12. Annexed hereto as Exhibit 9 is a true and correct copy of a press release issued by\n\nAnavex on June 6, 2023, titled \u201cCompletion of ANAVEX\u00ae2-73 (blarcamesine) EXCELLENCE\n\nPhase 2/3 Rett Syndrome Clinical Trial.\u201d\n\n 13. Annexed hereto as Exhibit 10 is a true and correct copy of a press release issued by\n\nAnavex on June 12, 2023, titled \u201cAnavex Life Sciences Reports Publication in Medical Journal\n\nfor Continued Commitment to Improve RSBQ.\u201d\n\n 14. Annexed hereto as Exhibit 11 is a true and correct copy of a press release issued by\n\nAnavex on August 8, 2023, titled \u201cAnavex Life Sciences Reports Fiscal 2023 Third Quarter\n\nFinancial Results.\u201d\n\n I declare under the penalty of perjury under the laws of the United States that the foregoing\n\nis true and correct.\n\n Executed this 23rd day of August, 2024, at Washington, DC.\n\n\n\n By: /s/ Theodore L. Kornobis s\n Theodore L. Kornobis\n\n K&L GATES LLP\n Theodore L. Kornobis\n 1601 K Street, NW\n Washington, DC 20006\n Tel: (202) 778-9180\n Fax: (202) 778-9100\n ted.kornobis@klgates.com\n\n\n\n\n 3\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:15.350772-07:00","document_number":"23","attachment_number":null,"pacer_doc_id":"127036039500","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Declaration in Support of Motion","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579224/","id":409579224,"tags":[],"absolute_url":"/docket/68511120/23/1/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.473331-07:00","date_modified":"2024-08-27T02:10:46.258497-07:00","sha1":"00bf9f335e342656d6f81371f6cebc2f5c7d492d","page_count":20,"file_size":439869,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.1.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.1.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 1 of 20\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 2 of 20\n\n\n\n\n UNITED STATES\n SECURITIES AND EXCHANGE COMMISSION\n Washington, D.C. 20549\n\n FORM 10-K\n(Mark One)\n\n \u2612 ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\n\n For the fiscal year ended September 30, 2023\n\n\u2610 TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\n\n For the transition period from ______________ to________________\n\n Commission file number: 001-37606\n\n\n ANAVEX LIFE SCIENCES CORP.\n (Exact name of registrant as specified in its charter)\n\n Nevada XX-XXXXXXX\n (State or other jurisdiction of incorporation or organization) (I.R.S. Employer Identification No.)\n\n 630 5th Avenue, 20th Floor, New York, NY USA 10111\n (Address of principal executive offices) (Zip Code)\n\n Registrant\u2019s telephone number, including area code 1-844-689-3939\n\n Securities registered under Section 12(b) of the Act:\n Common Stock, $0.001 par value AVXL NASDAQ Stock Market LLC\n Title of each class Trading Symbol Name of each exchange on which registered\n\n Securities registered pursuant to Section 12(g) of the Act:\n None\n (Title of class)\n\nIndicate by checkmark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.\n Yes \u2612 No \u2610\n\nIndicate by checkmark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act.\n Yes \u2610 No\u2612\n\nIndicate by checkmark whether the registrant has (1) filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of\n1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to\nsuch filing requirements for the past 90 days.\n Yes \u2612 No \u2610\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 3 of 20\n\n\nIndicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405\nof Regulation S-T (\u00a7232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit\nand post such files).\n Yes \u2612No \u2610\n\nIndicate by checkmark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or\nan emerging growth company. See the definitions of \u201clarge accelerated filer,\u201d \u201caccelerated filer\u201d, \u201csmaller reporting company\u201d and \u201cemerging growth\ncompany\u201d in Rule 12b-2 of the Exchange Act.\n\nLarge accelerated filer \u2612 Accelerated filer \u2610\nNon-accelerated filer \u2610 Smaller reporting company \u2610\n Emerging growth company\u2610\n\nIf an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with\nany new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act\n \u2610\nIndicate by check mark whether the registrant has filed a report on and attestation to its management\u2019s assessment of the effectiveness of its\ninternal controls over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting\nfirm that prepared or issued its audit report.\n Yes \u2612No \u2610\nIf securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in\nthe filing reflect the correction of an error to previously issued financial statements\n \u2610\n\nIndicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation\nreceived by any of the registrant\u2019s executive officers during the relevant recovery period pursuant to \u00a7240.10D-1(b).\n \u2610\n\nIndicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act).\n Yes \u2610 No \u2612\n\nState the aggregate market value of the voting and non-voting common equity held by non-affiliates computed by reference to the price at which\nthe common equity was last sold, or the average bid and asked price of such common equity, as of the last business day of the registrant\u2019s most\nrecently completed second fiscal quarter: $667 million based on a price of $8.57 per share, being the closing price of the registrant\u2019s common stock\non March 31, 2023.\n\nIndicate the number of shares outstanding of each of the registrant\u2019s classes of common stock, as of the latest practicable date: 82,086,511 issued\nand outstanding as of November 24, 2023.\n\n DOCUMENTS INCORPORATED BY REFERENCE\n\nNone.\n\n\n i\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 4 of 20\n\n\n TABLE OF CONTENTS\n\nPART I 6\nITEM 1. BUSINESS 6\nITEM 1A. RISK FACTORS 32\nITEM 1B. UNRESOLVED STAFF COMMENTS 60\nITEM 2. PROPERTIES 60\nITEM 3. LEGAL PROCEEDINGS 60\nITEM 4. MINE SAFETY DISCLOSURES 61\nPART II 61\nITEM 5. MARKET FOR REGISTRANT\u2019S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES 61\nOF EQUITY SECURITIES\nITEM 7 MANAGEMENT\u2019S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATION 61\nITEM 7A QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 67\nITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA F-1\nITEM 9. CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL MATTERS 69\nITEM 9A. CONTROLS AND PROCEDURES 69\nITEM 9B OTHER INFORMATION 70\nITEM 9C DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 70\nPART III 70\nITEM 10 DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 70\nITEM 11. EXECUTIVE COMPENSATION 74\nITEM 12. SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER 82\nMATTERS.\nITEM 13. CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS, AND DIRECTOR INDEPENDENCE 86\nITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES 86\nPART IV 88\nITEM 15. EXHIBITS, FINANCIAL STATEMENT SCHEDULES 88\nITEM 16. FORM 10-K SUMMARY 89\n\n\n iii\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 5 of 20\n\n\nForward Looking Statements.\n\nThis Annual Report on Form 10-K includes forward-looking statements. All statements other than statements of historical facts contained in this\nAnnual Report on Form 10-K, including statements regarding our anticipated future clinical and regulatory milestone events, future financial\nposition, business strategy and plans and objectives of management for future operations, are forward-looking statements. The words \u201cbelieve,\u201d\n\u201cmay,\u201d \u201cestimate,\u201d \u201ccontinue,\u201d \u201canticipate,\u201d \u201cintend,\u201d \u201cexpect,\u201d \u201cshould,\u201d \u201cforecast,\u201d \u201cpotential,\u201d \u201cpredict,\u201d \u201ccould,\u201d \u201cwould\u201d, \u201cwill\u201d, \u201csuggest,\u201d\n\u201cplan\u201d and similar expressions, as they relate to us, are intended to identify forward-looking statements. Such forward-looking statements include,\nwithout limitation, statements regarding:\n\n \u25cf volatility in our stock price and in the markets in general\u037e\n\n \u25cf our ability to successfully conduct preclinical studies and clinical trials for our product candidates\u037e\n\n \u25cf our ability to raise additional capital on favorable terms and the impact of such activities on our stockholders and stock price\u037e\n\n \u25cf our ability to generate any revenue or to continue as a going concern\u037e\n\n \u25cf our ability to execute our research and development plan on time and on budget\u037e\n\n \u25cf our product candidates\u2019 ability to demonstrate efficacy or an acceptable safety profile\u037e\n\n \u25cf our ability to obtain the support of qualified scientific collaborators\u037e\n\n \u25cf our ability, whether alone or with commercial partners, to successfully commercialize any of our product candidates that may be approved\n for sale\u037e\n\n \u25cf our ability to identify and obtain additional product candidates\u037e\n\n \u25cf our reliance on third parties in non-clinical studies and clinical trials\u037e\n\n \u25cf our ability to defend against product liability claims\u037e\n\n \u25cf our ability to safeguard against security breaches\u037e\n\n \u25cf our ability to obtain and maintain sufficient intellectual property protection for our product candidates\u037e\n\n \u25cf our ability to comply with our intellectual property licensing agreements\u037e\n\n \u25cf our ability to defend against claims of intellectual property infringement\u037e\n\n \u25cf our ability to comply with the maintenance requirements of the government patent agencies\u037e\n\n \u25cf our ability to protect our intellectual property rights throughout the world\u037e\n\n \u25cf competition\u037e\n\n \u25cf the anticipated start dates, durations and completion dates of our ongoing and future clinical trials\u037e\n\n \u25cf the anticipated designs of our future clinical trials\u037e\n\n \u25cf our ability to attract and retain qualified employees\u037e\n\n \u25cf the impact of Fast Track designation on receipt of actual FDA approval\u037e\n\n \u25cf our anticipated future regulatory submissions and our ability to receive regulatory approvals to develop and market our product\n candidates, including any orphan drug or Fast Track designations\u037e and\n\n \u25cf our anticipated future cash position and ability to obtain funding for our operations.\n\nWe have based these forward-looking statements largely on our current expectations and projections about future events, including the responses\nwe expect from the U.S. Food and Drug Administration, (\u201cFDA\u201d), and other regulatory authorities and financial trends that we believe may affect\nour financial condition, results of operations, business strategy, preclinical studies and clinical trials, and financial needs. These forward-looking\nstatements are subject to a number of risks, uncertainties and assumptions including, without limitation, the risks described in \u201cRisk Factors\u201d in\nPart I, Item 1A of this Annual Report on Form 10-K. These risks are not exhaustive. Other sections of this Annual Report on Form 10-K include\nadditional factors which could adversely impact our business and financial performance. Moreover, we operate in a very competitive and rapidly\nchanging environment. New risk factors emerge from time to time and it is not possible for our management to predict all risk factors, nor can we\nassess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ\nmaterially from those contained in any forward-looking statements. You should not rely upon forward-looking statements as predictions of future\nevents. We cannot assure you that the events and circumstances reflected in the forward-looking statements will be achieved or occur and actual\nresults could differ materially from those projected in the forward-looking statements. Except as required by applicable laws including the securities\nlaws of the United States, we assume no obligation to update or supplement forward-looking statements.\n\nAs used in this Annual Report on Form 10-K, the terms \u201cwe,\u201d \u201cus,\u201d \u201cour,\u201d, \u201cCompany\u201d and \u201cAnavex\u201d mean Anavex Life Sciences Corp., unless the\ncontext clearly requires otherwise.\n\n\n iv\n\fCase 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 6 of 20\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 7 of 20\n\n\nPART I\n\nITEM 1. BUSINESS\n\nOverview and Strategy\n\nAnavex Life Sciences Corp. is a clinical stage biopharmaceutical company engaged in the development of differentiated therapeutics by applying\nprecision medicine to central nervous system (\u201cCNS\u201d) diseases with high unmet need. We analyze genomic data from clinical trials to identify\nbiomarkers, which we use in the analysis of our clinical trials.\n\nOur lead product candidate, ANAVEX\u00ae2-73 (blarcamesine), is being developed to treat Alzheimer\u2019s disease, Parkinson\u2019s disease and potentially\nother central nervous system diseases, including rare diseases, such as Rett syndrome, a rare severe neurological monogenic disorder caused by\nmutations in the X-linked gene, methyl-CpG-binding protein 2 (\u201cMECP2\u201d).\n\nWe currently have two core programs and two seed programs. Our core programs are at various stages of clinical and preclinical development, in\nneurodegenerative and neurodevelopmental diseases.\n\nThe following table summarizes key information about our programs:\n\n\n\n\n* = Orphan Drug Designation by the FDA\u037e 1. EXCELLENCE: Ongoing trial\n\nAnavex has a portfolio of compounds varying in sigma-1 receptor (SIGMAR1) binding activities. The SIGMAR1 gene encodes the SIGMAR1\nprotein, which is an intracellular chaperone protein with important roles in cellular communication. SIGMAR1 is also involved in transcriptional\nregulation at the nuclear envelope and restores homeostasis and stimulates recovery of cell function when activated. In order to validate the ability\nof our compounds to activate quantitatively the SIGMAR1, we performed, in collaboration with Stanford University, a quantitative Positron\nEmission Tomography (PET) imaging scan in mice, which demonstrated a dose-dependent ANAVEX\u00ae2-73 (blarcamesine) target engagement or\nreceptor occupancy with SIGMAR1 in the brain.\n\n\n 6\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 8 of 20\n\n\n\n\nSource: Reyes S et al., Sci Rep. 2021 Aug 25\u037e11(1):17150\n\nCellular Homeostasis\n\nMany diseases are possibly directly caused by chronic homeostatic imbalances or cellular stress of brain cells. In pediatric diseases, such as Rett\nsyndrome or infantile spasms, the chronic cellular stress is possibly caused by the presence of a constant genetic mutation. In neurodegenerative\ndiseases, such as Alzheimer\u2019s and Parkinson\u2019s diseases, chronic cellular stress is possibly caused by age-correlated buildup of cellular insult and\nhence chronic cellular stress. Specifically, defects in homeostasis of protein or ribonucleic acid (\u201cRNA\u201d) lead to the death of neurons and\ndysfunction of the nervous system. The spreading of protein aggregates resulting in a proteinopathy, a characteristic found in Alzheimer\u2019s and\nParkinson\u2019s diseases that results from disorders of protein synthesis, trafficking, folding, processing or degradation in cells. The clearance of\nmacromolecules in the brain is particularly susceptible to imbalances that result in aggregation and degeneration in nerve cells. For example,\nAlzheimer\u2019s disease pathology is characterized by the presence of amyloid plaques, and neurofibrillary tangles, which are aggregates of\nhyperphosphorylated Tau protein that are a marker of other diseases known as tauopathies as well as inflammation of microglia. With the SIGMAR1\nactivation through SIGMAR1 agonists like ANAVEX\u00ae2-73 (blarcamesine), our approach is to restore cellular balance (i.e. homeostasis). Therapies\nthat correct defects in cellular homeostasis might have the potential to halt or delay neurodevelopmental and neurodegenerative disease\nprogression.\n\n\n 7\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 9 of 20\n\n\n\nANAVEX\u00ae2-73 (blarcamesine)-specific Biomarkers\n\nAs part of some of our clinical trials, we have incorporated a genomic analysis to better understand potential populations for whom our clinical\nprograms might benefit. In our clinical trials, a full genomic analysis of Alzheimer\u2019s disease patients treated with ANAVEX\u00ae2-73 (blarcamesine) has\nhelped us identify actionable genetic variants. A significant impact of the genomic biomarkers SIGMAR1, the direct target of ANAVEX\u00ae2-73\n(blarcamesine) and COMT, a gene involved in memory function, on the drug response level was identified, leading to an early ANAVEX\u00ae2-73\n(blarcamesine)-specific biomarker hypothesis. We believe that excluding patients with SIGMAR1 identified biomarker variant (approximately\n10%-20% of the population) in prospective studies would identify approximately 80%-90% patients that would display clinically significant\nimproved functional and cognitive scores. The consistency between the identified DNA and RNA data related to ANAVEX\u00ae2-73 (blarcamesine),\nwhich are considered independent of Alzheimer\u2019s disease pathology, as well as multiple endpoints and time-points, provides support for the\npotential precision medicine clinical development of ANAVEX\u00ae2-73 (blarcamesine) by using genetic biomarkers identified within the trial\npopulation itself to target patients who are most likely to respond to ANAVEX\u00ae2-73 (blarcamesine) treatment. We may in the future utilize such an\napproach in Alzheimer\u2019s disease as well as indications like Parkinson\u2019s disease dementia or Rett syndrome in which ANAVEX\u00ae2-73 (blarcamesine)\nis currently being studied.\n\nClinical Trials Overview\n\nAlzheimer\u2019s Disease\n\nIn November 2016, we completed a Phase 2a clinical trial, consisting of Part A and Part B, which lasted a total of 57 weeks, for ANAVEX\u00ae2-73 in\nmild-to-moderate Alzheimer\u2019s patients. This open-label randomized trial in Australia met both primary and secondary endpoints and was designed\nto assess the safety and exploratory efficacy of ANAVEX\u00ae2-73 in 32 patients. ANAVEX\u00ae2-73 targets sigma-1 and muscarinic receptors, which have\nbeen shown in preclinical studies to reduce stress levels in the brain believed to restore cellular homeostasis and to reverse the pathological\nhallmarks observed in Alzheimer\u2019s disease. In October 2017, we presented positive pharmacokinetic (\u201cPK\u201d) and pharmacodynamic (\u201cPD\u201d) data from\nthe Phase 2a clinical trial, which established a concentration-effect relationship between ANAVEX\u00ae2-73 and trial measurements. These measures\nobtained from all patients who participated in the entire 57 weeks include exploratory cognitive and functional scores as well as biomarker signals of\nbrain activity. Additionally, the clinical trial appeared to show that ANAVEX\u00ae2-73 activity was enhanced by its active metabolite (ANAVEX19-144),\nwhich also targets the SIGMAR1 receptor and has a half-life approximately twice as long as the parent molecule.\n\nTwo consecutive trial extensions for the Phase 2a trial have allowed participants who completed the 52-week Part B of the trial to continue taking\nANAVEX\u00ae2-73, providing an opportunity to gather extended safety data for a cumulative time period of five years. In August 2020, patients\ncompleting these Phase 2a trial extensions were granted continued access to treatment with ANAVEX\u00ae2-73 through the Australian Government\nDepartment of Health - Therapeutic Goods Administration\u2019s compassionate use Special Access Scheme.\n\nA larger Phase 2b/3 double-blind, placebo-controlled trial of ANAVEX\u00ae2-73 in Alzheimer\u2019s disease commenced in August 2018. The Phase 2b/3 trial\nenrolled 509 patients, which were treated with a convenient once-daily oral formulation of ANAVEX\u00ae2-73 for 48 weeks, randomized 1:1:1 to two\ndifferent ANAVEX\u00ae2-73 doses or placebo. The trial took place at 52 sites across North America, Europe and Australia. Primary and secondary\nendpoints to assess safety and both cognitive and functional efficacy, were measured through the Alzheimer\u2019s Disease Assessment Scale -\nCognitive Subscale test (\u201cADAS-Cog\u201d), Alzheimer\u2019s Disease Cooperative Study - Activities of Daily Living (\u201cADCS-ADL\u201d) and Clinical Dementia\nRating - Sum of Boxes for cognition and function (\u201cCDR-SB\u201d). In addition to the primary endpoints, the ANAVEX\u00ae2-73 Phase 2b/3 trial design\nincorporated pre-specified statistical analyses related to potential genomic precision medicine biomarkers previously identified in the ANAVEX\u00ae2-\n73 Phase 2a clinical trial. The trial was completed in mid-2022 and, in December 2022, the Company presented positive topline results from the Phase\n2b/3 clinical trial.\n\n\n 8\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 10 of 20\n\n\n\nANAVEX\u00ae2-73 met the co-primary endpoints ADAS-Cog and ADCS-ADL and key secondary endpoint CDR-SB. ANAVEX\u00ae2-73 treatment slowed\ndecline of cognition and function in patients with early Alzheimer\u2019s disease over 48 weeks. Patients treated with ANAVEX\u00ae2-73 had 1.84 times\nhigher odds, or likelihood, to improve cognitively compared to placebo, with a ADAS-Cog score threshold change of -0.5 points or better [Odds\nRatio = 1.84 (p = 0.015)]. At clinically significant levels of improvement in function (ADCS-ADL score threshold change of +3.5 points or better),\npatients treated with ANAVEX\u00ae2-73 had 2.67 times higher odds, or likelihood, to improve function compared to placebo [Odds Ratio = 2.67 (p =\n0.0255)]. Additionally, treatment with ANAVEX\u00ae2-73 reduced cognitive decline at end of treatment, measured with the ADAS-Cog, as compared to\nplacebo, by 45%, representing a treatment difference in mean score change of -1.85 points (p=0.033). Compared to placebo, ANAVEX\u00ae2-73 reduced\nclinical decline of cognition and function by 27% with mean score difference of -0.42 points (p=0.040) as measured by the CDR-SB. ANAVEX\u00ae2-73\nwas generally safe and well tolerated. All statistical analyses were performed by outside consultancy companies.\n\nIn September 2023, we provided additional data demonstrating that the clinical effect was complemented by two independent biomarkers. A\nsignificant reduction in pathological amyloid beta levels in plasma, as well as a significant slowing in the rate of pathological brain atrophy on MRI\n(Magnetic Resonance Imaging) scans. Validated biomarkers of amyloid beta pathology, plasma A\u03b242/40 ratio increased significantly (P = 0.048),\ndemonstrating strong anti-amyloid effects of ANAVEX\u00ae2-73 in Alzheimer\u2019s disease patients, while MRI revealed significant reduction in brain\nvolume loss, including whole brain (P = 0.0005), comparing treatment to placebo.\n\nFurthermore, all prespecified clinical endpoints were further analyzed using a mixed model for repeated measures (MMRM). Under the multiplicity\ncontrol rule, a trial is successful in meeting the co-primary endpoints if the significance of each endpoint is P < 0.05, or if the significance of only\none co-primary endpoint is P < 0.025. If only one primary endpoint is significant at an \u03b1 level of 0.025, then the secondary endpoint will be evaluated\nat the same level of 0.025. The trial was successful, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks\nbetween the ANAVEX\u00ae2-73 and placebo groups were \u22121.783 [95% CI, \u22123.314 to \u22120.251]\u037e (P = 0.0226) for ADAS-Cog13, and \u22120.456 [95% CI, \u22120.831\nto \u22120.080]\u037e (P = 0.0175) for CDR-SB in patients with early Alzheimer\u2019s disease.\n\nIn the respective safety population, common treatment-emergent adverse events included dizziness, which was transient and mostly mild to\nmoderate in severity, and occurred in 120 participants (35.8%) during titration and in 76 participants (25.2%) during maintenance with ANAVEX\u00ae2-\n73 and 10 (6.0%) during titration and 9 (5.6%) during maintenance with placebo.\n\nA subsequent long-term open label extension study of ANAVEX\u00ae2-73, entitled the ATTENTION-AD trial was initiated for patients who have\ncompleted the 48-week Phase 2b/3 placebo-controlled trial referenced above. This trial extension for an additional 96 weeks is currently ongoing,\nand provides an opportunity to evaluate longer term safety and efficacy of ANAVEX\u00ae2-73 in persons with Alzheimer\u2019s disease.\n\nRett Syndrome\n\nIn February 2016, we presented positive preclinical data for ANAVEX\u00ae2-73 in Rett syndrome, a rare neurodevelopmental disease. The data\ndemonstrated dose related and significant improvements in an array of behavioral and gait paradigms in a mouse model with an MECP2-null\nmutation that causes neurological symptoms that mimic Rett syndrome. The study was funded by the International Rett Syndrome Foundation\n(\u201cRettsyndrome.org\u201d). In January 2017, we were awarded a financial grant from Rettsyndrome.org of a minimum of $0.6 million to cover some of the\ncosts of a multicenter Phase 2 clinical trial of ANAVEX\u00ae2-73 for the treatment of Rett syndrome. This award was received in quarterly instalments\nwhich commenced during fiscal 2018.\n\nIn March 2019, we commenced the first Phase 2 clinical trial in a planned Rett syndrome program of ANAVEX\u00ae2-73 for the treatment of Rett\nsyndrome. The clinical trials are being conducted in a range of patient age demographics and geographic regions, utilizing an oral liquid once-daily\nformulation of ANAVEX\u00ae2-73.\n\n\n 9\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 11 of 20\n\n\n\nThe first Phase 2 trial, (ANAVEX\u00ae2-73-RS-001), which took place in the United States, was completed in December 2020. This trial was a randomized\ndouble-blind, placebo-controlled safety, tolerability, PK and efficacy trial of oral liquid ANAVEX\u00ae2-73 formulation in 25 adult female patients with\nRett syndrome over a 7-week treatment period including ANAVEX\u00ae2-73-specific genomic precision medicine biomarkers. The primary endpoint of\nthe trial was safety. The dosing of 5 mg ANAVEX\u00ae2-73 was well-tolerated and demonstrated dose-proportional PK. All secondary efficacy\nendpoints of the trial showed statistically significant and clinically meaningful response in the Rett Syndrome Behaviour Questionnaire (\u201cRSBQ\u201d)\nresponse, when compared to placebo, in the intent to treat (\u201cITT\u201d) cohort (all participants, p = 0.011). 66.7% of ANAVEX\u00ae2-73 treated subjects\nshowed a statistically significant improvement in RSBQ response as compared to 10% of the subjects on placebo in the ITT cohort (all participants,\np = 0.011). ANAVEX\u00ae2-73 treatment resulted in a sustained improvement in Clinical Global Impression Improvement (CGI-I) response throughout\nthe 7-week clinical trial, when compared to placebo in the ITT cohort (all participants, p = 0.014). Consistent with previous ANAVEX\u00ae2-73 clinical\ntrials, patients carrying the common form of the SIGMAR1 gene treated with ANAVEX\u00ae2-73 experienced stronger improvements in the prespecified\nefficacy endpoints.\n\nThe second, international trial of ANAVEX\u00ae2-73 for the treatment of Rett syndrome, called the AVATAR trial, commenced in June 2019. This trial\ntook place in Australia and the United Kingdom using a higher dose than the U.S. based Phase 2 trial for Rett syndrome. The trial was a Phase 3\nrandomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of ANAVEX\u00ae2-73 in 33 adult patients over a 7-week treatment\nperiod including ANAVEX\u00ae2-73 specific precision medicine biomarkers. Based upon the input from the successful U.S. Phase 2 Rett syndrome trial\n(ANAVEX\u00ae2-73-RS-001), we updated the endpoints for the AVATAR trial (ANAVEX\u00ae2-73-RS-002) to appropriately assess the clinically meaningful\noutcome following International Conference on Harmonization (ICH) guidelines. These updates were approved by the respective regulatory\nauthorities in the U.K. and in Australia, respectively, where the AVATAR trial was conducted.\n\nThe data from the AVATAR trial was released in February 2022. The clinical trial met all primary and secondary efficacy and safety endpoints, with\nconsistent improvements in primary efficacy endpoint, RSBQ response (p = 0.037), and secondary efficacy endpoints, ADAMS (p = 0.010) and CGI-\nI (p = 0.037) response. Efficacy endpoints demonstrated statistically significant and clinically meaningful reductions in Rett syndrome symptoms.\nConvenient once daily oral liquid doses of up to 30 mg of ANAVEX\u00ae2-73 were also well tolerated with good medication compliance. All patients\nwho participated in the trial were eligible to receive ANAVEX\u00ae2-73 under a voluntary open label extension protocol.\n\nIn July 2020, we commenced the third trial of ANAVEX\u00ae2-73 for the treatment of Rett syndrome, called the EXCELLENCE trial. This Phase 2/3 trial in\npediatric patients with Rett syndrome includes trial sites in Australia, the United Kingdom and Canada, and will evaluate the safety and efficacy of\nANAVEX\u00ae2-73 in approximately 84 pediatric patients, aged 5 to 18, over a 12-week treatment period incorporating ANAVEX\u00ae2-73 specific precision\nmedicine biomarkers. This trial completed enrollment in February 2023, exceeding the original enrollment target. In June 2023, this trial completed\ndosing of all participants, and topline results are expected in the second half of 2023. All patients who participate in the trial will be eligible to\nreceive ANAVEX\u00ae2-73 under a voluntary open label extension protocol, which is currently ongoing.\n\nParkinson\u2019s Disease\n\nIn September 2016, we presented positive preclinical data for ANAVEX\u00ae2-73 in an animal model of Parkinson\u2019s disease, which demonstrated\nsignificant improvements on behavioral, histopathological, and neuroinflammatory endpoints. The study was funded by the Michael J. Fox\nFoundation. Additional data announced in October 2017 indicated that ANAVEX\u00ae2-73 induced robust neurorestoration in experimental\nParkinsonism. We believe the encouraging results we have gathered in this preclinical model, coupled with the favorable profile of this product\ncandidate in the Alzheimer\u2019s disease trial, support the notion that ANAVEX\u00ae2-73 has the potential to treat Parkinson\u2019s disease dementia.\n\nIn October 2020, we completed a double-blind, randomized, placebo-controlled proof-of-concept Phase 2 trial with ANAVEX\u00ae2-73 in Parkinson\u2019s\ndisease dementia in Spain and Australia, to study the effect of the compound on both the cognitive and motor impairment of Parkinson\u2019s disease.\nThe Phase 2 trial enrolled approximately 132 patients for 14 weeks, randomized 1:1:1 to two different ANAVEX\u00ae2-73 doses, 30 mg and 50 mg, or\nplacebo. The ANAVEX\u00ae2-73 Phase 2 Parkinson\u2019s disease dementia trial design incorporated genomic precision medicine biomarkers identified in\nthe ANAVEX\u00ae2-73 Phase 2a Alzheimer\u2019s disease trial.\n\n\n 10\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 12 of 20\n\n\n\nThe trial demonstrated that ANAVEX\u00ae2-73 was safe and well tolerated in oral doses up to 50 mg once daily. The results showed clinically\nmeaningful, dose-dependent, and statistically significant improvements in the Cognitive Drug Research (\u201cCDR\u201d) computerized assessment system\nanalysis. Treatment with ANAVEX\u00ae2-73 also resulted in clinically meaningful improvements as measured by the global composite score of\nParkinson\u2019s disease symptom severity, MDS-Unified Parkinson\u2019s Disease Rating Scale (\u201cMDS-UPDRS\u201d) total score on top of standard of care\nincluding dopaminergic therapy, levodopa and other anti-PD medications after 14 weeks of treatment, suggesting ANAVEX\u00ae2-73\u2019s potential\ncapability of slowing and reversing symptoms that progress in Parkinson\u2019s disease. In addition, the trial confirmed the precision medicine approach\nof targeting SIGMAR1 as a genetic biomarker in response to ANAVEX\u00ae2-73 may result in improved clinical outcomes.\n\nA 48-week Open Label Extension (\u201cOLE\u201d) ANAVEX2-73-PDD-EP-001 Phase 2 trial was offered to participants after completion of the double-blind\nplacebo-controlled ANAVEX2-73-PDD-001 Phase 2 trial discussed above. The OLE trial assessed safety, tolerability and efficacy, measuring among\nothers, MDS-Unified Parkinson\u2019s Disease Rating Scale Parts I, II, III, REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Clinical\nGlobal Impression - Improvement (CGI-I), as well as cognitive efficacy endpoint Montreal Cognitive Assessment (MoCA) over a 48-week period.\n\nIn March 2023, we reported the preliminary ANAVEX2-73-PDD-EP-001 OLE trial data, which demonstrated longitudinal beneficial effects of\nANAVEX\u00ae2-73 on the prespecified primary and secondary objectives. Preliminary analysis reveals that ANAVEX\u00ae2-73 was found to be generally\nsafe and well tolerated\u037e and safety findings in this trial were consistent with the known safety profile of ANAVEX\u00ae2-73. In respect to efficacy,\nacross all efficacy endpoints, patients performed better while on ANAVEX\u00ae2-73. While all patients were on drug holiday due to COVID-19 between\nthe DB EOT and the OLE Baseline, the respective efficacy endpoints, including the MDS-UPDRS Part II + III and CGI-I, measured at the end of trial\nof the double-blind study (DB EOT) and the OLE Baseline, were worsening, as expected in a progressive disease like Parkinson\u2019s. However, when\npatients resumed daily oral ANAVEX\u00ae2-73 treatment, a consistent improvement was observed during the extension phase from OLE Baseline\nthrough OLE Week 24, and OLE Week 48, respectively. These results are consistent with the pattern observed for all efficacy measures in the\nextension phase. The two endpoints, MDS-UPDRS Part II + III and CGI-I measured in this study are the planned primary and key secondary\nendpoints in our forthcoming pivotal 6-month Parkinson\u2019s disease study.\n\nIn January 2021, we were awarded a research grant of $1.0 million from The Michael J. Fox Foundation for Parkinson\u2019s Research to develop\nANAVEX\u00ae2-73 for the treatment of Parkinson\u2019s disease. The award will explore utilization of PET imaging biomarkers to enable measurement of\ntarget engagement and pathway activation of the SIGMAR1 with clinically relevant doses, including in people with Parkinson\u2019s disease.\n\nSchizophrenia, Frontotemporal Dementia and Alzheimer\u2019s disease\n\nIn July 2020, we commenced the First-in-Human Phase 1 clinical trial of ANAVEX\u00ae3-71. ANAVEX\u00ae3-71 was previously granted orphan drug\ndesignation for the treatment of Frontotemporal Dementia (\u201cFTD\u201d) by the FDA. ANAVEX\u00ae3-71 is an orally administered small molecule targeting\nsigma-1 and M1 muscarinic receptors that is designed to be beneficial for neurodegenerative diseases. In preclinical studies, ANAVEX\u00ae3-71\ndemonstrated disease-modifying activity against the major hallmarks of Alzheimer\u2019s disease in transgenic (3xTg-AD) mice, including cognitive\ndeficits, amyloid and tau pathologies, as well as beneficial effects on mitochondrial dysfunction and neuroinflammation.\n\nThe Phase 1 clinical trial was a prospective double-blind, randomized, placebo-controlled trial in Australia. A total of 36 healthy male and female\nsubjects were included. Single escalating doses of ANAVEX\u00ae3-71 were administered in order to evaluate the safety, tolerability, and PK of\nANAVEX\u00ae3-71 and the effects of food and gender on its PK in healthy volunteers.\n\n\n 11\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 13 of 20\n\n\n\nThe trial met its primary and secondary endpoints of safety, with no serious adverse events (\u201cSAEs\u201d) or dose-limiting toxicities observed.\nANAVEX\u00ae3-71 was well tolerated in all cohorts receiving ANAVEX\u00ae3-71 in single doses ranging from 5 mg to 200 mg daily with no SAEs and no\nsignificant lab abnormalities in any subject. In the trial, ANAVEX\u00ae3-71 exhibited linear PK. Its pharmacokinetics was also dose proportional for\ndoses up to 160 mg. Gender had no effect on the PK of the drug and food had no effect on the bioavailability of ANAVEX\u00ae3-71. The trial also met\nthe secondary objective of characterizing the effect of ANAVEX\u00ae3-71 on electrocardiogram (\u201cECG\u201d) parameters. There were no clinically significant\nECG parameters throughout the trial. Participant QTcF measures were normal across all dose groups with no difference between ANAVEX\u00ae3-71 and\nplacebo.\n\nIn October 2023 a peer-reviewed publication in the journal Neurobiology of Aging, titled \u201cEarly treatment with an M1 and sigma-1 receptor agonist\nprevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology\u201d, featured the orally available small molecule\nANAVEX\u00ae3-71 (AF710B). The preclinical study described the potential disease-modifying properties of ANAVEX\u00ae3-71 on Alzheimer\u2019s disease\npathology as a possible drug candidate for a potential once daily oral preventive strategy for Alzheimer\u2019s disease.\n\nBased on these results, and ANAVEX\u00ae3-71\u2019s pre-clinical profile, we intend to advance ANAVEX\u00ae3-71 into a biomarker-driven clinical development\ndementia program for the treatment of schizophrenia, FTD and Alzheimer\u2019s disease, evaluating longitudinal effect of treatment with ANAVEX\u00ae3-71.\nWe believe the results of these clinical trials and preclinical study could serve as a basis for advancing into respective registration trials in the U.S.\n\nOur Pipeline\n\nOur research and development pipeline includes ANAVEX\u00ae2-73 currently in three different clinical trial indications, and several other compounds in\ndifferent stages of clinical and pre-clinical development.\n\nOur proprietary SIGMACEPTOR\u2122 Discovery Platform produced small molecule drug candidates with unique modes of action, based on our\nunderstanding of sigma receptors. Sigma receptors may be targets for therapeutics to combat many human diseases, both of neurodegenerative\nnature, including Alzheimer\u2019s disease, as well as of neurodevelopmental nature, like Rett syndrome. When bound by the appropriate ligands, sigma\nreceptors influence the functioning of multiple biochemical signals that are involved in the pathogenesis (origin or development) of disease.\nMultiple viruses including SARS-CoV-2 (COVID-19) induce cellular stress by intrinsic mitochondrial apoptosis and other related cellular processes,\nin order to ensure survival and replication. Hence, it is possible that SIGMAR1 could play a role in modulating the cellular response to viral\ninfection and ameliorate pathogenesis.\n\nCompounds that have been subjects of our research include the following:\n\nANAVEX\u00ae2-73 (blarcamesine)\n\nWe believe ANAVEX\u00ae2-73 may offer a disease-modifying approach in neurodegenerative and neurodevelopmental diseases by activation of\nSIGMAR1. ANAVEX\u00ae2-73 is being developed in an oral liquid once-daily formulation for rare diseases such as Rett syndrome as well as an oral\nonce-daily capsule formulation for diseases such as Alzheimer\u2019s disease.\n\nIn Rett syndrome, administration of ANAVEX\u00ae2-73 in liquid form resulted in both significant and dose related improvements in an array of\nbehavioral paradigms in the MECP2 HET Rett syndrome disease model. In addition, in a further experiment sponsored by Rettsyndrome.org,\nANAVEX\u00ae2-73 was evaluated in automatic visual response and respiration tests in 7-month old mice, an age at which advanced pathology is\nevident. Vehicle-treated MECP2 mice demonstrated fewer automatic visual responses than wild-type mice. Treatment with ANAVEX\u00ae2-73 for four\nweeks significantly increased the automatic visual response in the MECP2 Rett syndrome disease mice. Additionally, chronic oral dosing daily for\n6.5 weeks of ANAVEX\u00ae2-73 starting at ~5.5 weeks of age was conducted in the MECP2 HET Rett syndrome disease mouse model assessed the\ndifferent aspects of muscular coordination, balance, motor learning and muscular strengths, some of the core deficits observed in Rett syndrome.\nAdministration of ANAVEX\u00ae2-73 resulted in both significant and dose related improvements in an array of these behavioral paradigms in the\nMECP2 HET Rett syndrome disease model.\n\n\n 12\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 14 of 20\n\n\n\nIn May 2016 and June 2016, the FDA granted Orphan Drug Designation to ANAVEX\u00ae2-73 for the treatment of Rett syndrome and infantile spasms,\nrespectively. In November 2019, the FDA granted to ANAVEX\u00ae2-73 the Rare Pediatric Disease (RPD) designation for the treatment of Rett\nsyndrome. The RPD designation is intended to encourage the development of treatments for rare pediatric diseases.\n\nFurther, in February 2020, the FDA granted Fast Track designation for the ANAVEX\u00ae2-73 clinical development program for the treatment of Rett\nsyndrome. The FDA Fast Track program is designed to facilitate and expedite the development and review of new drugs to address unmet medical\nneeds in the treatment of serious and life-threatening conditions.\n\nFor Parkinson\u2019s disease, data demonstrates significant improvements and restoration of function in a disease-modifying animal model of\nParkinson\u2019s disease. Significant improvements were seen on all measures tested: behavioral, histopathological, and neuroinflammatory endpoints.\nIn October 2020, we completed a double-blind, randomized, placebo-controlled proof-of-concept Phase 2 trial with ANAVEX\u00ae2-73 in Parkinson\u2019s\ndisease dementia, to study the effect of the compound on both the cognitive and motor impairment of Parkinson\u2019s disease. The Phase 2 trial\nenrolled approximately 132 patients for 14 weeks, randomized 1:1:1 to two different ANAVEX\u00ae2-73 doses, 30mg and 50mg, or placebo. The\nANAVEX\u00ae2-73 Phase 2 Parkinson\u2019s disease dementia trial design incorporated genomic precision medicine biomarkers identified in the\nANAVEX\u00ae2-73 Phase 2a Alzheimer\u2019s disease trial.\n\nThe trial demonstrated that ANAVEX\u00ae2-73 was safe and well tolerated in oral doses up to 50mg once daily. The results showed clinically\nmeaningful, dose-dependent, and statistically significant improvements in the CDR computerized assessment system analysis. We anticipate\nconducting further clinical trials of ANAVEX\u00ae2-73 in Parkinson\u2019s disease dementia after submitting the results of the trial to the FDA to obtain\nregulatory guidance.\n\nIn Alzheimer\u2019s disease animal models, ANAVEX\u00ae2-73 has shown pharmacological, histological and behavioral evidence as a potential\nneuroprotective, anti-amnesic, anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to SIGMAR1 and moderate affinities\nto M1-4 type muscarinic receptors. In addition, ANAVEX\u00ae2-73 has shown a potential dual mechanism which may impact amyloid, tau pathology\nand inflammation. In a transgenic Alzheimer\u2019s disease animal model Tg2576, ANAVEX\u00ae2-73 induced a statistically significant neuroprotective\neffect against the development of oxidative stress in the mouse brain, as well as significantly increased the expression of functional and synaptic\nplasticity markers that is apparently amyloid-beta independent. It also statistically alleviated the learning and memory deficits developed over time\nin the animals, regardless of sex, both in terms of spatial working memory and long-term spatial reference memory.\n\nBased on the results of pre-clinical testing, we initiated and completed a Phase 1 single ascending dose (SAD) clinical trial of ANAVEX\u00ae2-73. In\nthis Phase 1 SAD trial, the maximum tolerated single dose was defined per protocol as 55-60 mg. This dose is above the equivalent dose shown to\nhave positive effects in mouse models of Alzheimer\u2019s disease. There were no significant changes in laboratory or ECG parameters. ANAVEX\u00ae2-73\nwas well tolerated below the 55-60 mg dose with only mild adverse events in some subjects. Observed adverse events at doses above the maximum\ntolerated single dose included headache and dizziness, which were moderate in severity and reversible. These side effects are often seen with drugs\nthat target CNS conditions, including Alzheimer\u2019s disease.\n\nIn November 2016, we completed a Phase 2a clinical trial for ANAVEX\u00ae2-73, for the treatment of Alzheimer\u2019s disease. The open-label randomized\ntrial was designed to assess the safety and exploratory efficacy of ANAVEX\u00ae2-73 in 32 patients with mild-to-moderate Alzheimer\u2019s disease. The\nPhase 2a trial met both primary and secondary objectives of the trial.\n\n\n 13\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 15 of 20\n\n\n\nIn July 2018, we presented the results of a genomic DNA and RNA evaluation of the participants in the Phase 2a clinical trial. More than 33,000\ngenes were analyzed using unbiased, data driven, machine learning, artificial intelligence (AI) system for analyzing DNA and RNA data in patients\ntreated with ANAVEX\u00ae2-73. The analysis identified genetic variants that impacted response to ANAVEX\u00ae2-73, among them variants related to the\nSIGMAR1, the target for ANAVEX\u00ae2-73. Results showed that trial participants with the common SIGMAR1 wild type gene variant, which is\nestimated to be about 80% of the population worldwide, demonstrated improved cognitive (MMSE) and functional (ADCS-ADL) scores. The\nresults from this evaluation supported the continued evaluation of genomic information in subsequent clinical trials, since these signatures can\nnow be applied to neurological indications tested in future clinical trials with ANAVEX\u00ae2-73 including Alzheimer\u2019s disease, Parkinson\u2019s disease\ndementia and Rett syndrome.\n\nANAVEX\u00ae2-73 data met prerequisite information in order to progress into a Phase 2b/3 placebo-controlled trial. On July 2, 2018, the Human\nResearch Ethics Committee in Australia approved the initiation of our Phase 2b/3, double-blind, randomized, placebo-controlled 48-week safety and\nefficacy trial of ANAVEX\u00ae2-73 for the treatment of early Alzheimer\u2019s disease. Clinical trial sites in Canada, the United Kingdom, the Netherlands\nand Germany were also added. This Phase 2b/3 trial design incorporates inclusion of genomic precision medicine biomarkers identified in the\nANAVEX\u00ae2-73 Phase 2a trial.\n\nWe believe preclinical data from our studies also supports further research into the use of ANAVEX\u00ae2-73 as a potential platform drug for other\nneurodegenerative diseases beyond Alzheimer\u2019s disease, Parkinson\u2019s disease or Rett syndrome, more specifically, epilepsy, infantile spasms,\nFragile X syndrome, Angelman syndrome, multiple sclerosis, and, more recently, tuberous sclerosis complex (TSC). ANAVEX\u00ae2-73 demonstrated\nsignificant improvements in all of these indications in the respective preclinical animal models.\n\nIn a preclinical study sponsored by the Foundation for Angelman Syndrome, ANAVEX\u00ae2-73 was assessed in a mouse model for the development\nof audiogenic seizures. The results indicated that ANAVEX\u00ae2-73 administration significantly reduced audiogenic-induced seizures in mice. In a\nstudy sponsored by FRAXA Research Foundation regarding Fragile X syndrome, data demonstrated that ANAVEX\u00ae2-73 restored hippocampal\nbrain-derived neurotrophic factor (BDNF) expression to normal levels. BDNF under-expression has been observed in many neurodevelopmental\nand neurodegenerative pathologies. BDNF signaling promotes maturation of both excitatory and inhibitory synapses. ANAVEX\u00ae2-73 normalization\nof BDNF expression could be a contributing factor for the positive preclinical data observed in both neurodevelopmental and neurodegenerative\ndisorders like Angelman and Fragile X syndromes.\n\nIn addition, preclinical data to-date also indicates that ANAVEX\u00ae2-73 has the potential to demonstrate protective effects of mitochondrial enzyme\ncomplexes during pathological conditions, which, if impaired, may play a role in the pathogenesis of neurodegenerative and neurodevelopmental\ndiseases.\n\nIn addition, preclinical data on ANAVEX\u00ae2-73 related to multiple sclerosis indicates that ANAVEX\u00ae2-73 may promote remyelination in multiple\nsclerosis disease. Further, our data also demonstrates that ANAVEX\u00ae2-73 has the potential to provide protection for oligodendrocytes (\u201cOL\u2019s\u201d)\nand oligodendrocyte precursor cells (\u201cOPC\u2019s\u201d), as well as central nervous system neurons in addition to helping repair by increasing OPC\nproliferation and maturation in tissue culture.\n\nIn March 2018, we presented preclinical data of ANAVEX\u00ae2-73 in a genetic mouse model of tuberous sclerosis complex (\u201cTSC\u201d). TSC is a rare\ngenetic disorder characterized by the growth of numerous benign tumors in many parts of the body with a high incidence of seizures. The\npreclinical data demonstrated that treatment with ANAVEX\u00ae2-73 significantly increased survival and reduced seizures in those mice.\n\nANAVEX\u00ae3-71\n\nANAVEX\u00ae3-71 is a clinical drug candidate with a novel mechanism of action via SIGMAR1 activation and M1 muscarinic allosteric modulation,\nwhich has been shown to enhance neuroprotection and cognition in Alzheimer\u2019s disease models. ANAVEX\u00ae3-71 is a CNS-penetrable potential\ndisease-modifying treatment for cognitive impairments. We believe it is effective in very small doses against the major Alzheimer\u2019s hallmarks in\ntransgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, and also has beneficial effects on inflammation and\nmitochondrial dysfunctions. ANAVEX\u00ae3-71 indicates extensive therapeutic advantages in Alzheimer\u2019s and other protein-aggregation-related\ndiseases given its ability to enhance neuroprotection and cognition via SIGMAR1 activation and M1 muscarinic allosteric modulation.\n\n\n 14\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 16 of 20\n\n\n\n SIGNATURES\nPursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed\non its behalf by the undersigned thereunto duly authorized.\n\nDate: November 27, 2023 ANAVEX LIFE SCIENCES CORP.\n\n By: /s/ Christopher Missling, PhD\n Name: Christopher Missling, PhD\n Title: Chief Executive Officer (Principal Executive Officer)\n\nPursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf of the\nregistrant and in the capacities and on the dates indicated.\n\n Signatures Title(s) Date\n\n/s/ Christopher Missling, PhD November 27, 2023\nChristopher Missling, PhD Chief Executive Officer (Principal Executive Officer) and Director\n\n/s/ Sandra Boenisch November 27, 2023\nSandra Boenisch, CPA, CGA Principal Financial Officer and Treasurer (Principal Accounting\n Officer)\n\n/s/ Jiong Ma, PhD November 27, 2023\nJiong Ma, PhD Director, Chair\n\n/s/ Athanasios Skarpelos November 27, 2023\nAthanasios Skarpelos Director\n\n/s/ Claus van der Velden, PhD November 27, 2023\nClaus van der Velden, PhD Director\n\n/s/ Steffen Thomas, PhD November 27, 2023\nSteffen Thomas, PhD Director\n\n/s/ Peter Donhauser, D.O. November 27, 2023\nPeter Donhauser, D.O. Director\n\n 90\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 17 of 20\n\n\n\n Exhibit 21.1\n\n SUBSIDIARIES OF THE REGISTRANT\n\nName of Subsidiary Jurisdiction of Incorporation or Organization\nAnavex Australia Pty Limited Australia\nAnavex Germany GmbH Germany\nAnavex Canada Ltd. Ontario, Canada\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 18 of 20\n\n\n\n EXHIBIT 23.1\n\n CONSENT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM\n\nWe have issued our reports dated November 27, 2023, with respect to the consolidated financial statements and internal control over financial\nreporting included in the Annual Report of Anavex Life Sciences Corp. on Form 10-K for the year ended September 30, 2023. We consent to the\nincorporation by reference of said reports in the Registration Statements of Anavex Life Sciences Corp. on Forms S-3 (No. 333-218292, and No. 333-\n259788) and Forms S-8 (No. 333-219934, No. 333-255166 and No. 333-265537).\n\n/s/ GRANT THORNTON LLP\n\nMelville, New York\nNovember 27, 2023\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 19 of 20\n\n\n\n EXHIBIT 23.2\n\n Consent of Independent Registered Public Accounting Firm\n\nAnavex Life Sciences Corp.\nNew York, New York\n\nWe hereby consent to the incorporation by reference in the Registration Statements on Form S-3 (No. 333-218292 and No. 333-259788) and Form S-8\n(No. 333-219934, No. 333-255166 and No. 333-265537) of Anavex Life Sciences Corp. and subsidiaries of our report dated November 24, 2021,\nrelating to the consolidated financial statements of Anavex Life Sciences Corp. and subsidiaries, which appears in this Annual Report on Form 10-\nK.\n\n/s/ BDO USA, P.C.\n\nNew York, New York\nNovember 27, 2023\n\f Case 1:24-cv-03529-CM Document 23-1 Filed 08/23/24 Page 20 of 20\n\n\n\n EXHIBIT 31.1\n\n CERTIFICATION\n\nI, Christopher Missling, certify that:\n\n1. I have reviewed this Annual Report on Form 10-K of Anavex Life Sciences Corp.\u037e\n\n2. Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make\n the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered\n by this report\u037e\n\n3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects\n the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report\u037e\n\n4. The registrant\u2019s other certifying officer(s) and I are responsible for establishing and maintaining disclosure controls and procedures (as\n defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-\n 15(f) and 15d-15(f)) for the registrant and have:\n\n a) Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our\n supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by\n others within those entities, particularly during the period in which this report is being prepared\u037e\n\n b) Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our\n supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for\n external purposes in accordance with generally accepted accounting principles\u037e\n\n c) Evaluated the effectiveness of the registrant\u2019s disclosure controls and procedures and presented in this report our conclusions about the\n effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation\u037e and\n\n d) Disclosed in this report any change in the registrant\u2019s internal control over financial reporting that occurred during the registrant\u2019s most\n recent fiscal quarter (the registrant\u2019s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely\n to materially affect, the registrant\u2019s internal control over financial reporting\u037e and\n\n5. The registrant\u2019s other certifying officer(s) and I have disclosed, based on our most recent evaluation of internal control over financial\n reporting, to the registrant\u2019s auditors and the audit committee of the registrant\u2019s board of directors (or persons performing the equivalent\n functions):\n\n a) All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are\n reasonably likely to adversely affect the registrant\u2019s ability to record, process, summarize and report financial information\u037e and\n\n b) Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant\u2019s internal\n control over financial reporting.\n\nDate: November 27, 2023\n\n/s/ Christopher Missling\n\nChristopher Missling, PhD\nChief Executive Officer, President, Secretary\n(Principal Executive Officer)\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:16.437791-07:00","document_number":"23","attachment_number":1,"pacer_doc_id":"127036039501","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Form 10-K","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579225/","id":409579225,"tags":[],"absolute_url":"/docket/68511120/23/2/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.540384-07:00","date_modified":"2024-08-27T02:13:02.887466-07:00","sha1":"a356aad46b4dc61b6d2bad448db887a28a0863af","page_count":18,"file_size":542054,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.2.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.2.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 1 of 18\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 2 of 18\n\n\n\n\n UNITED STATES\n SECURITIES AND EXCHANGE COMMISSION\n Washington, D.C. 20549\n\n FORM 10-K\n(Mark One)\n\n \u2612 ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\n For the fiscal year ended September 30, 2022\n\n\u2610 TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\n\n For the transition period from ______________ to________________\n\n Commission file number: 001-37606\n\n\n ANAVEX LIFE SCIENCES CORP.\n (Exact name of registrant as specified in its charter)\n\n Nevada XX-XXXXXXX\n (State or other jurisdiction of incorporation or organization) (I.R.S. Employer Identification No.)\n\n 630 5th Avenue, 20th Floor, New York, NY USA 10111\n (Address of principal executive offices) (Zip Code)\n\n Registrant\u2019s telephone number, including area code 1-844-689-3939\n\n Securities registered under Section 12(b) of the Act:\n\n Common Stock, $0.001 par value AVXL NASDAQ Stock Market LLC\n Title of each class Trading Symbol Name of each exchange on which registered\n\n Securities registered pursuant to Section 12(g) of the Act:\n None\n (Title of class)\n\nIndicate by checkmark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.\n Yes \u2612 No \u2610\n\nIndicate by checkmark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act.\n Yes \u2610 No \u2612\n\nIndicate by checkmark whether the registrant has (1) filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of\n1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to\nsuch filing requirements for the past 90 days.\n Yes \u2612 No \u2610\n\nIndicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405\nof Regulation S-T (\u00a7232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit\nand post such files).\n Yes \u2612 No \u2610\n\nIndicate by checkmark whether the registrant is a large accelerated filer, an accelerated filer, a non- accelerated filer, a smaller reporting company, or\nan emerging growth company. See the definitions of \u201clarge accelerated filer,\u201d \u201caccelerated filer\u201d, \u201csmaller reporting company\u201d and \u201cemerging growth\ncompany\u201d in Rule 12b-2 of the Exchange Act.\n\nLarge accelerated filer \u2612 Accelerated filer \u2610\n Smaller reporting company \u2610\nNon-accelerated filer \u2610\n Emerging growth company \u2610\n\nIf an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with\nany new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act\n \u2610\n\nIndicate by check mark whether the registrant has filed a report on and attestation to its management\u2019s assessment of the effectiveness of its\ninternal controls over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting\nfirm that prepared or issued its audit report.\n Yes \u2612 No \u2610\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 3 of 18\n\nIndicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act).\n Yes \u2610 No \u2612\n\nState the aggregate market value of the voting and non-voting common equity held by non-affiliates computed by reference to the price at which\nthe common equity was last sold, or the average bid and asked price of such common equity, as of the last business day of the registrant\u2019s most\nrecently completed second fiscal quarter: $921 million based on a price of $12.31 per share, being the closing price of the registrant\u2019s common stock\non March 31, 2022.\n\nIndicate the number of shares outstanding of each of the registrant\u2019s classes of common stock, as of the latest practicable date: 77,961,815 issued\nand outstanding as of November 28, 2022.\n\n DOCUMENTS INCORPORATED BY REFERENCE\n\nNone.\n\n\n i\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 4 of 18\n\n\n TABLE OF CONTENTS\n\nPART I 6\nITEM 1. BUSINESS 6\nITEM 1A. RISK FACTORS 30\nITEM 1B. UNRESOLVED STAFF COMMENTS 51\nITEM 2. PROPERTIES 51\nITEM 3. LEGAL PROCEEDINGS 51\nITEM 4. MINE SAFETY DISCLOSURES 51\nPART II 51\nITEM 5. MARKET FOR REGISTRANT\u2019S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF 51\nEQUITY SECURITIES\nITEM 6 [Reserved] 52\nITEM 7 MANAGEMENT\u2019S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATION\n 52\nITEM 7A QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 57\nITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 58\nITEM 9. CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL MATTERS 82\nITEM 9A. CONTROLS AND PROCEDURES 82\nITEM 9B OTHER INFORMATION 82\nPART III 83\nITEM 10 DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 83\nITEM 11. EXECUTIVE COMPENSATION 83\nITEM 12. SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER 83\nMATTERS.\nITEM 13. CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS, AND DIRECTOR INDEPENDENCE\n 83\nITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES 83\nPART IV 84\nITEM 15. EXHIBITS, FINANCIAL STATEMENT SCHEDULES 84\nITEM 16. FORM 10-K SUMMARY 85\n\n\n iii\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 5 of 18\n\n\nForward Looking Statements.\n\nThis Annual Report on Form 10-K includes forward-looking statements. All statements other than statements of historical facts contained in this\nAnnual Report on Form 10-K, including statements regarding our anticipated future clinical and regulatory milestone events, future financial\nposition, business strategy and plans and objectives of management for future operations, are forward-looking statements. The words \u201cbelieve,\u201d\n\u201cmay,\u201d \u201cestimate,\u201d \u201ccontinue,\u201d \u201canticipate,\u201d \u201cintend,\u201d \u201cexpect,\u201d \u201cshould,\u201d \u201cforecast,\u201d \u201cpotential,\u201d \u201cpredict,\u201d \u201ccould,\u201d \u201cwould,\u201d \u201cwill,\u201d \u201csuggest,\u201d\n\u201cplan\u201d and similar expressions, as they relate to us, are intended to identify forward-looking statements. Such forward-looking statements include,\nwithout limitation, statements regarding:\n\n \u25cf volatility in our stock price and in the markets in general\u037e\n\n \u25cf our ability to successfully conduct preclinical studies and clinical trials for our product candidates\u037e\n\n \u25cf our ability to raise additional capital on favorable terms and the impact of such activities on our stockholders and stock price\u037e\n\n \u25cf the impact of the COVID-19 outbreak and its effect on us\u037e\n\n \u25cf our ability to generate any revenue or to continue as a going concern\u037e\n\n \u25cf our ability to execute our research and development plan on time and on budget\u037e\n\n \u25cf our products candidates\u2019 ability to demonstrate efficacy or an acceptable safety profile\u037e\n\n \u25cf our ability to obtain the support of qualified scientific collaborators\u037e\n\n \u25cf our ability, whether alone or with commercial partners, to successfully commercialize any of our product candidates that may be approved\n for sale\u037e\n\n \u25cf our ability to identify and obtain additional product candidates\u037e\n\n \u25cf our reliance on third parties in non-clinical studies and clinical trials\u037e\n\n \u25cf our ability to defend against product liability claims\u037e\n\n \u25cf our ability to safeguard against security breaches\u037e\n\n \u25cf our ability to obtain and maintain sufficient intellectual property protection for our product candidates\u037e\n\n \u25cf our ability to comply with our intellectual property licensing agreements\u037e\n\n \u25cf our ability to defend against claims of intellectual property infringement\u037e\n\n \u25cf our ability to comply with the maintenance requirements of the government patent agencies\u037e\n\n \u25cf our ability to protect our intellectual property rights throughout the world\u037e\n\n \u25cf competition\u037e\n\n \u25cf the anticipated start dates, durations and completion dates of our ongoing and future clinical trials\u037e\n\n \u25cf the anticipated designs of our future clinical trials\u037e\n\n \u25cf our ability to attract and retain qualified employees\u037e\n\n \u25cf the impact of Fast Track designation on receipt of actual FDA approval\u037e\n\n \u25cf our anticipated future regulatory submissions and our ability to receive regulatory approvals to develop and market our product\n candidates, including any orphan drug or Fast Track designations\u037e and\n\n \u25cf our anticipated future cash position and ability to obtain funding for our operations.\n\nWe have based these forward-looking statements largely on our current expectations and projections about future events, including the responses\nwe expect from the U.S. Food and Drug Administration, (\u201cFDA\u201d), and other regulatory authorities and financial trends that we believe may affect\nour financial condition, results of operations, business strategy, preclinical and clinical trials, and financial needs. These forward-looking\nstatements are subject to a number of risks, uncertainties and assumptions including, without limitation, the risks described in \u201cRisk Factors\u201d in\nPart I, Item 1A of this Annual Report on Form 10-K. These risks are not exhaustive. Other sections of this Annual Report on Form 10-K include\nadditional factors which could adversely impact our business and financial performance. Moreover, we operate in a very competitive and rapidly\nchanging environment. New risk factors emerge from time to time and it is not possible for our management to predict all risk factors, nor can we\nassess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ\nmaterially from those contained in any forward-looking statements. You should not rely upon forward-looking statements as predictions of future\nevents. We cannot assure you that the events and circumstances reflected in the forward-looking statements will be achieved or occur and actual\nresults could differ materially from those projected in the forward-looking statements. Except as required by applicable laws including the securities\nlaws of the United States, we assume no obligation to update or supplement forward-looking statements.\n\nAs used in this Annual Report on Form 10-K, the terms \u201cwe,\u201d \u201cus,\u201d \u201cour,\u201d, \u201cCompany\u201d and \u201cAnavex\u201d mean Anavex Life Sciences Corp., unless the\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 6 of 18\n\ncontext clearly requires otherwise.\n\n\n iv\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 7 of 18\n\n\nPART I\n\nITEM 1. BUSINESS\n\nOverview and Strategy\n\nAnavex Life Sciences Corp. is a clinical stage biopharmaceutical company engaged in the development of differentiated therapeutics by applying\nprecision medicine to central nervous system (\u201cCNS\u201d) diseases with high unmet need. We analyze genomic data from clinical trials to identify\nbiomarkers, which we use in the analysis of our clinical trials.\n\nOur lead product candidate, ANAVEX\u00ae2-73, is being developed to treat Alzheimer\u2019s disease, Parkinson\u2019s disease and potentially other central\nnervous system diseases, including rare diseases, such as Rett syndrome, a rare severe neurological monogenic disorder caused by mutations in\nthe X-linked gene, methyl-CpG-binding protein 2 (\u201cMECP2\u201d).\n\nWe currently have two core programs and two seed programs. Our core programs are at various stages of clinical and preclinical development, in\nneurodegenerative and neurodevelopmental diseases.\n\nThe following table summarizes key information about our programs:\n\n\n\n\n* = Orphan Drug Designation by the FDA\u037e Dashed lines indicate planned clinical trials to-date\n\nAnavex has a portfolio of compounds varying in sigma-1 receptor (SIGMAR1) binding activities. The SIGMAR1 gene encodes the SIGMAR1\nprotein, which is an intracellular chaperone protein with important roles in cellular communication. SIGMAR1 is also involved in transcriptional\nregulation at the nuclear envelope and restores homeostasis and stimulates recovery of cell function when activated. In order to validate the ability\nof our compounds to activate quantitatively the SIGMAR1, we performed, in collaboration with Stanford University, a quantitative Positron\nEmission Tomography (PET) imaging scan in mice, which demonstrated a dose-dependent ANAVEX\u00ae2-73 target engagement or receptor\noccupancy with SIGMAR1 in the brain.\n\n\n 6\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 8 of 18\n\n\n\n\nSource: Reyes S et al., Sci Rep. 2021 Aug 25\u037e11(1):17150\n\nCellular Homeostasis\n\nMany diseases are possibly directly caused by chronic homeostatic imbalances or cellular stress of brain cells. In pediatric diseases, such as Rett\nsyndrome or infantile spasms, the chronic cellular stress is possibly caused by the presence of a constant genetic mutation. In neurodegenerative\ndiseases, such as Alzheimer\u2019s and Parkinson\u2019s diseases, chronic cellular stress is possibly caused by age-correlated buildup of cellular insult and\nhence chronic cellular stress. Specifically, defects in homeostasis of protein or ribonucleic acid (\u201cRNA\u201d) lead to the death of neurons and\ndysfunction of the nervous system. The spreading of protein aggregates resulting in a proteinopathy, a characteristic found in Alzheimer\u2019s and\nParkinson\u2019s diseases that results from disorders of protein synthesis, trafficking, folding, processing or degradation in cells. The clearance of\nmacromolecules in the brain is particularly susceptible to imbalances that result in aggregation and degeneration in nerve cells. For example,\nAlzheimer\u2019s disease pathology is characterized by the presence of amyloid plaques, and neurofibrillary tangles, which are aggregates of\nhyperphosphorylated Tau protein that are a marker of other diseases known as tauopathies as well as inflammation of microglia. With the SIGMAR1\nactivation through SIGMAR1 agonists like ANAVEX\u00ae2-73, our approach is to restore cellular balance (i.e. homeostasis). Therapies that correct\ndefects in cellular homeostasis might have the potential to halt or delay neurodevelopmental and neurodegenerative disease progression.\n\nANAVEX\u00ae2-73-specific Biomarkers\n\nAs part of some of our clinical trials, we have incorporated a genomic analysis to better understand potential populations for whom our clinical\nprograms might benefit. In our clinical trials, a full genomic analysis of Alzheimer\u2019s disease patients treated with ANAVEX\u00ae2-73 has helped us\nidentify actionable genetic variants. A significant impact of the genomic biomarkers SIGMAR1, the direct target of ANAVEX\u00ae2-73 and COMT, a\ngene involved in memory function, on the drug response level was identified, leading to an early ANAVEX\u00ae2-73-specific biomarker hypothesis. We\nbelieve that excluding patients with SIGMAR1 identified biomarker variant (approximately 10%-20% of the population) in prospective studies\nwould identify approximately 80%-90% patients that would display clinically significant improved functional and cognitive scores. The consistency\nbetween the identified DNA and RNA data related to ANAVEX\u00ae2-73, which are considered independent of Alzheimer\u2019s disease pathology, as well\nas multiple endpoints and time-points, provides support for the potential precision medicine clinical development of ANAVEX\u00ae2-73 by using\ngenetic biomarkers identified within the trial population itself to target patients who are most likely to respond to ANAVEX\u00ae2-73 treatment. We may\nin the future utilize such an approach in Alzheimer\u2019s disease as well as indications like Parkinson\u2019s disease dementia or Rett syndrome in which\nANAVEX\u00ae2-73 is currently being studied.\n\n\n 7\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 9 of 18\n\n\n\nClinical Trials Overview\n\nAlzheimer\u2019s Disease\n\nIn November 2016, we completed a Phase 2a clinical trial, consisting of Part A and Part B, which lasted a total of 57 weeks, for ANAVEX\u00ae2-73 in\nmild-to-moderate Alzheimer\u2019s patients. This open-label, randomized trial in Australia met both primary and secondary endpoints and was designed\nto assess the safety and exploratory efficacy of ANAVEX\u00ae2-73 in 32 patients. ANAVEX\u00ae2-73 targets sigma-1 and muscarinic receptors, which have\nbeen shown in preclinical studies to reduce stress levels in the brain believed to restore cellular homeostasis and to reverse the pathological\nhallmarks observed in Alzheimer\u2019s disease. In October 2017, we presented positive pharmacokinetic (\u201cPK\u201d) and pharmacodynamic (\u201cPD\u201d) data from\nthe Phase 2a clinical trial, which established a concentration-effect relationship between ANAVEX\u00ae2-73 and trial measurements. These measures\nobtained from all patients who participated in the entire 57 weeks include exploratory cognitive and functional scores as well as biomarker signals of\nbrain activity. Additionally, the clinical trial appeared to show that ANAVEX\u00ae2-73 activity was enhanced by its active metabolite (ANAVEX19-144),\nwhich also targets the SIGMAR1 receptor and has a half-life approximately twice as long as the parent molecule.\n\nTwo consecutive trial extensions for the Phase 2a trial have allowed participants who completed the 52-week Part B of the trial to continue taking\nANAVEX\u00ae2-73, providing us an opportunity to gather extended safety data for a cumulative time period of five years. In August 2020, patients\ncompleting these Phase 2a trial extensions were granted continued access to treatment with ANAVEX\u00ae2-73 through the Australian Government\nDepartment of Health - Therapeutic Goods Administration\u2019s compassionate use Special Access Scheme.\n\nA larger Phase 2b/3 double-blind, placebo-controlled trial of ANAVEX\u00ae2-73 in Alzheimer\u2019s disease commenced in August 2018. The Phase 2b/3 trial\nenrolled 509 patients for 48 weeks, randomized 1:1:1 to two different ANAVEX\u00ae2-73 doses or placebo. The trial commenced in Australia\u037e and during\nfiscal 2020 additional regions were added in the United Kingdom, The Netherlands, Germany and Canada. Primary and secondary endpoints will\nassess safety and both cognitive and functional efficacy, measured through Alzheimer\u2019s Disease Assessment Scale - Cognition (ADAS-Cog),\nADCS-ADL and Clinical Dementia Rating - Sum of Boxes for cognition and function (CDR-SB). In addition to the primary endpoints, the\nANAVEX\u00ae2-73 Phase 2b/3 trial design incorporated pre-specified statistical analyses related to potential genomic precision medicine biomarkers\nidentified in the ANAVEX\u00ae2-73 Phase 2a clinical trial. The trial completed enrollment in June 2021, exceeding the 450 patient enrollment target at 52\nsites across Canada, Europe and Australia.\n\nIn October 2019, we initiated a long-term open label extension study of ANAVEX\u00ae2-73, entitled the ATTENTION-AD trial, for patients who have\ncompleted the 48-week Phase 2b/3 placebo-controlled trial referenced above. This trial extension for an additional two years gives patients the\nopportunity to continue their treatment. Upon request by patients, caretakers and investigators, this extension trial was extended by one additional\nyear.\n\nRett Syndrome\n\nIn February 2016, we presented positive preclinical data for ANAVEX\u00ae2-73 in Rett syndrome, a rare neurodevelopmental disease. The data\ndemonstrated dose related and significant improvements in an array of behavioral and gait paradigms in a mouse model with a MECP2-null mutation\nthat causes neurological symptoms that mimic Rett syndrome. The study was funded by the International Rett Syndrome Foundation\n(\u201cRettsyndrome.org\u201d). In January 2017, we were awarded a financial grant from Rettsyndrome.org of a minimum of $0.6 million to cover some of the\ncosts of a multicenter Phase 2 clinical trial of ANAVEX\u00ae2-73 for the treatment of Rett syndrome. This award was received in quarterly instalments\nwhich commenced during fiscal 2018.\n\n\n 8\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 10 of 18\n\n\n\nIn March 2019, we commenced the first Phase 2 clinical trial in a planned Rett syndrome program of ANAVEX\u00ae2-73 for the treatment of Rett\nsyndrome. The clinical trials are being conducted in a range of patient age demographics and geographic regions, utilizing an oral liquid once-daily\nformulation of ANAVEX\u00ae2-73.\n\nThe first Phase 2 trial, (ANAVEX\u00ae2-73-RS-001), which took place in the United States, was completed in December 2020. This trial was a\nrandomized double-blind, placebo-controlled safety, tolerability, PK and efficacy trial of oral liquid ANAVEX\u00ae2-73 formulation in 25 adult female\npatients with Rett syndrome over a 7-week treatment period including ANAVEX\u00ae2-73-specific genomic precision medicine biomarkers. The primary\nendpoint of the trial was safety. The dosing of 5 mg ANAVEX\u00ae2-73 was well-tolerated and demonstrated dose-proportional PK. All secondary\nefficacy endpoints of the trial showed statistically significant and clinically meaningful response in the Rett Syndrome Behaviour Questionnaire\n(\u201cRSBQ\u201d) response, when compared to placebo, in the intent to treat (\u201cITT\u201d) cohort (all participants, p = 0.011). 66.7% of ANAVEX\u00ae2-73 treated\nsubjects showed a statistically significant improvement in RSBQ response as compared to 10% of the subjects on placebo in the ITT cohort (all\nparticipants, p = 0.011). ANAVEX\u00ae2-73 treatment resulted in a sustained improvement in Clinical Global Impression Improvement (\u201cCGI-I\u201d) response\nthroughout the 7-week clinical trial, when compared to placebo in the ITT cohort (all participants, p = 0.014). Consistent with previous ANAVEX\u00ae2-\n73 clinical trials, patients carrying the common form of the SIGMAR1 gene treated with ANAVEX\u00ae2-73 experienced stronger improvements in the\nprespecified efficacy endpoints.\n\nThe second, international trial of ANAVEX\u00ae2-73 for the treatment of Rett syndrome, called the AVATAR trial, commenced in June 2019. This trial\ntook place in Australia and the United Kingdom using a higher dose than the U.S. based Phase 2 trial for Rett syndrome. The trial was a Phase 3\nrandomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of ANAVEX\u00ae2-73 in 33 adult patients over a 7-week treatment\nperiod including ANAVEX\u00ae2-73 specific precision medicine biomarkers. Based upon the input from the successful U.S. Phase 2 Rett syndrome trial\n(ANAVEX\u00ae2-73-RS-001), we updated the endpoints for the AVATAR trial (ANAVEX\u00ae2-73-RS-002) to appropriately assess the clinically meaningful\noutcome following International Conference on Harmonization (ICH) guidelines. These updates were approved by the respective regulatory\nauthorities in the U.K. and in Australia, respectively, where the AVATAR trial was conducted.\n\nThe data from the AVATAR trial was released in February 2022. The clinical trial met all primary and secondary efficacy and safety endpoints, with\nconsistent improvements in primary efficacy endpoint, RSBQ response (p = 0.037), and secondary efficacy endpoints, ADAMS (p = 0.010) and CGI-\nI (p = 0.037) response. Efficacy endpoints demonstrated statistically significant and clinically meaningful reductions in Rett syndrome symptoms.\nConvenient once daily oral liquid doses of up to 30 mg of ANAVEX\u00ae2-73 were also well tolerated with good medication compliance. All patients\nwho participated in the trial were eligible to receive ANAVEX\u00ae2-73 under a voluntary open label extension protocol.\n\nIn July 2020, we commenced the third trial of ANAVEX\u00ae2-73 for the treatment of Rett syndrome, called the EXCELLENCE trial. This Phase 2/3 trial in\npediatric patients with Rett syndrome includes trial sites in Australia, the United Kingdom, and Canada, and will evaluate the safety and efficacy of\nANAVEX\u00ae2-73 in approximately 84 pediatric patients, aged 5 to 18, over a 12-week treatment period incorporating ANAVEX\u00ae2-73 specific precision\nmedicine biomarkers. All patients who participate in the trial will be eligible to receive ANAVEX\u00ae2-73 under a voluntary open label extension\nprotocol, which is currently ongoing.\n\nParkinson\u2019s Disease\n\nIn September 2016, we presented positive preclinical data for ANAVEX\u00ae2-73 in an animal model of Parkinson\u2019s disease, which demonstrated\nsignificant improvements on behavioral, histopathological, and neuroinflammatory endpoints. The study was funded by the Michael J. Fox\nFoundation. Additional data announced in October 2017 indicated that ANAVEX\u00ae2-73 induced robust neurorestoration in experimental\nParkinsonism. We believe that the encouraging results we have gathered in this preclinical model, coupled with the favorable profile of this product\ncandidate in the Alzheimer\u2019s disease trial, support the notion that ANAVEX\u00ae2-73 has the potential to treat Parkinson\u2019s disease dementia.\n\n\n 9\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 11 of 18\n\n\n\n SIGNATURES\nPursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed\non its behalf by the undersigned thereunto duly authorized.\n\nDate: November 28, 2022 ANAVEX LIFE SCIENCES CORP.\n\n By: /s/ Christopher Missling, PhD\n Name Christopher Missling, PhD\n :\n Title: Chief Executive Officer (Principal Executive\n Officer)\n\nPursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf of the\nregistrant and in the capacities and on the dates indicated.\n\n Signatures Title(s) Date\n\n November 28, 2022\n/s/ Christopher Missling, PhD\nChristopher Missling, PhD Chief Executive Officer (Principal Executive Officer)\n\n/s/ Sandra Boenisch November 28, 2022\n\nSandra Boenisch, CPA, CGA Principal Financial Officer and Treasurer (Principal Accounting\n Officer)\n\n/s/ Athanasios Skarpelos November 28, 2022\nAthanasios Skarpelos Director\n\n/s/ Claus van der Velden, PhD November 28, 2022\nClaus van der Velden, PhD Director\n\n/s/ Steffen Thomas, PhD November 28, 2022\nSteffen Thomas, PhD Director\n\n/s/ Peter Donhauser, D.O. November 28, 2022\nPeter Donhauser, D.O. Director\n\n/s/ Jiong Ma, PhD November 28, 2022\nJiong Ma, PhD Director\n\n 86\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 12 of 18\n\n\n\n EXHIBIT 4.1\n\n DESCRIPTION OF THE REGISTRANT\u2019S SECURITIES REGISTERED PURSUANT TO SECTION 12 OF THE SECURITIES EXCHANGE ACT\n OF 1934\n\nAnavex Life Sciences Corp (the \u201cCompany\u201d) has one class of securities registered under Section 12 of the Securities Exchange Act of 1934, as\namended: the Company\u2019s common stock, par value $0.001 per share (the \u201cCommon Stock\u201d)\n\n Description of Common Stock\n\nThe following summary description sets forth some of the general terms and provisions of the Common Stock. Because this is a summary\ndescription, it does not contain all of the information that may be important to you. For a more detailed description of the Company\u2019s Common\nStock, you should refer to the provisions of the Company\u2019s Articles of Incorporation, as amended (the \u201cCharter\u201d) and the Company\u2019s Bylaws (the\n\u201cBylaws\u201d), each of which is an exhibit to the Annual Report on Form 10-K to which this description is an exhibit.\n\nAuthorized Shares\n\nWe are authorized to issue 200,000,000 shares of Common Stock with a par value of $0.001.\n\nVoting Rights\n\nThe outstanding shares of our Common Stock are fully paid and non-assessable. The holders of Common Stock are entitled to one vote per share\nfor the election of directors and with respect to all other matters submitted to a vote of stockholders.\n\nLiquidation, Dissolution or Similar Rights\n\nUpon liquidation, dissolution or winding up of the corporation, the holders of Common Stock are entitled to share ratably in all net assets available\nfor distribution to stockholders after payment to creditors. The Common Stock is not convertible or redeemable and has no preemptive,\nsubscription or conversion rights. There are no conversion, redemption, sinking fund or similar provisions regarding the Common Stock. Each\noutstanding share of Common Stock is entitled to one vote on all matters submitted to a vote of stockholders. There are no cumulative voting\nrights.\n\nDividend Rights\n\nEach stockholder is entitled to receive the dividends as may be declared by our board of directors out of funds legally available for dividends and,\nin the event of liquidation, to share pro rata in any distribution of our assets after payment of liabilities. Our board of directors is not obligated to\ndeclare a dividend. Any future dividends will be subject to the discretion of our board of directors and will depend upon, among other things,\nfuture earnings, the operating and financial condition of our Company, its capital requirements, general business conditions and other pertinent\nfactors. It is not anticipated that dividends will be paid in the foreseeable future.\n\nNevada Anti-Takeover Law and Charter and Bylaws Provisions\n\nNevada Revised Statutes sections 78.378 to 78.3793 provide state regulation over the acquisition of a controlling interest in certain Nevada\ncorporations unless the articles of incorporation or bylaws of the corporation provide that the provisions of these sections do not apply. The\nstatute creates a number of restrictions on the ability of a person or entity to acquire control of a Nevada company by setting down certain rules of\nconduct and voting restrictions in any acquisition attempt, among other things. Our bylaws provide that these sections do not apply.\n\nThere are no provisions in our articles of incorporation or our bylaws that would delay, defer or prevent a change in control of our Company.\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 13 of 18\n\n\nIndemnification Of Directors And Executive Officers And Limitation On Liability.\n\nOur Bylaws provide that any person who was or is a party or is threatened to be made a party to any threatened, pending or completed action, suit\nor proceeding, whether civil, criminal, administrative or investigative, by reason of the fact that such person is or was a director, officer, employee or\nagent of the Company (or is or was serving at the request of the Company as a director, officer, employee or agent of another corporation,\npartnership, joint venture, trust or other enterprise) shall be indemnified and held harmless by the Company to the fullest extent permitted by\nNevada law against expenses including attorneys\u2019 fees, judgments, fines and amounts paid in settlement actually and reasonably incurred by such\nperson in connection with such proceeding.\n\nThe Bylaws also provide that the expenses of officers and directors incurred in defending a civil or criminal action, suit or proceeding must be paid\nby the Company as they are incurred and in advance of the final disposition of the action, suit or proceeding upon receipt of an undertaking by or\non behalf of the director or officer to repay the amount if it is ultimately determined by a court of competent jurisdiction that he is not entitled to be\nindemnified by the Company. Such right of indemnification shall be a contract right which may be enforced in any manner desired by such person.\nSuch right of indemnification shall not be exclusive of any other right which such directors, officers or representatives may have or hereafter\nacquire and, without limiting the generality of such statement, they shall be entitled to their respective rights of indemnification under any bylaw,\nagreement, vote of stockholders, provision of law or otherwise, as well as their rights under the Bylaws.\n\nThe Bylaws provide that the Board of Directors may cause the Company to purchase and maintain insurance on behalf of any person who is or was\na director or officer of the Company, or is or was serving at the request of the Company as a director or officer of another Company, or as its\nrepresentative in a partnership, joint venture, trust or other enterprise against any liability asserted against such person and incurred in any such\ncapacity or arising out of such status, whether or not the Company would have the power to indemnify such person.\n\nNevada Revised Statutes 78.751 and 78.7502 have provisions that provide for discretionary and mandatory indemnification of officers, directors,\nemployees, and agents of a corporation. Under these provisions, such persons may be indemnified by a corporation against expenses, including\nattorney\u2019s fees, judgment, fines and amounts paid in settlement, actually and reasonably incurred by him in connection with the action, suit or\nproceeding, if he acted in good faith and in a manner which he reasonably believed to be in or not opposed to the best interests of the corporation\nand with respect to any criminal action or proceeding had no reasonable cause to believe his conduct was unlawful.\n\nTo the extent that a director, officer, employee or agent has been successful on the merits or otherwise in defense of any action, suit or proceeding,\nor in defense of any claim, issue or matter, the Nevada Revised Statues provide that he must be indemnified by the Company against expenses,\nincluding attorney\u2019s fees, actually and reasonably incurred by him in connection with the defense.\n\nSection 78.7502 of the Nevada Revised Statues also provides that any discretionary indemnification, unless ordered by a court or advanced by the\nCompany, may be made only as authorized in the specific case upon a determination that indemnification of the director, officer, employee or agent\nis proper in the circumstances.\n\nThe determination must be made:\n\n \u25cf By the stockholders\u037e\n\n \u25cf By the Company\u2019s Board of Directors by majority vote of a quorum consisting of directors who were not parties to that act, suit or\n proceeding\u037e\n\n \u25cf If a majority vote of a quorum consisting of directors who were not parties to the act, suit or proceeding cannot be obtained, by\n independent legal counsel in a written opinion\u037e or\n\n \u25cf If a quorum consisting of directors who were not parties to the act, suit or proceeding cannot be obtained, by independent legal counsel in\n a written opinion.\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 14 of 18\n\n\n\n\n EXHIBIT 23.1\n\n CONSENT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM\n\nWe have issued our reports dated November 28, 2022, with respect to the consolidated financial statements and internal control over financial\nreporting included in the Annual Report of Anavex Life Sciences Corp. on Form 10-K for the year ended September 30, 2022. We consent to the\nincorporation by reference of said reports in the Registration Statements of Anavex Life Sciences Corp. on Forms S-3 (No. 333-218292, and No. 333-\n259788) and Forms S-8 (No. 333-219934, No. 333-255166 and No. 333-265537)\n\n/s/ GRANT THORNTON LLP\n\nHartford, CT\nNovember 28, 2022\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 15 of 18\n\n\n\n\n EXHIBIT 23.2\n Consent of Independent Registered Public Accounting Firm\n\nAnavex Life Sciences Corp.\nNew York, New York\n\nWe hereby consent to the incorporation by reference in the Registration Statements on Form S-3 (No. 333-218292 and No. 333-259788) and Form S-8\n(No. 333-219934, No. 333-255166 and No. 333-265537) of Anavex Life Sciences Corp. and subsidiaries of our reports dated November 24, 2021,\nrelating to the consolidated financial statements and the effectiveness of Anavex Life Science Corp.\u2019s internal control over financial reporting,\nwhich appear in this Annual Report on Form 10-K.\n\n/s/ BDO USA, LLP\nNew York, New York\n\nNovember 28, 2022\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 16 of 18\n\n\n\n\n EXHIBIT 31.1\n\n CERTIFICATION\n\nI, Christopher Missling, certify that:\n\n1. I have reviewed this Annual Report on Form 10-K of Anavex Life Sciences Corp.\u037e\n\n2. Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make\n the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered\n by this report\u037e\n\n3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects\n the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report\u037e\n\n4. The registrant\u2019s other certifying officer(s) and I are responsible for establishing and maintaining disclosure controls and procedures (as\n defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-\n 15(f) and 15d-15(f)) for the registrant and have:\n\n a) Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our\n supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by\n others within those entities, particularly during the period in which this report is being prepared\u037e\n\n b) Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our\n supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements\n for external purposes in accordance with generally accepted accounting principles\u037e\n\n c) Evaluated the effectiveness of the registrant\u2019s disclosure controls and procedures and presented in this report our conclusions about the\n effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation\u037e\n and\n\n d) Disclosed in this report any change in the registrant\u2019s internal control over financial reporting that occurred during the registrant\u2019s most\n recent fiscal quarter (the registrant\u2019s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably\n likely to materially affect, the registrant\u2019s internal control over financial reporting\u037e and\n\n5. The registrant\u2019s other certifying officer(s) and I have disclosed, based on our most recent evaluation of internal control over financial\n reporting, to the registrant\u2019s auditors and the audit committee of the registrant\u2019s board of directors (or persons performing the equivalent\n functions):\n\n a) All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are\n reasonably likely to adversely affect the registrant\u2019s ability to record, process, summarize and report financial information\u037e and\n\n b) Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant\u2019s internal\n control over financial reporting.\n\nDate: November 28, 2022\n\n/s/ Christopher Missling\n\nChristopher Missling, PhD\nChief Executive Officer, President,\nSecretary\n(Principal Executive Officer)\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 17 of 18\n\n\n\n\n EXHIBIT 31.2\n\n CERTIFICATION\n\nI, Sandra Boenisch, certify that:\n\n1. I have reviewed this Annual Report on Form 10-K of Anavex Life Sciences Corp.\u037e\n\n2. Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make\n the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered\n by this report\u037e\n\n3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects\n the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report\u037e\n\n4. The registrant\u2019s other certifying officer(s) and I are responsible for establishing and maintaining disclosure controls and procedures (as\n defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-\n 15(f) and 15d-15(f)) for the registrant and have:\n\n a) Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our\n supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by\n others within those entities, particularly during the period in which this report is being prepared\u037e\n\n b) Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our\n supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements\n for external purposes in accordance with generally accepted accounting principles\u037e\n\n c) Evaluated the effectiveness of the registrant\u2019s disclosure controls and procedures and presented in this report our conclusions about the\n effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation\u037e\n and\n\n d) Disclosed in this report any change in the registrant\u2019s internal control over financial reporting that occurred during the registrant\u2019s most\n recent fiscal quarter (the registrant\u2019s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably\n likely to materially affect, the registrant\u2019s internal control over financial reporting\u037e and\n\n5. The registrant\u2019s other certifying officer(s) and I have disclosed, based on our most recent evaluation of internal control over financial\n reporting, to the registrant\u2019s auditors and the audit committee of the registrant\u2019s board of directors (or persons performing the equivalent\n functions):\n\n a) All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are\n reasonably likely to adversely affect the registrant\u2019s ability to record, process, summarize and report financial information\u037e and\n\n b) Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant\u2019s internal\n control over financial reporting.\n\nDate: November 28, 2022\n\n/s/ Sandra Boenisch\n\nSandra Boenisch, CPA, CGA\nPrincipal Financial Officer, Treasurer\n(Principal Financial and Accounting\nOfficer)\n\f Case 1:24-cv-03529-CM Document 23-2 Filed 08/23/24 Page 18 of 18\n\n\n\n\n EXHIBIT 32.1\n\n\n CERTIFICATION\n\nIn connection with the Annual Report of Anavex Life Sciences Corp. (the \u201cCompany\u201d) on Form 10-K for the fiscal year ending September 30, 2022\nas filed with the Securities and Exchange Commission (the \u201cReport\u201d), the undersigned, in the capacities and on the date indicated below, hereby\ncertify, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, that to the best of our\nknowledge:\n\n(1) The Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934, and\n(2) The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the\n Company.\n\n\nDate: November 28, 2022\n\n/s/ Christopher Missling\nChristopher Missling, PhD\nChief Executive Officer, President, Secretary (Principal\nExecutive Officer)\n\n/s/ Sandra Boenisch\n\nSandra Boenisch, CPA, CGA\nPrincipal Financial Officer, Treasurer\n(Principal Financial and Accounting\nOfficer)\n\n The foregoing certification is being furnished solely to accompany the Report pursuant to 18 U.S.C. \u00a7 1350, and is not being filed for purposes\nof Section 18 of the Securities Exchange Act of 1934, as amended, and is not to be incorporated by reference into any filing of the Company,\nwhether made before or after the date hereof, regardless of any general incorporation language in such filing. A signed original of this written\nstatement required by Section 906, or other document authenticating, acknowledging, or otherwise adopting the signature that appears in typed\nform within the electronic version of this written statement required by Section 906, has been provided to the Company and will be retained by the\nCompany and furnished to the Securities and Exchange Commission or its staff upon request.\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:17.100834-07:00","document_number":"23","attachment_number":2,"pacer_doc_id":"127036039502","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Form 10-K","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579226/","id":409579226,"tags":[],"absolute_url":"/docket/68511120/23/3/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.582321-07:00","date_modified":"2024-08-27T02:13:03.507779-07:00","sha1":"accc7e6594cf4f2826c4f2c13a4f7eb200da85b0","page_count":7,"file_size":808401,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.3.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.3.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 1 of 7\n\f Case 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 2 of 7\nJun 21, 2021\n\n\nAnavex Life Sciences Announces ANAVEX\u00ae2-73\nBiomarker Correlated with Efficacy Endpoint in\nTrial\nANAVEX\u00ae2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker that significantly\n correlated with improvements in the two primary clinical efficacy endpoints RSBQ (p = 0.035) and CGI-I (p = 0.029)\n\n\n Data strengthens milestone to advance regulatory approval pathway for adult patients with Rett syndrome and continued\n development in other autism spectrum disorders\n\n\n\n\nNEW YORK \u2013 June 21, 2021\nAnavex Life Sciences Corp. (\u201cAnavex\u201d or the \u201cCompany\u201d) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company\ndeveloping differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders\nincluding Alzheimer\u2019s disease, Parkinson\u2019s disease, Rett syndrome and other central nervous system (CNS) disorders,\ntoday reported predictive biomarker of response established with SIGMAR1 mRNA expression correlates significantly\nwith responses in primary clinical efficacy endpoints from the U.S. Phase 2 randomized, double-blind, placebo-controlled\ntrial of ANAVEX\u00ae2-73 (blarcamesine) in adult female patients with Rett syndrome.\n\n\nANAVEX\u00ae2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the\nrestoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and\n\f Case 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 3 of 7\npromoting neuroplasticity. [1] Recent independent findings strengthen the understanding of the beneficial effect of\nSIGMAR1 activation as compensatory mechanism to chronic CNS diseases. [2]\n\n\nRett syndrome is a chronic CNS disease caused by a spontaneous mutation of one gene, MECP2. This study\ndemonstrates for the first-time that a biomarker correlates with clinical efficacy in Rett syndrome. ANAVEX\u00ae2-73\ntreatment resulted in increases in the mRNA expression of SIGMAR1, the gene coding for the receptor targeted by\nANAVEX\u00ae2-73, which correlated with clinical efficacy as measured by both primary efficacy endpoints (ITT population),\nnamely RSBQ (p = 0.035) and CGI-I (p = 0.029).\n\n\nIn addition, prespecified patients with WT SIGMAR1 in the clinical trial demonstrated a clinically meaningful and\nstatistically significant 14.5-point (p = 0.009) improvement over placebo in the RSBQ total score, the trial\u2019s key efficacy\nendpoint. This magnitude of the improvement with ANAVEX\u00ae2-73 compares favorably to published data currently in\nclinical development, which reported an average difference of 4.4 points in RSBQ total score versus placebo, despite an\nadvantage of higher dose and lower age compared to ANAVEX\u00ae2-73-RS-001 trial. [3]\n\n\nThe RSBQ demonstrated balanced improvements across all the instrument\u2019s subscales during the trial period of 7\nweeks, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior,\nfear/anxiety, walking/standing.\n\n\nThe Anxiety, Depression, and Mood Scale (ADAMS), which is a measure of anxiety and mood symptoms in individuals\nwith intellectual disability,[4] has been clinically validated for use in Rett syndrome[5] and in Fragile X syndrome,[6]\ndemonstrated clinically meaningful and statistically significant 12.9-point (p = 0.005) improvement for ANAVEX\u00ae2-73\ntreated adult patients with Rett syndrome vs placebo in prespecified patients with WT SIGMAR1.\n\n\nThe ADAMS also demonstrated balanced improvements across all different subscales during the trial period of 7 weeks,\nincluding manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, obsessive compulsive\nbehavior.\n\n\n\u201cThe biomarker-driven clinical evidence is very exciting and opens the possibility of successful treatment for both adults\nand children with Rett syndrome and early interventions for modifying the course of the disease,\u201d commented Walter E.\nKaufmann, MD, Principal Investigator and Chief Medical Officer of Anavex. \u201cThe outcome of this trial is very promising in\nterms of both safety and clinical improvement. Despite the challenges of the older age of the cohort (patients were on\naverage 24 years of age) and the relatively low dose (5 mg daily), ANAVEX\u00ae2-73 demonstrated clinically meaningful\nimprovements in outcome measures evaluating multiple impairments, which are supported by correlations with\nobjective biomarkers.\u201d\n\n\nWith this convincing biomarker correlating efficacy data of U.S. Phase 2 (ANAVEX\u00ae2-73-RS-001)[7] study in adult\npatients with Rett syndrome, Anavex is planning to meet with the FDA to discuss the approval pathway. There are no\nFDA-approved drugs for Rett syndrome. ANAVEX\u00ae2-73 has Fast Track designation, Rare Pediatric Disease designation\nand Orphan Drug designation from the FDA for the treatment of Rett syndrome and may be considered for accelerated\napproval. The study was supported by the Rettsyndrome.org Foundation.\n\f Case 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 4 of 7\nANAVEX\u00ae2-73 is currently being evaluated for Rett syndrome in two other ongoing late-stage placebo-controlled\nclinical studies: The AVATAR trial in adult Rett syndrome (ANAVEX\u00ae2-73-RS-002)[8] and the EXCELLENCE pediatric\nRett syndrome trial (ANAVEX\u00ae2-73-RS-003)[9].\n\n\n\u201cThese are strong and consistent data demonstrating biomarker-correlated rapid and clinically meaningful\nimprovements in key measures of Rett syndrome symptoms in the ANAVEX\u00ae2-73 treatment group compared to\nplacebo,\u201d said Christopher U. Missling, PhD, President & Chief Executive Officer of Anavex. \u201cOur team is dedicated to\nprovide for this urgent unmet need of patients with Rett syndrome, and we believe our ANAVEX\u00ae2-73 Rett syndrome\nprogram sets us on a course to potentially offer a new, unique and mechanistically differentiated treatment option also\nfor other diseases associated with autism spectrum disorder.\u201d\n\n\nAnavex Life Sciences\u2019 product portfolio platform includes small molecule drug lead candidate ANAVEX\u00ae2-73 for the\ntreatment of Alzheimer\u2019s disease, Parkinson\u2019s disease and Rett syndrome and ANAVEX\u00ae3-71 for frontotemporal\ndementia.\n\n\nAbout Rett Syndrome\nRett syndrome is a devastating, non-inherited genetic post-natal progressive neurodevelopmental disorder that occurs\nalmost exclusively in girls and leads to severe impairments, affecting nearly every aspect of the child\u2019s life: their ability to\nspeak, walk, eat and easily breathe. The hallmark of Rett syndrome is near constant repetitive hand movements while\nawake. The disease is characterized by normal early growth and development (6 to 18 months) followed by a slowing of\ndevelopment, loss of purposeful use of the hands, distinctive hand movements, autistic features, slowed brain and head\ngrowth, ataxia, seizures, and intellectual disability.\n\n\nRett syndrome is caused by mutations in the MECP2 gene and strikes all racial and ethnic groups. The disease occurs\nworldwide in approximately one in every 10,000 to 15,000 live births. The population of patients with Rett syndrome is\nestimated to be approximately 11,000 patients in the U.S. There is currently no cure for Rett syndrome.\n\n\nAbout ANAVEX\u00ae2-73-RS-001 Clinical Study (NCT03758924)\nThe Phase 2 trial is a randomized double-blind, placebo-controlled safety, tolerability, pharmacokinetic and efficacy\nstudy of oral liquid ANAVEX\u00ae2-73 to treat Rett syndrome in a total of 31 adult patients with Rett syndrome over a 7-\nweeks treatment period (End of Trial, EOT) were evaluated incorporating precision medicine biomarkers. Preceding the\nplacebo-controlled randomization of 25 patients (Part B), a 6-patient cohort (Part A) underwent a 7-weeks\npharmacokinetic (PK) assessment with safety, tolerability, pharmacokinetic and efficacy evaluation of ANAVEX\u00ae2-73.\nAll patients who participated in the study were eligible to receive ANAVEX\u00ae2-73 under an open label extension\nprotocol.\nThe primary endpoint of the trial was safety. The convenient oral liquid once-daily dosing of 5 mg ANAVEX\u00ae2-73 was\nwell-tolerated and demonstrated dose-proportional PK (pharmacokinetics). Adverse events related to study drug were\nsimilar between ANAVEX\u00ae2-73 (13.3%) and placebo (10%), with no reported serious adverse events (SAEs). The safety\nprofile of ANAVEX\u00ae2-73 in this trial is consistent with prior clinical trial data.\n\n\nAll secondary efficacy endpoints of the trial showed statistically significant and clinically meaningful sustained\nimprovements for ANAVEX\u00ae2-73 compared to placebo, consisting of the Rett Syndrome Behaviour Questionnaire\n(RSBQ) (p = 0.048) and the Clinical Global Impression Improvement Scale (CGI-I) score (p = 0.014) in the intent-to-treat\n\f Case 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 5 of 7\n(ITT) population (n = 25). Statistically significant differences in patient symptoms between the active and placebo groups\noccurred as early as 4 weeks following the initiation of ANAVEX\u00ae2-73 administration.\n\n\nAbout Rettsyndrome.org\nRettsyndrome.org is the most comprehensive nonprofit organization dedicated to accelerating research of treatments\nand a cure for Rett syndrome and related disorders while providing information and family empowerment. As the\nworld\u2019s leading private funder of Rett syndrome research, Rettsyndrome.org has funded over $40M in high-quality,\npeer-reviewed research grants and programs to date. The organization hosts the largest global gathering of Rett\nresearchers and clinicians to establish research direction for the future. Rettsyndrome.org, a 501(c)(3) organization, has\nearned Charity Navigator\u2019s most prestigious 4 star rating year after year. To learn more about our work and Rett\nsyndrome, visit www.rettsyndrome.org or call (800) 818-7388 (RETT).\n\n\nAbout Anavex Life Sciences Corp.\nAnavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the\ndevelopment of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders\nincluding Alzheimer\u2019s disease, Parkinson\u2019s disease, Rett syndrome and other central nervous system (CNS) diseases,\npain and various types of cancer. Anavex\u2019s lead drug candidate, ANAVEX\u00ae2-73 (blarcamesine), successfully completed a\nPhase 2a clinical trial for Alzheimer\u2019s disease and recently a Phase 2 proof-of-concept study in Parkinson\u2019s disease\ndementia and a Phase 2 study in adult patients with Rett syndrome. ANAVEX\u00ae2-73 is an orally available drug candidate\nthat restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its\npotential to halt and/or reverse the course of Alzheimer\u2019s disease. ANAVEX\u00ae2-73 also exhibited anticonvulsant, anti-\namnesic, neuroprotective and anti-depressant properties in animal models, indicating its potential to treat additional\nCNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson\u2019s Research previously awarded Anavex a\nresearch grant, which fully funded a preclinical study to develop ANAVEX\u00ae2-73 for the treatment of Parkinson\u2019s\ndisease. ANAVEX\u00ae3-71, which targets sigma-1 and muscarinic receptors, is a promising clinical stage drug candidate\ndemonstrating disease-modifying activity against the major hallmarks of Alzheimer\u2019s disease in transgenic (3xTg-AD)\nmice, including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX\u00ae3-71 has shown beneficial\neffects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You\ncan also connect with the company on Twitter, Facebook, Instagram and LinkedIn.\n\n\nForward-Looking Statements\nStatements in this press release that are not strictly historical in nature are forward-looking statements. These\nstatements are only predictions based on current information and expectations and involve a number of risks and\nuncertainties. Actual events or results may differ materially from those projected in any of such statements due to\nvarious factors, including the risks set forth in the Company\u2019s most recent Annual Report on Form 10-K filed with the\nSEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the\ndate hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life\nSciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after\nthe date hereof.\n\n\nFor Further Information:\nAnavex Life Sciences Corp.\nResearch & Business Development\nToll-free: 1-844-689-3939\n\f Case 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 6 of 7\nEmail: info@anavex.com\n\n\nInvestors:\nAndrew J. Barwicki\nInvestor Relations\nTel: 516-662-9461\nEmail: andrew@barwicki.com\n\n\n[1] Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as\nTherapeutic Targets.\n[2] Prasanth MI, Malar DS, Tencomnao T, Brimson JM. The emerging role of the sigma-1 receptor in autophagy: Hand-in-\nhand targets for the treatment of Alzheimer\u2019s. Expert Opin Ther Targets. 2021 Jun 10. doi:\n10.1080/14728222.2021.1939681. Epub ahead of print. PMID: 34110944.\n[3] Glaze DG, Neul JL, Kaufmann WE, Berry-Kravis E, Condon S, Stoms G, Oosterholt S, Della Pasqua O, Glass L, Jones\nNE, Percy AK; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric\nRett syndrome. Neurology. 2019 Apr 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316. Epub 2019\nMar 27. PMID: 30918097; PMCID: PMC6550498.\n[4] Esbensen AJ, Rojahn J, Aman MG, Ruedrich S. Reliability and validity of an assessment instrument for anxiety,\ndepression, and mood among individuals with mental retardation. J Autism Dev Disord. 2003;33:617\u201329 Kluwer\nAcademic Publishers-Plenum Publishers.\n[5] Barnes KV, Coughlin FR, O\u2019Leary HM, Bruck N, Bazin GA, Beinecke EB, Walco AC, Cantwell NG, Kaufmann WE.\nAnxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales. J Neurodev Disord.\n2015;7(1):30. doi: 10.1186/s11689-015-9127-4. Epub 2015 Sep 15.\n[6] Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome:\nprevalence and characterization. J Neurodev Disord. 2011;3:57\u201367. doi: 10.1007/s11689-010-9067-y. Epub 2010\nDec 3.\n[7] ClinicalTrials.gov Identifier: NCT03758924\n[8] ClinicalTrials.gov Identifier: NCT03941444\n[9] ClinicalTrials.gov Identifier: NCT04304482\n\fCase 1:24-cv-03529-CM Document 23-3 Filed 08/23/24 Page 7 of 7\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:17.931702-07:00","document_number":"23","attachment_number":3,"pacer_doc_id":"127036039503","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Press Release","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579227/","id":409579227,"tags":[],"absolute_url":"/docket/68511120/23/4/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.626692-07:00","date_modified":"2024-08-27T02:17:52.839180-07:00","sha1":"680fcb80c36ff48d5f5ea81b9dfafc53f7de5123","page_count":15,"file_size":213984,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.4.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.4.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 1 of 15\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 2 of 15\n\n\n\n\nFile Name:\n\nANAVEX 2-73 (Blarcamesine) AVATAR Phase 3 Trial met Primary and Secondary\nEndpoints for the Treatment of Adult Patients with Rett Syndrome\nFebruary 1, 2022\n\nLEGEND:\n\n[UI]: Unintelligible\n[PH]: Phonetic\n\nCORPORATE PARTICIPANTS\n\nClint Tomlinson\nVice President -Operations Anavex Life Sciences Corp.\n\nChristopher U. Missling\nPresident, Chief Executive Officer & Director Anavex Life Sciences Corp.\n\nEdward R. Hammond\nChief Medical Officer\nAnavex Life Sciences Corp.\n\nOTHER PARTICIPANTS\n\nCharles C. Duncan\nAnalyst\nCantor Fitzgerald & Co.\n\nSoumit Roy\nAnalyst\nJonesTrading Institutional Services LLC\n\nYun Zhong\nAnalyst\nBTIG LLC\n\nMANAGEMENT DISCUSSION SECTION\n\nClint Tomlinson\nGood morning and welcome, everyone. Welcome to the ANAVEX Life Sciences\nAVATAR ANAVEX 2-73 Phase 3. Top-Line Data Conference Call. My name is Clint\nTomlinson, and I will be your host for today's call. At this time, all participants are in a\nlisten-only mode. Later, we will conduct a question-and-answer session. During this\nsession, if you would like to ask a question, please use the Q&A box or raise your hand.\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 3 of 15\n\n\n\n\nPlease note this conference is being recorded. The call will be available for replay on\nANAVEX's website at www.anavex.com.\n\nWith us today is Dr. Christopher Missling, President and Chief Executive Officer\u037e and Dr.\nEd Hammond, Chief Medical Officer\u037e and Walter E. Kaufmann, Chief Scientific Officer.\n\nBefore we begin, please note that during this conference call, the company will make some\nprojections and forward-looking statements. These statements are only predictions based\non current information and expectations and involve a number of risks and uncertainties.\nWe encourage you to review the company filings with the SEC. This includes, without\nlimitation, the company's Forms 10-K and 10-Q, which identify specific factors that may\ncause actual results or events to differ materially from those described in these forward-\nlooking statements. These factors may include, without limitation, risks inherent in the\ndevelopment and/or commercialization of potential products, uncertainty in the results of\nclinical trials or regulatory approvals, need and ability to obtain future capital, and\nmaintenance of intellectual property rights.\n\nAnd with that, I would like to turn the call over to Dr. Missling.\n\nChristopher U. Missling\nThank you, Clint. We appreciate everyone joining us on today's conference call to review\nour reported AVATAR Phase 3 ANAVEX 2-73 study in Rett syndrome top-line data\nresults. In summary, we are very pleased to report the positive results from the Phase 3\nclinical trial of the ANAVEX 2-73 AVATAR in adult patients with Rett syndrome.\n\nThe study reached primary and secondary endpoints of efficacy, safety, respectively. The\nstudy reached primary and all secondary efficacy and safety endpoints, which were all pre-\nspecified, with consistent improvements in RSBQ AUC p value of 0.037, ADAMS p value\nof 0.010, and CGI-I p value of 0.037 response. Efficacy endpoints demonstrated\nstatistically significant and clinically meaningful reductions in Rett syndrome symptoms,\nwith related changes in potential biomarkers GABA and L-AAA of disease pathology. The\nkey milestones were met to advance now for regulatory approval pathway for adult patients\nwith Rett syndrome.\n\nI'd like now to share the presentation, which goes along with the data today. First, I'd like\nto share with you what is Rett syndrome. Rett syndrome is a devastating\nneurodevelopmental disease in girls and adult girls with both movement impairments and\ncognitive impairments. This is not inherited, and it's a spontaneous mutation of one gene\ncalled the MECP2 gene. It occurs almost exclusively in girls, and boys die right away or\nbefore birth. It leads to severe impairments affecting nearly every aspect of the child's life.\nThe impairment includes the ability to speak, the ability to walk, eat and even breathe\neasily.\n\nThe hallmarks of Rett syndrome is near constant, repetitive head movements while awake.\nIt occurs worldwide and approximately 1 in every 10,000 to 15,000 live female births, and\nthe population of patients with Rett syndrome is estimated to be approximately 11,000\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 4 of 15\n\n\n\n\npatients in the US and similar numbers in Europe and Japan as well. So three times that\nnumber in the developing countries at least. And there's not currently any cure for Rett\nsyndrome.\n\nThe mechanism of action of ANAVEX 2-73 is now known to be very upstream. We\nunderstand now that the activation of SIGMAR1, which is the mode of action of ANAVEX\n2-73, prevents cellular stress before and after gene transcription. And that might play out\nvery handily in a genetically caused disease like Rett syndrome. And we see that\nSIGMAR1 is able to prevent and protect chromatin remodeling from worsening, as well as\nit prevents the RNA, which is toxic, which is caused by a mutated gene, to be expressed\ninto a protein which is toxic as well or not healthy, to guardrail this and to prevent it to\nexpress it in a toxic protein, so only healthy proteins are expressed.\n\nAs an overview of the Rett syndrome program, we have now almost completed the entire\nprogram. We completed the US Phase 2 study, and we just announced the completion of\nthe Phase 3 AVATAR adult Rett syndrome study. And ongoing is still the EXCELLENCE\nstudy, which includes patients aged 5 to 17, which is a pediatric clinical study in Rett\nsyndrome under the ANAVEX 2-73 Rett syndrome program.\n\nI'd also like to mention that we received the fast track designation, orphan drug designation,\nas well as orphan drug in rare pediatric disease designation. So with that, we now have one\npivotal study, Phase 3 in adult Rett syndrome, one Phase 2 study which could be a\nsupportive efficacy study in Rett syndrome, and we have extensive database and\ntolerability data of ANAVEX 2-73 from various other trials as well, which complete the\nsafety package.\n\nLet me share with you the design of the study. It was a relatively small study, 33 patients\nin total. 20 were randomized to active arm, who received up to 30 milligram once-daily\nliquid formulation in a convenient formulation, and 13 patients received placebo. They\nwere measured along seven weeks with a data point also captured in addition to baseline\nat week four. All patients are now eligible to an extension study which lasts 48 weeks.\n\nAs a primary endpoint, which was pre-specified, the RSBQ AUC response in safety was\nmeasured. In the secondary endpoint, which were efficacy endpoints as well, the emotional\nbehavior, ADAMS response, was measured, as well as the clinical global impression of\nimprovement response, CGI-I. We also had several other exploratory endpoints thereafter,\nand I'd like to highlight, especially today the Child Health Questionnaire-Patient (sic)\n[Parent] Form 50, as well as the seizure diary, which we address later today in the\nslideshow. The other endpoints like biomarker SIGMAR1 are still being assessed, as well\nas Mrna, and are not available yet for the top-line data but will be available later at some\npoint in time, which we will report.\n\nLet me share with you the baseline characteristics. You see across the two arms a very\nrelatively well-balanced baseline in regard to the age, weight, and the severity of the\ndisease. You could even say that the ANAVEX arm had a slightly higher marked ill\nbaseline compared to the placebo. But overall, it's a relatively balanced picture of the\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 5 of 15\n\n\n\n\npatients' respective features. I\u2019d also like to point out that the seizure medication was higher\nthan compared to the RS-001 US study, with N average of 82%. So these patients were on\naverage more severely impaired than the study we reported from the US RS-001 study.\n\nSo let me give you some background, however, about the endpoints, the primary endpoint,\nwhich is very important. It has been demonstrated that statistically significance, and it is\nrequired for a successful Phase 3 study, is not alone sufficient for approving a drug. It's\nalso required that the outcome of the effect of the patients is clinically meaningful for the\nindividual patient, and that can be measurable, assessed.\n\nAnd for that reason, to pick the right endpoint is very important. As we know now, and we\nknew when we started the trial, the RSBQ is not the most suited standalone caregiver\nendpoint or outcome assessment for Rett syndrome. It had been shown and recently\npublished that it could lead to either type 1 or type 2 error.\n\nThe FDA hence recommended, and it's also provided in the guidelines from the FDA and\nrecommended specifically in these cases because you don't have many choices of endpoints\nto pick from, which have been validated for rare diseases like Rett syndrome, to use instead\nthe RSBQ with an anchor. That's called anchor-based responder method, which links the\nscore from one clinical outcome assessment, the RSBQ in this case, with scores from a\nsimple reference anchor, which is the outcome assessment with a clinically meaningful\nthreshold, which is the CGI-I. And that facilitates the interpretation of what constitutes a\nmeaningful within and between patient change in clinical outcome assessment. And so,\nthis RSBQ AUC was born.\n\nThe additional advantage of this method is that we're able to capture clinically meaningful\ntreatment effect and disease progression at the same time. The RSBQ AUC, which stands\nfor area under the effect curve, the summary measure that combines both treatment effect\nand disease progression into one composite score. It captures not only the end of the\ntreatment effect, but also the progression of the disease over the course of the study, with\nbetter precision than only an end-of-treatment score. And it's been published and\ndemonstrated, as you can see the reference.\n\nThe CGI-I, clinical global impression of improvement anchored RSBQ AUC score, is now\nusing the improvement threshold of at least 1 full point in the 7-point scale, which reaches\nfrom no change, which is a score of 4, to at least a score of minimally improved, which is\na score of 3, or even higher to much improved, which is a score of 2, or very much\nimproved, which is a score of 1. So the responder is now defined as a study participant who\nexceeds the clinically meaningful CGI-I threshold, with corresponding RSBQ AUC link\nvalue indicating clear improvement. Importantly, the CGI and RSBQ AUC has been\npreviously successfully assessed as an efficacy endpoint in the US Rett syndrome trial RS-\n001.\n\nI\u2019d like to also now share more details about the CGI scale, because it's important in that\ncontext. The clinical global impression of improvement scale is a measure developed for\nuse in clinical trials to provide a brief, standalone assessment of the clinician's view of the\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 6 of 15\n\n\n\n\npatient's global functioning prior to and after initiating a study medication. Each time the\npatient is seen after the medication has been initiated, the clinician compares the patient's\noverall clinical condition to the period just prior to the initiation of medication use, which\nis the so-called baseline visit. That mimics what a physician would do in practice if an\nintervention is helping, and he could assess that. It measures both global and individual\ndomain ratings, like CGI-S, which is the clinical global impression of severity, and the\nCGI-I measures clinical change in a very much worse, which is score 7, to very much\nimproved, score 1 range.\n\nThe CGI-S score obtained at the baseline initiation visit serves as a good basis for making\nthe assessment. The following question is rated on a 7-point scale, and the question is posed\nto the physician compared to the patient's condition at admission to the project, prior to\nmedication initiation. This patient's condition is, 1, very much improved since initiation of\ntreatment\u037e 2, much improved\u037e 3, minimally improved\u037e 4, no change from baseline\u037e and 5,\nminimally worse\u037e 6, much worse\u037e 7, very much worse since the initiation of treatment. So\nyou can see that only the scores of 1 or 2 or 3 are defined as treatment responders, which\nis a very high bar. Score of 3 or less represent clearly observable clinically meaningful\nmanifestation of drug effect. That implies that the minimal important difference is a change\nof one unit at least, which is from the CGI of 4 to a CGI of 3.\n\nLet me now share briefly the ADAMS score, which is the Anxiety, Depression and Mood\nScale. The Anxiety, Depression and Mood Scale, ADAMS, is the measure of anxiety and\nmood symptoms in individuals with intellectual disability. It has been clinically validated\nfor use in Rett syndrome and in Fragile X syndrome. The ADAMS generates a total score\nin five subscale scores. It encompasses manic hyperactivity behavior, depressed mood,\nsocial avoidance, general anxiety, and obsessive compulsive behavior. So let me now share\nthe key endpoints, and then I will hand over to Ed Hammond, Dr. Hammond, for continuing\nthe slides of the other endpoints.\n\nSo very pleased to announce that the primary endpoint, which I just described, that\nANAVEX 2-73 induces a clinically meaningful improvement of RSBQ AUC, which is the\nCGI anchored minimum required improvement for reaching a significant clinically\nmeaningful improvement, with 72.2% of all patients in the study. That is a very meaningful\nscore, as compared to 38.5% on placebo. What's also noticeable is that the Cohen's d effect\nsize is very large, with 1.91 points.\n\nLet me move to the secondary endpoints. The secondary efficacy endpoints, ADAMS and\nCGI-I, the left side, we see that the ADAMS score had a clinically meaningful and\nstatistically significant reduction of emotional behavior symptoms response for ANAVEX\n2-73 treated adult patients with Rett syndrome, of 52.9%, versus placebo of 8.3%. Also\nhere there's a threshold. The threshold is defined by an improvement of at least 20 points\nchange, 20% point change, which is an improvement of the ADAMS total score from\nbaseline.\n\nAnd on the right side, the CGI-I score, which demonstrated significantly more patients\nachieved clinically meaningful CGI-I response over the treatment duration in ANAVEX\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 7 of 15\n\n\n\n\n2-73 treated group was 72.2% as compared to placebo of 38.5%, with also meaningful and\nsignificant p value. The Cohen's d effect size is also very large, with 1.91. So the threshold\nagain was here, at least a minimal improved, if not much improved or very much improved.\nSo now I'd like to hand over to Dr. Hammond to explore and explain the other endpoints.\nPlease kindly proceed.\n\nEdward R. Hammond\nThank you very much, Christopher. Hello, everybody. So we will now cover the other\nendpoints that were assessed in the AVATAR study, including here, the quality of life and\nseizures, and then in subsequent slides contextualized with biomarker assessments that\nwere obtained during the study.\n\nBeginning with quality of life assessed by the Child Health Questionnaire-Parent Form 50,\nthe CHQ-PF50, this is an internationally recognized general health-related global measure\nof quality of life, and it encompasses physical and psychosocial concepts. These would\ninclude physical function, psychosocial behavior, bodily pain, emotional impact, family\nactivities, family cohesion, and general health perceptions. ANAVEX 2-73 demonstrated\ndose-related significant improvement in overall quality of life as measured by the CHQ-\nPF50 total score, with a p value of 0.030.\n\nTo the right of this slide, what we display here is the frequency of seizures during the study\nperiod for ANAVEX 2-73 in blue, and for placebo in red. And you can observe that\nANAVEX 2-73 reduces the frequency of seizures, and it was \u2013 treatment with ANAVEX\n2-73 was associated with a 50.7 reduction in weekly seizure risk.\n\nNext slide, please. So the AVATAR Rett syndrome clinical trial evaluated potential\nbiomarkers of clinical response. There is evidence that a use of biomarkers in drug\ndevelopment increases the chances of success through early stages of development or\nthrough to new drug or to biologic license application filing. Biomarkers in drug\ndevelopment will set the stage for consistency and for reproducibility of trial findings, by\nreducing the variability in trial participant and also for endpoint selection. And this is one\nof the reasons why we sought to develop biomarkers for our program as well.\n\nNext slide, please. Here's an overview of the ANAVEX 2-73 mechanism of action, which\nwe have covered at the beginning of this presentation, but here in reference to Rett\nsyndrome. So the MECP2 mutation leading to Rett syndrome induces alteration of synaptic\ndevelopment and drives chronic cellular stress by unraveling chromatin. The ensuing\nmitochondrial dysfunction and increased inflammation contributes to the symptoms that\nare expressed in persons with Rett syndrome.\n\nOf important mention is a decrease in GABA in patients who have Rett syndrome. GABA\nis an inhibitory neurotransmitter, and in the brain has anti-seizure and anti-anxiety effects,\nwhich leaves persons with Rett syndrome prone to seizures and mood disorders. L-alpha-\naminoadipic acid, L-AAA, has also been shown to be increased in persons with Rett\nsyndrome. L-AAA is involved in the neuroligin pathway and involved in excitatory\nneurotransmission, as well as in neurodegenerative processes and diseases. ANAVEX 2-\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 8 of 15\n\n\n\n\n73 reverses these behavioral, motor and synaptic imbalances by activation of the\nSIGMAR1.\n\nOn to next slide, please. So we will now speak of GABA as a potential biomarker,\npredicting clinical outcome in ANAVEX 2-73 Rett syndrome study. In patients with Rett\nsyndrome, the MECP2 deficiency disrupts this GABAergic cycle, resulting in decreased\nGABA, and impairs synaptic and mitochondrial function. The AVATAR efficacy endpoint\ndemonstrated statistically significant and clinically meaningful reductions in Rett\nsyndrome's symptoms, and these were related to changes in potential biomarkers of disease\npathology.\n\nGABA was significantly increased at p of 0.0205. The gliotoxin, L-alpha-aminoadipic acid,\nL-AAA, was significantly decreased with a p value of 0.0392. These changes in biomarkers\ntaken together are supportive and contextualize the findings of decreased seizure\nfrequency, improved health-related quality of life, and behavioral measures that were\nobserved in the AVATAR trial. So now what we'll cover here then are safety and adverse\nevents that occurred during the treatment period.\n\nANAVEX 2-73 was well-tolerated with very good medication compliance of 95%. We\nobserved similar treatment, emergent adverse events, TEAEs, in the ANAVEX 2-73\ntreated persons and the placebo arms. Adverse events at the 10% threshold or more were\npredominantly mild or moderate. The 10% threshold translates the occurrence of two or\nmore events and is set because of this small sample size where one event was over 7%.\n\nNo clinically significant changes in vital signs, laboratory values, ECG parameters were\nobserved in the ANAVEX 2-73 or the placebo groups. There was no incidence of diarrhea\nor vomiting. These safety findings are indeed consistent with a known safety profile of\nANAVEX 2-73. I will hand over back to you, Dr. Missling.\n\nChristopher U. Missling\nThank you very much, Dr. Hammond. So overall, in summary, we can confirm that the\nPhase 3 AVATAR clinical trial for adult patients with Rett syndrome accomplished the\nprimary efficacy endpoint of RSBQ AUC, the secondary efficacy endpoints of ADAMS\nand CGI-I, all statistically significant, as well as safety endpoints were met.\n\nThe efficacy endpoints were statistically significant and clinically meaningful in Rett\nsyndrome symptoms with related changes in potential biomarkers of disease pathology.\nThereof, GABA was significantly increased, which is decreased in Rett syndrome patients;\nand L-AAA was significantly decreased, which is usually increased in Rett syndrome\npatients.\n\nWe have a convenient once-daily oral liquid formulation, which was well-tolerated up to\n30 milligram per day without safety concerns identified. We also confirmed a dose\nresponse. The RS-001 study used 5 milligram as you know, and the RSBQ AUC Cohen's\nd effect size was 0.517. and the RS-002 AVATAR study with higher dose, 30 milligrams\nwas by a magnitude higher and reached the effect size of 1.91.\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 9 of 15\n\n\n\n\nThe analysis of weekly seizure counts indicated that relative to placebo, ANAVEX 2-73 is\nassociated with a 50.7% reduction in weekly seizure risk. And ANAVEX 2-73\ndemonstrated dose-related significant improvements in the overall quality of life, which is\nmeasured with the CHQ-PF50 and a p value of 0.030, which is very important for\ndiscussion of the pricing with insurance companies. And the key milestone was meant to\nadvance regulatory approval pathway for the adult patients with Rett syndrome. As a matter\nof fact, we are now in discussion \u2013 discussing with the FDA a pathway for potential\napproval of ANAVEX 2-73 for adult patients with Rett syndrome.\n\nI'd like to acknowledge and thank all of the patients and their family members who\nparticipated in the Rett syndrome study, as well as the investigators and their staff\nconducting these studies, and the global Rett Syndrome Association. And last but not least,\nalso the team at ANAVEX, which worked very hard to execute this trial.\n\nIn summary, we\u2019d also like to finish with an overview of the ANAVEX pipeline, which\nnow has reached even a stronger foothold as a platform for targeting neurodegenerative\ndiseases, including Alzheimer's and Parkinson, as well as neurodevelopmental diseases,\nwhich now includes the franchise of Rett syndrome, but also other autism spectrum related\ndisorder, which are infantile spasms, Fragile X, Angelman syndrome, and other related\ndisorders.\n\nSo in summary, we believe ANAVEX is at this point the only company pursuing the large\nmarkets with application of precision medicine, with confirmed biomarker response, to\ndevelop treatment for both global aging, which includes CNS, Alzheimer's and Parkinson's\ndisease, as well as catastrophic orphan genetically caused diseases like Rett syndrome, with\nhigh unmet need. We found and confirmed the platform with the AVATAR study today,\nand we identified even further biomarkers of pathology responding to the drug effect,\nwhich as we know improves the chance of clinical success and makes the data more robust.\n\nWe also have strong IP position around our novel mechanism of action of ANAVEX 2-73,\nwith composition of matter up to at least 2037. And we have now a compelling human data\nplatform, which includes the Phase 3 AVATAR study in Rett syndrome, the Phase 2 Rett\nsyndrome study, and the Phase 2 study in Parkinson's disease dementia, PDD, and a Phase\n2a study in ANAVEX in Alzheimer's disease, with favorable and exploratory efficacy\nresults through 148 weeks.\n\nAnd we also like to mention, last one but not least, we're expecting the Phase 2/3 ANAVEX\n2-73-AD-004 Alzheimer's study to readout on time in the second half of this year.\nWith that, I'd like to go back \u2013 get back to Clint for Q&A. Thank you.\n\nQ&A\n\nClint Tomlinson\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 10 of 15\n\n\n\n\nThank you, Christopher. We'll now begin the question-and-answer session. If you have a\nquestion, please raise your hand or enter it in the Q&A box. The first question is coming\nfrom Charles Duncan from Cantor Fitzgerald.\n\nCharles C. Duncan Q\nYeah. Hi. Can you hear me?\n\nClint Tomlinson A\nYeah. We're good.\n\nCharles C. Duncan Q\nOkay. Super. Good morning. Yeah, thanks for taking the question. And Christopher,\ncongratulations on these provocative results in a very high unmet need patient population.\nI had a couple of questions on the trial conduct, and then I wanted to ask you about next\nsteps. With regard to the sample, I guess I'm kind of wondering if you can help me\nunderstand why the sample numbers are imbalanced between control and experimental\narms, 20 versus 13, I guess, in the reverse order?\n\nAnd then if you could help us understand a little bit more about the titration paradigm, and\nthen the number of patients that were a little bit higher weight on the control arm. I guess\nI'm wondering if any of these factors may have played into the results. And then I'll ask\nyou about the endpoint question that I wanted to ask.\n\nChristopher U. Missling A\nRight. So let me start first with the last question, the weight. We have done extensive\nanalysis, the drug does not depend on weight of a participant. It's weight independent. So\nwe believe that does not have any effect. Regarding the imbalance of the active arm being\nrandomized 3:2, it was the wish of the community to have at least as possible exposure to\nplacebo in a trial, given that these patients are highly vulnerable, hard to find, and not easy\nto be convinced to participate in a study. So that was the reason why we have that 3:2\nrandomization, basically favoring slightly higher number of active arm and placebo arm.\n\nCharles C. Duncan Q\nOkay. That makes sense. And then regarding the titration, how did it actually work? What\nwas the percentage of patients that got to that 30-milligram dose? And can you give us a\nsense of how that progressed over, call it the seven-week trial? What was the exposure, I\nguess, response that you were looking for?\n\nChristopher U. Missling A\nSo almost all patients reached the 30-milligram dose, I think it was 80%. And some patients\nwere, because the seven weeks relatively was a flat titration, didn't get fully there. But you\ncan definitely say that the totality of the data is based on the average of slightly short of 30\nmilligram.\n\nCharles C. Duncan Q\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 11 of 15\n\n\n\n\nOkay. And then relative to or regarding the endpoint, I guess I'm really intrigued with the\nanchor-based endpoint analysis, and I like it in some ways. But I also kind of wonder if, I\nmean, didn't the trial start off within RSBQ total? And isn't that the endpoint in the ongoing\nEXCELLENCE trial? And I guess I'm wondering if you also looked at the data with regard\nto a change in RSBQ relative to baseline. And then the other thing I wanted to ask, which\nI'm confused on, is it looks like the CGI data is exactly the same as the primary endpoint\ndata. And I'm wondering if I'm just confused in seeing that.\n\nChristopher U. Missling A\nYeah, good point. So let me also get \u2013 address the second part. So the CGI-I response is\nindeed numerically similar or same as the RSBQ response, but it's coincidental. It's not the\nsame in its patients\u2019 response.\n\nCharles C. Duncan Q\nOkay.\n\nChristopher U. Missling A\nThe RSBQ total score is actually \u2013 and we had included that in our analysis, and we\nbasically did not change the \u2013 or the CRO didn't change on time, in the ClinicalTrials.gov\nthat's why it looks like it was changed. But it was actually pre-specified. In a Phase 3 you\ncannot really move around with the endpoint, so it was pre-specified. As I mentioned, we\nalso included that in the RS-001 and we also showed it in our slides, but we didn't highlight\nthat that analysis. But the discussion with FDA led to a conviction that the RSBQ alone is\nnot sufficient as a standalone to measure because of its likely type 1 and type 2 error\npotential. So the anchor-based correlated threshold based RSBQ was then chosen, which\nis the RSBQ AUC.\n\nAgain, I want to make sure everybody understands that is a much higher threshold, because\nif you have just the average improvement of a very small percentage or a very small effect\nof the RSBQ, for example, you are not helping the patient. You might have a significant\nsignal, but it's not helping the patient. What we have is a much more rigorous threshold\nyou'd have to overcome, and then you start looking at the RSBQ. So that is much a higher\nhurdle and much more difficult to accomplish.\n\nThe analogies to a trial, for example in psoriasis, where this also performed such analysis,\nyou have to have a minimum of 75% of removal of the area of the arm or the body part\nwhere psoriasis is affected. And it's not just 5% on average improvement over placebo, it\nhas to be at least 75%. And then from that moment on, you count as a responder. So the\nthreshold is much higher in the calculation, and that's what is actually on our end here, an\naccomplishment because we had to adhere to this more rigorous approach.\n\nCharles C. Duncan Q\nThat makes sense to me. And I assume the clinician is blinded to the treatment\nrandomization arm when doing the assessment of CGI?\n\nChristopher U. Missling A\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 12 of 15\n\n\n\n\nAbsolutely. It's four times blinded. The participant, the patient, we and the assessment and\nthe CRO. So everybody is blinded.\n\nCharles C. Duncan Q\nOkay. Last question. Sorry for all of them, but I promise it's last. Next steps regarding\nmeeting with the agency, I assume you don't know the exact timing, but could you give us\nkind of a goal on that? And then would you be discussing a second Phase 3 to replicate\nthese results? Or would you rely on EXCELLENCE and the body of data that you have\nthus far to potentially support the filing of an NDA?\n\nChristopher U. Missling A\nYeah. I mean, it's not unheard of. We've seen it with the approval of the vaccines for\nCOVID, that it was first tested in adults and it was then approved for adults, and then it\nwas tested in younger children, and then it was approved in younger children, and now the\nage group was expanded further. So we don't want to exclude the ability now with this data\npackage to seek approval for retinue for adult patients. On the other hand, we\u2019d like to have\nthe discussion with FDA first, because we also have the, as you know, EXCELLENCE\nstudy ongoing which includes patients 5 to 17. So regarding timing, I would like to say at\nthis point in time, as soon as we can. So we'd like to able to move forward the discussion\nas soon as possible.\n\nCharles C. Duncan Q\nThank you.\n\nChristopher U. Missling A\nThank you.\n\nClint Tomlinson A\nThank you, Charles. The next question comes from Soumit Roy from Jones Research.\nSoumit, you can go ahead when you're ready. Soumit, are you there?\n\nSoumit Roy Q\nHi. Can you hear me?\n\nClint Tomlinson A\nYeah. Soumit, go ahead. Go ahead, please.\n\nSoumit Roy Q\nApologies for that. So one question, I guess we are getting a bunch of questions from the\ninvestors, is going back to the endpoint. When \u2013 we were not \u2013 when was the switch\nhappened, we weren't really sure of RSBQ score to AUC, but I guess the bigger question\nis what is the delta between the baseline in the treatment arm and the placebo arm and the\nRSBQ score? If you can give us a number or at least qualitatively tell us if it's more than\n14.5 we saw in the previous, or less? Any color would be appreciated?\n\nChristopher U. Missling A\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 13 of 15\n\n\n\n\nYeah, absolutely. So we had \u2013 the 14.5 came from the wild type in all patients in the US\nRett study. So the total includes also patients without the wild type. So we definitely can\nsay comfortably that the correlation is from the \u2013 with the threshold, the bar of one point\nCGI-I score, that it must be in the range of above 10 to 29 in that range. So 10 to 29 in that\nrange is the likely range of the RSBQ response.\n\nSoumit Roy Q\nGot it. And the seven-week exposure, do you believe a longer drug exposure could further\nimprove it, or this is somewhere you have seen this maxes out? Any thoughts around that?\n\nChristopher U. Missling A\nRight. It's an excellent question. So we have now expanded the study in extension, and we\nhad some patients not getting the drug extension right away. So we will be able to see in a\nfresh new baseline how these patients progress, which were also on study drug prior and\nwere on placebo prior. So we will have data on that upcoming to see if the effect of the\ndrug requires longer duration of drug, or the 7-week is sufficient. We believe the 7-week\nis sufficient. It will be something which we will explore and find out.\n\nSoumit Roy Q\nPerfect. And just the last question, have you done the analysis like previous Phase 1 trial\npercent to responders versus non-responders yet?\n\nChristopher U. Missling A\nYes. As I said, we should go all and look back up in the presentation of the ANAVEX\npresentation corporate slide deck, which is included in, and let me look it up the slide where\nwe have it shown, the respond analysis. So it's not that we didn\u2019t it for the first time, but\nwe just did not highlight it. So it was like probably not noticed as much as now, since this\nis the requirement for the Phase 3, which is a much more rigorous threshold to be able to\naccomplish. So slide 22 in the ANAVEX global corporate presentation, you see the respond\nanalysis of the CGI-I, the ADAMS, the RSBQ, CGI-I and the ADAMS as well.\n\nSoumit Roy Q\nThank you so much and congratulations again.\n\nChristopher U. Missling A\nThank you.\n\nClint Tomlinson A\nThank you, Soumit. The next question is coming from Yun Zhong from BTIG.\n\nYun Zhong Q\nHi. Thanks very much for taking the question. So one question, follow-up question on the\nendpoint, I assume that when you report top-line data from the EXCELLENCE study, it\nwill be RSBQ AUC as well. Do you have to go back to the US Phase 2 study to reanalyze\nthe data using AUC versus the \u2013 as compared to the original RSBQ to make everything\nconsistent?\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 14 of 15\n\n\n\n\nChristopher U. Missling A\nGood question. Thank you. So that's right, the EXCELLENCE study will use the same\nendpoint because as just described, it is just the preference of the FDA. Regarding going\nback to redo the analysis, it's not actually necessary. It's already out there. It's already\nincluded in slide 22 of the presentation. We just did not provide the fine points of the\nthreshold levels in those slides, but we pointed out. And I see here on the bullet in the\nbottom of the slide 22, the slide, we said respond analysis is capturing the progression of\nthe disease and treatment effect over the course of the disease and the improvement in the\nadults required meaningful according to published criteria. So we basically have already\nanalyzed that; it's the same analysis which we applied here, which was already done prior.\nWe just didn't highlight the exact method in the US study, but it was exactly done the same\nway. And the data is actually on slide 22.\n\nYun Zhong Q\nOkay. And now that we know the dose used in the AVATAR study, are you able to disclose\nthe dose being tested in the pediatric study?\n\nChristopher U. Missling A\nYeah. I would say at this point in time, it's in the ballpark of the dose of the AVATAR\nstudy.\n\nYun Zhong Q\nOkay. And another question is on the biomarker, very interesting biomarker data. But if I\nremember correctly, from the US Phase 2 study, you initially saw a very interesting\nbiomarker, glutamate and GABA. But then from the entire study, the signal seems to have\ndisappeared. So are you worried that the biomarker truly is reflecting what's going on? And\nalso, have you looked at the \u2013 any correlation between biomarker response and clinical\nresponse as you did before?\n\nChristopher U. Missling A\nNo. We are now doing the analysis of the biomarker response correlation, as well as what\nI pointed out at the beginning, we have not yet the data of the SIGMAR1 mRNA, which\nwas a very strong correlation of the effect of the drug with the SIGMAR1 expression in\ncorrelating very nicely with the endpoints. The question about the glutamate and GABA,\nthey are interrelated. And I like to point out, we only had showed in the open-label study\npreceding the US study, which was a six patients open label, we had some weak signal of\nglutamate reduction, which is considered positive. The glutamate is too much elevated in\nthe Rett syndrome. But in the AVATAR study, we didn't see that strong enough. But the\nGABA was strong enough, which is basically the opposite. We have to also appreciate that\nthese measures from the blood are sometimes not perfect, and they just also have their own\nvariability.\n\nBut the fact that the GABA was increased is really important because we had a higher \u2013\nwe didn't see that in the US study, which we believe is based on the fact that the US study\nwas lower in dose. So it might be that you need to have a higher dose to push through to\n\f Case 1:24-cv-03529-CM Document 23-4 Filed 08/23/24 Page 15 of 15\n\n\n\n\nsee the biomarker effect. And we saw that in the AVATAR study, as well as the other\nbiomarker measure, which was the L-AAA, which was decreased which usually is too high.\nSo I think that's kind of like a strong picture.\n\nYun Zhong Q\nOkay, so last question. Are we able to see any additional data from the study before maybe\nmid-year when you report pediatric side data?\n\nChristopher U. Missling A\nYes, we expect more data. as I mentioned, the mRNA and additional biomarker data, as\nwell as what I referred to before, the analysis of the patients, which were on the prior study\nand then switching to the extension study, what happen to them. And also, I'd like to point\nout at this occasion here that all these biomarker effects, the GABA increase and the L-\nAAA decrease, are all applicable to diseases beyond Rett syndrome. So we have the same\npathology of biological negative loop or imbalances in the pathology of other autism\nspectrum disorders like Fragile X, but also in Parkinson and in Alzheimer's disease. So\nthese biomarkers actually are quite important indications, potentially for the effect also of\nthe other indications which we are pursuing right now.\n\nYun Zhong Q\nOkay. Thank you very much and congratulations.\n\nChristopher U. Missling A\nThank you.\n\nClint Tomlinson\nThank you, Yun. So I don't see any further questions at this time, Dr. Missling.\n\nChristopher U. Missling\nThank you. So we're very excited and thank you for joining us. We're very excited to have\nreached this milestone and expect to continue our momentum, including the release of the\nupcoming Phase 2/3 EXCELLENCE ANAVEX 2-73 clinical trial in pediatric Rett\npatients, as well as the Phase 2b/3 in ANAVEX 2 -73 in Alzheimer's patients. And we will\nlook ahead and we continue to focus on driving meaningful growth across our broad\nSIGMAR1 receptor platform portfolio, to deliver transformational treatments for patients\nwith both degenerative and developmental neurologic disorders around the world. We look\nforward to providing you further updates as advancements continue. Thank you very much.\n\nClint Tomlinson\nThank you, ladies and gentlemen. This concludes today's conference call. Thank you for\nparticipating. You may now disconnect.\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:18.521029-07:00","document_number":"23","attachment_number":4,"pacer_doc_id":"127036039504","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Transcript","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579228/","id":409579228,"tags":[],"absolute_url":"/docket/68511120/23/5/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.668741-07:00","date_modified":"2024-08-28T02:15:31.842892-07:00","sha1":"71ef5823d28263d28ccbf26273adca0789ba26af","page_count":13,"file_size":10159945,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.5.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.5.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 1 of 13\n\f Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 2 of 13\n\n\n EXHIBIT 99.1\n\n\n\n\n Forward Looking Statement\nThis presentation contains forward-looking statements made within the meaning of the Private Securities Litigation\nReform Act of 1995 by Anave x\u00ae Life Sciences Corp. and its representatives. These statements can be identified by\nintroductory words such as \"expects,\" \"plans,\" \"intends,\" \"believes,\" \"will,\" \"estimates, \" \"forecasts ,\" \"projects,\" or words of\nsimilar meaning, and by the fact that they do not relate strictly to historical or current facts. Forward-looking statements\nfrequently are used in discussing potential product applications, potential collaborations, product development activities,\nclinical studies, regulatory submissions and approvals, and similar operating matters. Many factors may cause actual\nresu lts to differ from forward-looking statements, including inaccurate assumptions and a broad variety of risks and\nuncertainties, some of which are known and others of which are not. Known risks and uncertainties include those\nidentified from time to time in reports filed by Anavex Life Sciences Corp. with the Securities and Exchange\nCommission, which should be considered together with any forward-looking statement. No forward-looking statement is\na guarantee of future results or events, and one should avoid placing undue reliance on such statements. Anavex Life\nSciences Corp. undertakes no obligation to update publicly any forward-looking statements, whether as a result of new\ninformation, future events or otherwise . Anavex Life Sciences Corp. cannot be sure when or if it will be permitted by\nregulatory agencies to undertake clinical trials or to commence any particular phase of any clinical trials. Because of\nthis, statements regarding the expected timing of clinical trials cannot be regarded as actual predictions of when Anavex\nLife Sciences Corp. will obtain regulatory approval for any \"phase\" of clinical trials. We also cannot be sure of the clinical\noutcome for efficacy or safety of our compounds. Potential investors should refer to the risk factors in our reports filed\non Edgar.\n\n\n\n anavex 2\n\f Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 3 of 13\n\n\n\n What is Rett Syndrome?\n Devastating Neuro-developmental Disease in Girls with both Movement Impairment and Cogn t ve\n Impairment\n\n\n\n\n Rett Syndrome (RTT)\n\n\u2022 Non-Inherited genetic postnatal disorder caused by mutations\n In the MECP2 gene\n Occurs almost exclusively in girls\n Leads to severe impairments, affecting nearly every aspect of the child's life\n Impairment includes ability to speak, walk, eat and even breathe easily\n Hallmark of RTT is near constant repetitive hand movements while awake\n Occurs worldwide in approximately one in every 10,000 to 15,000 live female\n births\n The population of patients with Rett syndrome is estimated to be -11,000\n patients in the U.S.\n There is currently no cure for Rett syndrome\n\n\nSource: https:llwww.rettsy11ti-0 HQ d dcee ongoing\n Week 0 Week 4 Week 7\n (Base line) (End of Trial [E OT] )\n\n Assessments:\n Primary: Assessment of RSBQ AUC response and safety\n \u2022 Secondary: Emotional behavior (ADAMS) response and CGl-1 (Clinical Global Impression of Improvement) response\n \u2022 Exploratory: Sleep (CSHQ), VAS (top caregiver concerns), Child Health Questionnaire PFSO (CHQ-PFSO), Rett syndrome\n Caregiver Inventory Assessment (RTT-CIA), Seizure diary\n\n \u2022 Biomarkers of response and/or surrogate endpoints: DNA & mRNA profiles and metabolomics biomarkers\n SIGMAR1 variants: Prespecified analyses of population with wi ld type (WT) variant\nCfinfcBITriBls.gov: NCT0394 1444\nSeparate paUenl co/Jori (n=3) underwent \" 3-weeh inlensi\"\" ph1Jm>acok1netic (PK) assessment wlfh s1Jfely, toiembiMy. phann,,colII P. Validity of area-under-the-curve analysis lo summarize effect in\nrheumatoid arthritis c/10,ca/ lna/s. J Rheumalol. 1999;26(3):712-716. anavex\n\n\n CG -1 Scale\n crn\u00b7cal Glob I lmpress\u00b7on of l11provem t (CGl-1)\n The Clinical Global Impression of Improvemen t Scale (CGl-I) is a measure developed for use in clinical trials to provide a brief. stand-alone assessment of\n the clinician's view of the patient's global functioning prior to and after initiating a study medication. Each time the patient is seen after medication has been\n initiated. the clinician compares the patient's overall clinical condition to the period just prior to the initiation of medication use (the so-called baseline visit).'\n Mimics what a physician would do in practice if an intervention is helping\n Measure both global and individual domain ratings like CGI-S (Clinical Global Impression of Severity)\n CGl-I measures clinical change in a \"Very Much Worse\" (7 score) to \"Very Much Improved\" (1 score) range\n The CGI-S score obtained at the baseline (initiation) visit serves as a good basis for making this assessment The following question is rated on a\n seven-point scale: \u00b7compared to the patient's condition at admission to the project [prior to medication initiation], this patient's condition is: 1=very much\n improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally\n worse; 6= much worse: l=very much worse since the initiation of treatment.\u00b7\u00b7\n\n Only scores of 1 or 2 or 3 are defined as treatment \"responders\"\n Score of 3 or less represent clearly observable clinically meaningful manifestation of drug effect\n\n This implies that the minimal important difference is a change of 1 unit from a CGl-1 of 4 (no change) to a CGl-I of 3 (minimal improvement)\n\n\n\n iltillllll=El1ll1l\u00b7II\n Il\n X\n 7\n X\n 6\n X\n 5\n X\n 4 \" 3 \"2\n T\n \"1\n\n Very Much Much Mi nimally Minima lly Much Very M uch\n No Change\n Worse Wors e Wor:se Im p roved lmp,oved Im proved\n\n ' Busner J, T8fgtim SD. The cliroca/ global impressions scale.\u00b7 applying a research loo/ in cl,mca/ practice. Psychiatry (Edgroonl), 2007;4(7):28-37, 10\n\f Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 7 of 13\n\n\n ADAMS Scale\n Anxiety, Depression, and Mood Scale (ADAMS)\n\n The Anxiety, Depression, and Mood Scale (ADAMS) is a measure of anxiety and mood symptoms in\n individuals with intellectual disability. 1 It has been clinically validated for use in Rett syndrome 2 and in\n Fragile X syndrome 3\n\n\n The ADAMS generates a total score and 5 subscale scores:\n Manic/hyperactive behavior\n Depressed mood\n Social avoidance\n General anxiety\n Obsessive compulsive behavior\n\n1) Esbensen AJ, Roja Im J, Amen MG, Ruedlicll S. Reliability and validity of an assessme/l/ 1ns/romen/ tor anxiety, depression, and mood among individuals with ment,,t retardatioo. J Autism\n Dev D,sord. 2003;33:617-29 K!u\"\"'r Academ,c Publishers-Plenum Publishers.\n2) Bames KV; Coughlin FR, O'Lea,y HM, Bruck N, Baz,n GA, &in<>cke EB, Walco AC, Cantwell NG, Kaufmann WE. Anri<>ty-llke l)ehavK)I\" in Reff syndrome: characterislics and assessment t,y\n anxiety scales, J Neurodev Disord, 2015;7(1):30, do,; 10, 11Ws11689-0115-9127-4 Epub 2015 Sep 15.\n3) Corr:leiro L. Ballinger E, Hi!!J6rman R. Hess/ D. Clinical assessment of DSM-IV anxo,ty disorders in fra,}ila >< syndrome: prevalanca and charar;terizali-On. J Neurodev Disord. 2011;3.57-oT.\n do/: 10.1007/s11689.()10\u2022~7-y. Epub 2010 Dec 3.\n anav _ 11\n\n\n\n\n Primary Endpoint\n Primary Efficacy Endpoint\n 80\n 72.2\n 70\n\n\n\n\n p = 0037\n\n 38.S\n\n\n\n\n 10\n\n\n\n ANAVEX2-73 Placebo\n\n\n ANAVEX\u00ae2-73 induces a clinical meaningful improvement of RSBQ AUC* in 72.2% of\n patients as compared to 38.5% on placebo; (p = 0.037)\n\n Cohen's d effect size 1.91 (very large)\n\"Improvement tl,reshold of al leas/ 1 full point in the CGl-1 scale from 'No Change ' (I.e .. 4) to at least 'Minimally Improved' (I.e., 3) or 'Much Improved' (I.e.. 2) or\n'Ve,y Much Improved \u00b7 (i.e .. 1) :vex 12\n\f Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 8 of 13\n\n\n Secondary Endpoints\n Secondary Efficacy Endpoints ADAMS and CGl-1\n\n\n\n . 80\n 72.l\n \"' 70\n \"'\n .\n '7\n\n Lo\n ;::- 60\n p = 0.010 p = 0.037\n\n ,. 40\n 38.5\n\n\n ,. \u00a7. 30\n 20\n a\n u\n IO\n 10\n\n 0\n ANil.'a'flQ -73 pi.c.,t,(> A.NA\\IE:Q\u202273\n\n\n\n\n Clinically meaningful and statistically significant reduction of Significantly more patients achieve clinically meaningful CGl-I\n emotional behavioral symptoms (ADAMS) response\u2022 for response'* over the treatment duration in ANAVEX\u00ae2-73-treated\n ANAVEX\u00ae2-73 treated adult patients with Rett syndrome (52 .9%) group (72.2%) as compared with placebo (38.5%); (p = 0.037)\n vs placebo (8.3%); (p = 0.010)\n Cohen 's d effect size 1.91 (very large)\n Cohen's d effect size 0.609 (large)\n\n\u2022 /mprow,meol I/iresllold o/ al /eaS/ -20% c/Jar,ge (lmprovemenl) o/ ADAMS Iota/ \u2022\u2022 Improve men/ lhreshold of al least 1 full point in /he CGl-1 scale from 'No Change\u00b7\nscorn from baseline\n (i.e., 4) lo al leas/ 'Minimally Improved\u00b7 (1.e., 3) or \"Much Improved' (i.e., 2) or 'Ve,y\n\n a\n Much Improved' /i.e., 1)\n 13\n\n\n\n\n Other Endpoints\n Quality of Life (QoL) Assessment and Distribution of Seizure Count by Treatment Arm\n\n ANAVEX2-73 Placebo\n Child Health Questionnaire-Parent\n Form 50 (CHQ-PF50)\n The CHQ-PF50 is an internationally\n recognized general health-related 60-\n global measure of Quality of Life (Qol)\n encompassing physical and\n Treatment\n psychosocial concepts (physical ANAVEX2-73\n function , psychosocial, behavior, bodily Plocebo\n\n pain, emotional impact, family\n activities, family cohesion, and general 20-\n health perception)\n ANAVEX\u00ae2-73 demonstrated dose-\n related significant improvement in o- \u2022 \u2022 \u2022\n 0 2'5 5'0 75 I) 2'5 50 75\n\n .\n overall Quality of Life (Qol) measured Seizure counts\n with CHQ-PF50 Total Score (p = 0.030)\n ANAVEX\u00ae2-73 is associated with a 50.7%\n reduction in weekly seizure risk\n :vex 14\n\f Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 9 of 13\n\n\n\n Biomarkers Increase Probability of Success\n Precision Medicine\n 76%\n Patient\n selection\n biomarkers\n 55%\n\n 46% Higher\n therapeutic\n response\n 28%\n\n\n Lower\n variability in\n the target\n population\n Phase 11to Phase Il l Phase Ill to NDNBLA\n \u2022 Without Bi oma rkers Wi lh Patient Selecti on Biomarkers\n\n\n\n\nThomas DWel 81. CJ,nicaJ Development Sucoess RB/es 2006-2015. BIO Industry Analysis anavex 15\n\n\n\n\n ANAVEX\u00ae2-73 Mechanism of Action for Rett Syndrome\n SIG AR1 Activation is e efcial i Restoring Neuronal Homeostasis\n MECP2 mutation alters S/GMAR1 act1vatlon closes ANAVEX\u00ae2-73 reverses\n synaptic development and chromatin to counteract ch ron,c behaviora l, motor, and\n drives ch ronic cellu lar stress cell ular stress, restoring synaptic imbalances by\n by open ing chromatin 1,2 mitochondria and synapses 3.4 activating StGMAR1s. 6 7.a,\n\n\n\n\n !\n l;',:.~:;'i:;::.:~\n MECP2\n Aberrant Expression\n Synaptic Balance\n\n\n\n\n V\n Mitochondrial Function\n\n\n f Inflammation\n Synaptogenesis\n M,tochondnal Function\n\n l\n l\n 1nflammat1on\n\n GABA\n Neurotrophic Factors\n\n\n\n\n l\n (BONF)\n\n Seizures\n Neurodegeneration Markers\n (L-AAA)\n\n\n\n\n1/ U et o/.. 2020; 2) Wang eta/ 2020; 3/ Crouzieret o/., 2020: 4/ Lee el al, 2020; 5) Kaufmann et a/, 2019;\nij/ Kaolmann el al , 201!11;,; 7) Lahmy el al, 2015; ~) Lioak el al., 2020; 9) ANAVfaX2-7J-R$-002 Dalo :vex 16\n\f Case 1:24-cv-03529-CM Document 23-5 Filed 08/23/24 Page 10 of 13\n\n\n GABA a Potential Biomarker, Predicting Clinical Outcome in\n ANAVEX\u00ae2-73 Rett Syndrome Study\n In patients with RTT. MECP2 \u2022 AVATAR efficacy endpoints\n deficiency disrupts the demonstrated statistically significant\n and clinically meaningful reductions\n GABAergic cycle 1, resulting in\n in Rett syndrome symptoms with\n decreased GABA, and impaired related changes in potential\n synaptic and mitochondrial biomarkers of disease pathology:\n fu net ion 1.2,3,4.5,s\n \u2022 GABA7was significantly increased\n (p = 0.0205)\n GAIAP;athw;rys\n Otli1t1illll!llo - Onli-mfl\n\n\n\n\n \u2022 Gliotoxin L-Alpha-aminoadipic acid\n (L-AAA) 8 was significantly decreased\n (p = 0.0392)\n\n\n\n\n1) Jin et Bl., 2015: 2) Chao et Bl., 2020: 3) HBmbergeret Bl. , 1992: 4) l..appB/Binen et Bl., 1996; 5) Neu/ et al., 2020 6) KBufmBnn et Bl., 2005\n7} U,e K, Lu H, Wang W, el Bl. RestornlHJn of Meq,2 express,oo m GABAe,gic neurons ,s sufficient to rescue mu/~ple disease featu,es m a mouse model of Rett syndrome. Elite\n2016 Jun 21;5:e 14198; 8) Wu HQ, Ungerste.3'}' kll'Phre!Dklglcal llra,11 plaebcty In m,oe Ellf\n ~europ,;yd,oph;mn.,CDI 2(120 Od:39 29-45 l1ol 10 1016,lj i:tJrnn~uro 2020 08 010\n\n tt.,r.tshi T Su TP\" Si.ginit-1 r~~pklr d1.:1pero11es.itl 1t11~ ERr11irocho11drion inl.t!rfit0e regul.:!!e Ca(2\u2022)s~n!!tmy 1111d ot!ll surviv~ Cell. 2007 No~ 2 131(3).596-610. doi. 10.1D16.\u2022j ~1.2007.08.03.EI\n\n l(eufmM'ln WE S~IJlie J. Retl0'\"\"9 N. Haner,111 T Klami;ir D. Mlsslil'l!J CU ANA'VEX\u00a92-f3.(tllercarn9illl4!/. a Sl!lma-1 r909Ptor 9gonl&t Bn1ellQJate& n0vrok)glc1mp miB'f!tEi In a mou:e,,e m:idl;ll Flelti;~mtome\n Ph1nm:2col Biochcr11 Beh;:i-.,_ 2019 187.17279113 dai. 10.1D1EI~ pbb.2019. 172796\n l(aufmann WE. Pett:-/ A\u00a5. Lane JB. OD8fl'Tl1111 LM Touta,n S. F\u00abiroch JA, ~IS611ng CU Treelrn~of Aet1 &:;ndrome ..,.,th the :sigma-1 recep1orblareame&lne prel1n,r1111\")' effcacyanaty.&es lnadul15 NORD R11re\n Di~.:12!1 zmd Orpho,m Producl.!i 6r~k1!1rough Surrir11il (1:1bslntct/, Oe1olit!1 2t-22 20Hfu W1t!ihlr1glon.. 0 C\n\n Lahmy V, Loog Fl. Mc,rin D Vd~ V, \"'1aur,ce T. toctlondrl&I prol&etlon by lhe mlJ:edmo&CllftOO'o1 Ilg.and A.NAVEX2-73, a 1e-trah)'iittll'uren l8. J NeurCNmmWlAd~. J Neoroscl. 2015 Feb 11,J5161.2516-29 001. 10.1523/JNEUROSCl.277B-14.2D15\n K.,ufrn.1Tifl WE. Jotin,;ton Ml/, Blut1 r,.i E Mr.CP2 r-xprr-.,;~il)lt .ind frJnr.tion d.1ring br.a'1 dcvr.Jopmr.nt implc.1bon~ ftir Rr.tt ,;:,nliromr.\"s p,,ittiogr.nr.:-.,~ ;md cinir~ r.,v,oiuhOfl Br.iin Or.y 2005 t,,lcw 27 SuFJ!I 1\u00b7S77-S87\n 1101 10 1016,'j 1>ra1n<1e~.2~.1D.008\n\n Lappalain,en Fl R kon&n RS Hl;ih leYel& of oeretro&p nal lluh:t ~tamale In Rett &\"~l'l(JtOIJ'le Pedl~r Neurol 1996 Oct H,{3}21~ dol\u00b7 10 1016ts08Bt-8994({)6)0021S-4\n N~ul JL SJw,n~ SA. Armet1e f Lane J. Ht!yder11i:iru1 P' Jare11, M, Kl!Ufn'll!lnn WE Gl.:!Lt! P ~ AK M~labolil: Siyna!ure11, Difft!~nlii:ill!I Rt!l! Syndron,e frcrn UrllLffl!ld.t!d Slilir,g11, Frcr1I lnlft!Jf ~rD:M:i. 2020 Ft!b\n 2~14\u00b7/ dol\u00b7 1033,8.9,'tn,nt2:02000001\n\n\n\n\n dn~vex \u20224\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:20.328996-07:00","document_number":"23","attachment_number":5,"pacer_doc_id":"127036039505","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Presentation","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579229/","id":409579229,"tags":[],"absolute_url":"/docket/68511120/23/6/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.709977-07:00","date_modified":"2024-08-27T02:13:03.311328-07:00","sha1":"9ad2fe5c163afa5c3af4cac5e895d02987ef428e","page_count":44,"file_size":696566,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.6.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.6.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 1 of 44\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 2 of 44\n\n\n\n\nGuidance for Industry\nPatient-Reported Outcome Measures:\nUse in Medical Product Development\n to Support Labeling Claims\n\n\n\n\n U.S. Department of Health and Human Services\n Food and Drug Administration\n Center for Drug Evaluation and Research (CDER)\n Center for Biologics Evaluation and Research (CBER)\n Center for Devices and Radiological Health (CDRH)\n\n December 2009\n Clinical/Medical\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 3 of 44\n\n\n\n\nGuidance for Industry\nPatient-Reported Outcome Measures:\nUse in Medical Product Development\n to Support Labeling Claims\n Additional copies are available from:\n\n Office of Communications, Division of Drug Information\n Center for Drug Evaluation and Research\n Food and Drug Administration\n 10903 New Hampshire Ave., Bldg. 51, rm. 2201\n Silver Spring, MD 20993-0002\n Tel: 301-796-3400; Fax: 301-847-8714; E-mail: druginfo@fda.hhs.gov\n http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm\n\n or\n\n Office of Communication, Outreach, and Development, HFM-40\n Center for Biologics Evaluation and Research\n Food and Drug Administration\n 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448\n Tel: 800-835-4709 or 301-827-1800; E-mail: ocod@fda.hhs.gov\n http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm\n\n or\n\n Office of Communication, Education, and Radiation Programs\n Division of Small Manufacturers, International, and Consumer Assistance, HFZ-220\n Center for Devices and Radiological Health\n Food and Drug Administration\n 1350 Piccard Drive, Rockville, MD 20850-4307\n DSMICA E-mail: dsmica@cdrh.fda.gov\n DSMICA Fax: 301-443-8818\n (Tel) Manufacturers Assistance: 800-638-2041 or 301-443-6597\n (Tel) International Staff: 301-827-3993\n http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm\n\n\n U.S. Department of Health and Human Services\n Food and Drug Administration\n Center for Drug Evaluation and Research (CDER)\n Center for Biologics Evaluation and Research (CBER)\n Center for Devices and Radiological Health (CDRH)\n\n December 2009\n Clinical/Medical\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 4 of 44\n\n\n\n\n TABLE OF CONTENTS\n\nI. INTRODUCTION............................................................................................................. 1\nII. BACKGROUND ............................................................................................................... 2\nIII. EVALUATION OF A PRO INSTRUMENT ................................................................. 3\n A. Endpoint Model.............................................................................................................................. 3\n B. Choice of PRO Instrument............................................................................................................ 5\n C. Conceptual Framework of a PRO Instrument............................................................................ 7\n 1. Concepts Measured.......................................................................................................................... 7\n 2. Intended Population....................................................................................................................... 10\n D. Content Validity ........................................................................................................................... 12\n 1. Item Generation ............................................................................................................................. 12\n 2. Data Collection Method and Instrument Administration Mode .................................................... 13\n 3. Recall Period ................................................................................................................................. 14\n 4. Response Options........................................................................................................................... 14\n 5. Instrument Format, Instructions, and Training ............................................................................. 16\n 6. Patient Understanding ................................................................................................................... 16\n 7. Scoring of Items and Domains....................................................................................................... 16\n 8. Respondent and Administrator Burden.......................................................................................... 17\n E. Reliability, Other Validity, and Ability to Detect Change ....................................................... 18\n 1. Reliability....................................................................................................................................... 18\n 2. Other Validity ................................................................................................................................ 19\n 3. Ability to Detect Change................................................................................................................ 20\n F. Instrument Modification ............................................................................................................. 20\n G. PRO Instruments Intended for Specific Populations ............................................................... 21\n 1. Children and Adolescents .............................................................................................................. 21\n 2. Patients Cognitively Impaired or Unable to Communicate........................................................... 21\n 3. Culture or Language Subgroups.................................................................................................... 22\nIV. CLINICAL TRIAL DESIGN......................................................................................... 22\n A. General Protocol Considerations................................................................................................ 22\n 1. Blinding and Randomization.......................................................................................................... 22\n 2. Clinical Trial Quality Control ....................................................................................................... 23\n 3. Handling Missing Data.................................................................................................................. 23\n B. Frequency of Assessments........................................................................................................... 24\n C. Clinical Trial Duration ................................................................................................................ 24\n D. Design Considerations for Multiple Endpoints ......................................................................... 24\n E. Planning for Clinical Trial Interpretation Using a Responder Definition.............................. 24\n F. Specific Concerns When Using Electronic PRO Instruments ................................................. 26\nV. DATA ANALYSIS .......................................................................................................... 27\n A. General Statistical Considerations ............................................................................................. 27\n B. Statistical Considerations for Using Multiple Endpoints ......................................................... 28\n\n\n i\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 5 of 44\n\n\n\n C. Statistical Considerations for Composite Endpoints ................................................................ 29\n D. Statistical Considerations for Patient-Level Missing Data....................................................... 29\n 1. Missing Items within Domains....................................................................................................... 30\n 2. Missing Entire Domains or Entire Measurements......................................................................... 30\n E. Interpretation of Clinical Trial Results ..................................................................................... 30\nGLOSSARY................................................................................................................................. 31\nAPPENDIX: INFORMATION ON A PRO INSTRUMENT REVIEWED BY THE FDA 35\n\n\n\n\n ii\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 6 of 44\n\n Contains Nonbinding Recommendations\n\n\n Guidance for Industry1\n Patient-Reported Outcome Measures:\n Use in Medical Product Development\n to Support Labeling Claims\n\n\n\nThis guidance represents the Food and Drug Administration\u2019s (FDA\u2019s) current thinking on this topic. It\ndoes not create or confer any rights for or on any person and does not operate to bind FDA or the public.\nYou can use an alternative approach if the approach satisfies the requirements of the applicable statutes\nand regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for\nimplementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate\nnumber listed on the title page of this guidance.\n\n\n\n\nI. INTRODUCTION\n\nThis guidance describes how the Food and Drug Administration (FDA) reviews and evaluates\nexisting, modified, or newly created patient-reported outcome (PRO) instruments used to\nsupport claims in approved medical product labeling. 2 A PRO instrument (i.e., a questionnaire\nplus the information and documentation that support its use) is a means to capture PRO data used\nto measure treatment benefit or risk in medical product clinical trials. This guidance does not\naddress the use of PRO instruments for purposes beyond evaluation of claims made about a\nmedical product in labeling. This guidance also does not address disease-specific issues.\nGuidance on clinical trial endpoints for specific diseases can be found on various FDA Web\nsites. 3\n\nBy explicitly addressing the review issues identified in this guidance, sponsors can increase the\nefficiency of their discussions with the FDA during the medical product development process,\nstreamline the FDA\u2019s review of PRO instrument adequacy and resultant PRO data collected\n\n1\n This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the\nCenter for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH)\nat the Food and Drug Administration.\n2\n Labeling, as used in this guidance, refers to the information about an FDA-approved medical product intended for\nthe clinician to use in treating patients. See 21 CFR 201.56 and 201.57 for regulations pertaining to prescription\ndrug (including biological drug) labeling. Section 201.56 specifically describes the need for labeling that is not false\nor misleading. See 21 CFR part 801 for medical device labeling. See 21 CFR 606.122 for blood and blood products\nfor transfusion.\n3\n See the following FDA Web sites:\nhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (CDER),\nhttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm (CBER), and\nhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm (CDRH).\n 1\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 7 of 44\n\n Contains Nonbinding Recommendations\n\nduring a clinical trial, and provide optimal information about the patient perspective for use in\nmaking conclusions about treatment effect at the time of medical product approval. PRO\ninstrument development is an iterative process and we recognize there is no single correct way to\ndevelop a PRO instrument. Different strategies and methods can be used to address FDA review\nissues.\n\nThe Glossary defines many of the terms used in this guidance. Words or phrases found in the\nGlossary appear in bold italics at first mention. Specifically, we encourage sponsors to\nfamiliarize themselves with the terms conceptual framework of a PRO instrument, endpoint\nmodel, and content validity.\n\nFDA\u2019s guidance documents, including this guidance, do not establish legally enforceable\nresponsibilities. Instead, guidances describe the Agency\u2019s current thinking on a topic and should\nbe viewed only as recommendations, unless specific regulatory or statutory requirements are\ncited. The use of the word should in Agency guidances means that something is suggested or\nrecommended, but not required.\n\n\nII. BACKGROUND\n\nA PRO is any report of the status of a patient\u2019s health condition that comes directly from the\npatient, without interpretation of the patient\u2019s response by a clinician or anyone else. The\noutcome can be measured in absolute terms (e.g., severity of a symptom, sign, or state of a\ndisease) or as a change from a previous measure. In clinical trials, a PRO instrument can be used\nto measure the effect of a medical intervention on one or more concepts (i.e., the thing being\nmeasured, such as a symptom or group of symptoms, effects on a particular function or group of\nfunctions, or a group of symptoms or functions shown to measure the severity of a health\ncondition).\n\nGenerally, findings measured by a well-defined and reliable PRO instrument in appropriately\ndesigned investigations can be used to support a claim in medical product labeling if the claim is\nconsistent with the instrument\u2019s documented measurement capability. The amount and kind of\nevidence that should be provided to the FDA is the same as for any other labeling claim based on\nother data. Use of a PRO instrument is advised when measuring a concept best known by the\npatient or best measured from the patient perspective. A PRO instrument, like physician-based\ninstruments, should be shown to measure the concept it is intended to measure, and the FDA will\nreview the evidence that a particular PRO instrument measures the concept claimed. The\nconcepts measured by PRO instruments that are most often used in support of labeling claims\nrefer to a patient\u2019s symptoms, signs, or an aspect of functioning directly related to disease status.\nPRO measures often represent the effect of disease (e.g., heart failure or asthma) on health and\nfunctioning from the patient perspective.\n\nClaims generally appear in either the Indications and Usage or Clinical Studies section of\nlabeling, but can appear in any section. Regardless of the labeling section, PRO instrument\nevaluation principles described here apply.\n\n\n\n\n 2\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 8 of 44\n\n Contains Nonbinding Recommendations\n\n\nIII. EVALUATION OF A PRO INSTRUMENT\n\nThe evaluation of a PRO instrument to support claims in medical product labeling includes the\nfollowing considerations:\n\n \u2022 The population enrolled in the clinical trial\n \u2022 The clinical trial objectives and design\n \u2022 The PRO instrument\u2019s conceptual framework\n \u2022 The PRO instrument\u2019s measurement properties\n\nBecause the purpose of a PRO measure is to capture the patient\u2019s experience, an instrument will\nnot be a credible measure without evidence of its usefulness from the target population of\npatients. Sponsors should provide documented evidence of patient input during instrument\ndevelopment and of the instrument\u2019s performance in the specific application in which it is used\n(i.e., population, condition). An existing instrument can support a labeling claim if it can be\nshown to reliably measure the claimed concept in the patient population enrolled in the clinical\ntrial.\n\n A. Endpoint Model\n\nSponsors should define the role a PRO endpoint is intended to play in the clinical trial (i.e., a\nprimary, key secondary, or exploratory endpoint) so that the instrument development and\nperformance can be reviewed in the context of the intended role, and appropriate statistical\nmethods can be planned and applied. It is critical to plan these approaches in what can be called\nan endpoint model.\n\nFigures 1 and 2 show examples of endpoint models. In Figure 1, a PRO symptom assessment is\na secondary endpoint with a physiologic measure as the primary endpoint intended to support an\nindication for the treatment of Disease X. In this case, the clinical trial would need to succeed on\nthe physiologic endpoint before success could be attained on the secondary endpoints. In Figure\n2, a PRO symptom assessment is the primary clinical trial endpoint intended to support an\nindication for the treatment of symptoms associated with Disease Y and the physical\nperformance and limitation measures would be the key secondary endpoints. PRO instrument\nadequacy depends on its role and relationships with other clinical trial endpoints as depicted in\nthe endpoint model. The endpoint model explains the exact demands placed on the PRO\ninstrument to attain the evidence to meet the clinical trial objectives and support the targeted\nclaims corresponding to the concepts measured.\n\n\n\n\n 3\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 9 of 44\n\n Contains Nonbinding Recommendations\n\n\nFigure 1. Endpoint Model: Treatment of Disease X\n Concept Endpoints\n\n Indication Primary\n Treatment of Disease X Physiologic effect\n (non-PRO assessment)\n\n Supportive Concepts Secondary\n Improvement in symptoms/ Symptoms diary\n signs of Disease X (PRO assessment)\n Signs diary\n (PRO assessment)\n Physical exam\n (non-PRO assessment)\n Physical performance\n (PRO or non-PRO\n assessment)\n\n\n\nFigure 2. Endpoint Model: Treatment of Symptoms Associated with Disease Y\n Concept Endpoints\n\n Indication Primary\n Treatment of symptoms Total Disease Y symptoms score\n of Disease Y (PRO assessment)\n\n\n Supportive Concepts Secondary\n Other treatment benefit Physical performance\n (PRO or non-PRO\n assessment)\n Disease Y-related physical\n limitations (PRO\n assessment)\n\nTo help specify potential labeling claims and to facilitate communication with the FDA about the\nspecific clinical trials designed to assess the planned concepts, sponsors can use a target product\nprofile (TPP), which is a clinical development program summary in the context of prescribing\ninformation goals (i.e., targeted labeling claims). 4,5\n4\n See the draft guidance for industry and review staff Target Product Profile \u2014 A Strategic Development\nProcess Tool. When final, this guidance will represent the FDA\u2019s current thinking on this topic.\nFor the most recent version of a guidance, check the FDA Drug guidance Web page at\nhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.\n5\n Although the TPP process is used for drug and biologic approvals, the concept of beginning with the desired\nclaims and designing the clinical trials to assess these claims is similar for medical devices.\n 4\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 10 of 44\n\n Contains Nonbinding Recommendations\n\n\n\n B. Choice of PRO Instrument\n\nEarly in medical product development, sponsors planning to use a PRO instrument in support of\na labeling claim are encouraged to determine whether an adequate PRO instrument exists to\nassess and measure the concepts of interest. If it does not, a new PRO instrument can be\ndeveloped. In some situations, the new instrument can be developed by modifying an existing\ninstrument.\n\nThe adequacy of any PRO instrument, whether existing, modified, or newly developed, as a\nmeasure to support medical product labeling claims depends on whether its characteristics (see\nthis section), conceptual framework (see section III.C.), content validity (see section III.D.), and\nother measurement properties (see section III.E.) are satisfactory. The FDA will review\ndocumentation of PRO instrument development and testing in conjunction with clinical trial\nresults to determine whether a labeling claim is substantiated. The Appendix lists the type of\nPRO information sponsors should provide to the FDA to facilitate instrument review.\n\nCharacteristics of PRO instruments that are reviewed by the FDA include the following:\n\n \u2022 Concepts being measured\n \u2022 Number of items\n \u2022 Conceptual framework of the instrument\n \u2022 Medical condition for intended use\n \u2022 Population for intended use\n \u2022 Data collection method\n \u2022 Administration mode\n \u2022 Response options\n \u2022 Recall period\n \u2022 Scoring\n \u2022 Weighting of items or domains\n \u2022 Format\n \u2022 Respondent burden\n \u2022 Translation or cultural adaptation availability\n\nWe encourage instrument developers to make their instruments and related development history\navailable and accessible publicly. When development history is not available, sponsors generally\nshould provide documentation of content validity with an application (i.e., evidence that the\ninstrument measures what it is intended to measure), including open-ended patient input from the\nappropriate population. Content validity is discussed in more detail in section III.D., Content\nValidity. In addition, we anticipate empiric evidence of an instrument\u2019s other measurement\nproperties, discussed in more detail in section III.E., Reliability, Other Validity, and Ability to\nDetect Change.\n\nWe suggest that an instrument\u2019s measurement properties be well established before enrollment\nbegins for confirmatory clinical trials. Therefore, sponsors should begin instrument development\nand evaluation early in medical product development, and engage the FDA in a discussion about\na new or unique PRO instrument before confirmatory clinical trial protocols are finalized.\n 5\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 11 of 44\n\n Contains Nonbinding Recommendations\n\nRequests for FDA input should be addressed to the review division responsible for the medical\nproduct in question. For the FDA to provide useful early input, sponsors should provide their\nlabeling goals, a hypothesized PRO instrument conceptual framework, and the relationship of the\nPRO endpoints to other clinical trial endpoints in preliminary endpoint models for the planned\nconfirmatory trials.\n\nIf the measurement goal is to support a complex, multidomain concept, PRO instruments that\nmeasure a simple concept may not be adequate to substantiate the complex claim. For example,\nPRO-based evidence of improved symptoms alone will only support claims specific to\nimprovement of the symptoms and would not support a general claim related to improvement in\na patient\u2019s ability to function or the patient\u2019s psychological state. In addition, a complex,\nmultidomain claim cannot be substantiated by instruments that do not adequately measure the\nindividual component domain concepts adequately.\n\nPRO instruments can be used to measure important safety concerns if those concerns represent\nsymptoms or signs that are best captured from the patient perspective. The principles for PRO\ninstrument development are not different for this application.\n\nClaims representing general concepts often are not supported, even though the PRO instrument\nwas developed to measure the general concepts, because the instrument may not distinguish\nadverse side effects of treatment that affect the general concept and that may not be known at the\ntime the clinical trials are designed. If adverse effects are captured, PRO instruments should aim\nto measure the adverse consequences of treatment separately from the effectiveness of treatment.\nAs with any clinical trial evaluating FDA-regulated medical products, all adverse events detected\nwith a PRO instrument should be included in the clinical trial report.\n\nFigure 3 summarizes the iterative process used in developing a PRO instrument for use in\nclinical trials. FDA review of the developmental process documentation is discussed in more\ndetail in section III.C., Conceptual Framework of a PRO Instrument, through section III.G., PRO\nInstruments Intended for Specific Populations.\n\n\n\n\n 6\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 12 of 44\n\n Contains Nonbinding Recommendations\n\n\nFigure 3. Development of a PRO Instrument: An Iterative Process\n i. Hypothesize Conceptual Framework\n \u2022 Outline hypothesized concepts and potential claims\n \u2022 Determine intended population\n \u2022 Determine intended application/characteristics (type of scores,\n mode and frequency of administration)\n \u2022 Perform literature/expert review\n \u2022 Develop hypothesized conceptual framework\n \u2022 Place PROs within preliminary endpoint model\n \u2022 Document preliminary instrument development\n\n\nv. Modify Instrument ii. Adjust Conceptual\n\u2022 Change wording of items, Framework and Draft\n populations, response options, recall\n period, or mode/method of Instrument\n administration/data collection \u2022 Obtain patient input\n\u2022 Translate and culturally adapt to PRO \u2022 Generate new items\n other languages \u2022 Select recall period, response\n\u2022 Evaluate modifications as \u2195 options and format\n appropriate Claim \u2022 Select mode/method of\n\u2022 Document all changes administration/data collection\n \u2022 Conduct patient cognitive\n interviewing\n \u2022 Pilot test draft instrument\niv. Collect, Analyze, and \u2022 Document content validity\n Interpret Data\n\u2022 Prepare protocol and statistical analysis plan\n (final endpoint model and responder iii. Confirm Conceptual Framework and\n definition)\n\u2022 Collect and analyze data\n Assess Other Measurement Properties\n \u2022 Confirm conceptual framework with scoring rule\n\u2022 Evaluate treatment response using\n \u2022 Assess score reliability, construct validity, and ability to\n cumulative distribution and responder\n detect change\n definition\n \u2022 Finalize instrument content, formats, scoring, procedures\n\u2022 Document interpretation of treatment benefit\n and training materials\n in relation to claim\n \u2022 Document measurement development\n\n\n\n\n C. Conceptual Framework of a PRO Instrument\n\nThe adequacy of a proposed instrument to support a claim depends on the conceptual framework\nof the PRO instrument. The conceptual framework explicitly defines the concepts measured by\nthe instrument in a diagram that presents a description of the relationships between items,\ndomain (subconcepts), and concepts measured and the scores produced by a PRO instrument.\n\n 1. Concepts Measured\n\nOne fundamental consideration in the review of a PRO instrument is the adequacy of the item\ngeneration process to support the final conceptual framework of the instrument. In some cases,\nthe question of what to measure may be obvious given the condition being treated. For example,\nto assess the effect of treatment on pain, patients from the target population are queried about\npain severity using a single-item PRO instrument. Generally, when it is not obvious, instrument\ndevelopers initially can hypothesize a conceptual framework to support the measurement of the\nconcept of interest drafting the domains and items to be measured based on literature reviews\nand expert opinion. Subsequently, patient interviews, focus groups, and qualitative cognitive\ninterviewing ensures understanding and completeness of the concepts contained in the items.\n(See section III.D.1., Item Generation.)\n\nThe conceptual framework of a PRO instrument will evolve and be confirmed over the course of\ninstrument development as a sponsor gathers empiric evidence to support item grouping and\nscores. When used in a clinical trial, the PRO instrument\u2019s conceptual framework should again\nbe confirmed by the observed relationships among items and domains.\n\n 7\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 13 of 44\n\n Contains Nonbinding Recommendations\n\n\n\nDocumentation of the instrument development process should reveal the means by which the\nitems and domains were identified. The exact words used to represent the concepts measured by\ndomain or total scores should be derived using patient input to ensure the conclusions drawn\nusing instrument scores are valid.\n\nFor measures of general concepts, we intend to review how individual items are thought to be\nassociated with each other, how items are associated with each domain, and how domains are\nassociated with each other and the general concept of interest based on the conceptual framework\nof the PRO instrument. The diagram in Figure 4 depicts a generic example of a conceptual\nframework of a PRO instrument where Domain 1, Domain 2, and General Concept each\nrepresent related but separate concepts. Items in this diagram are aggregated into domains. The\nfinal framework is derived and confirmed by measurement property testing.\n\nFigure 4. Diagram of the Conceptual Framework of a PRO Instrument\n Item 1\n\n Item 2 Domain\n 1\n Item 3\n\n Item 4 General\n Concept\n\n Item 5\n Domain\n Item 6 2\n\n\n\n\nThe conceptual framework of a PRO instrument may be straightforward if a single item is a\nreliable and valid measure of the concept of interest (e.g., pain intensity). If the concept of\ninterest is general (e.g., physical function), a single-item PRO instrument does not provide a\nuseful understanding of the treatment\u2019s effect because a stand-alone single item does not capture\nthe domains of the general concept. For this reason, single-item questions about general\nconcepts that include multiple items or domains rarely provide sufficient evidence to support\nclaims about that general concept. For example, in clinical trials of functional disorders defined\nby clusters of specific symptoms and signs, a PRO instrument consisting of a single-item global\nquestion usually would be inadequate as an endpoint to support labeling claims and would be\nuninformative about the effects on each specific symptom and sign. Instead, the effect of\ntreatment on each of the appropriate symptoms and signs should be adequately measured.\n\nThe conceptual framework for PRO instruments intended to measure a general concept will be\ncomplex because identifying all of the appropriate domains and items of the general concept can\nbe difficult. Multidomain PRO instruments can be used to support claims about a general\nconcept if the PRO instrument has been developed to measure the important and relevant\n\n 8\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 14 of 44\n\n Contains Nonbinding Recommendations\n\ndomains of the general concept contained in the claim. However, the complex nature of\nmultidomain PRO instruments often raises significant questions about how to interpret and report\nresults in a way that is not misleading. For example, if improvement in a score for a general\nconcept (e.g., symptoms associated with a certain condition) is driven by a single responsive\nitem (e.g., pain intensity improvement) whereas other important items (e.g., other symptoms) did\nnot show a response, a general claim about the general concept (e.g., improvements in symptoms\nassociated with the condition) cannot be supported. However, that single responsive item or\ndomain may support a claim specific to that item or domain.\n\nWe intend to examine the final version of an instrument in light of its development history,\nincluding documentation of the complete list of items generated and the reasons for deleting or\nmodifying items, as illustrated in Table 1. We will determine from empiric evidence provided\nwhether the PRO instrument\u2019s final conceptual framework (e.g., the hypothesized relationships\namong items, domains, and concepts measured) is confirmed in the appropriate study population\nand is consistent with the endpoint model of the planned clinical trials.\n\n Table 1. Common Reasons for Changing Items during PRO Instrument Development\n Item Property Reason for Change or Deletion\n Clarity or relevance \u2022 Reported as not relevant by a large segment of the target population\n \u2022 Generates an unacceptably large amount of missing data points\n \u2022 Generates many questions or requests for clarification from patients as they\n complete the PRO instrument\n \u2022 Patients interpret items and responses in a way that is inconsistent with the\n PRO instrument\u2019s conceptual framework\n Response range \u2022 A high percent of patients respond at the floor (response scale\u2019s worst end)\n or ceiling (response scale\u2019s optimal end)\n \u2022 Patients note that none of the response choices applies to them\n \u2022 Distribution of item responses is highly skewed\n\n Variability \u2022 All patients give the same answer (i.e., no variance)\n \u2022 Most patients choose only one response choice\n \u2022 Differences among patients are not detected when important differences are\n known\n Reproducibility \u2022 Unstable scores over time when there is no logical reason for variation from\n one assessment to the next\n Inter-item correlation \u2022 Item highly correlated (redundant) with other items in the same concept of\n interest\n Ability to detect change \u2022 Item is not sensitive (i.e., does not change when there is a known change in\n the concepts of interest)\n Item discrimination \u2022 Item is highly correlated with measures of concepts other than the one it is\n intended to measure\n \u2022 Item does not show variability in relation to some known population\n characteristics (i.e., severity level, classification of condition, or other known\n characteristic)\n Redundancy \u2022 Item duplicates information collected with other items that have equal or\n better measurement properties\n Recall period \u2022 The population, disease state, or application of the instrument can affect the\n appropriateness of the recall period\n\n\n\n 9\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 15 of 44\n\n Contains Nonbinding Recommendations\n\n 2. Intended Population\n\nUsing documentation of the process described in Figure 3 and of the measurement properties as\ndescribed in Table 2, we plan to compare the patient population studied in the PRO instrument\ndevelopment process to the population enrolled in the clinical trial to determine whether the\ninstrument is applicable for that population. See the Appendix for a description of the types of\ninformation sponsors should provide for FDA discussion and review of PRO instruments.\n\nSpecific measurement considerations posed by pediatric, cognitively impaired, or seriously ill\npatients are discussed in section III.G., PRO Instruments Intended for Specific Populations.\n\n\n\n\n 10\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 16 of 44\n\n Contains Nonbinding Recommendations\n\n\nTable 2. Measurement Properties Considered in the Review of PRO Instruments Used in Clinical Trials\n Measurement Type What Is Assessed? FDA Review Considerations\n Property\nReliability Test-retest or intra- Stability of scores over time when no change \u2022 Intraclass correlation coefficient\n interviewer reliability (for is expected in the concept of interest \u2022 Time period of assessment\n interviewer-administered\n PROs only)\n Internal consistency \u2022 Extent to which items comprising a scale \u2022 Cronbach\u2019s alpha for summary scores\n measure the same concept \u2022 Item-total correlations\n \u2022 Intercorrelation of items that contribute\n to a score\n \u2022 Internal consistency\n Inter-interviewer reliability Agreement among responses when the PRO \u2022 Interclass correlation coefficient\n (for interviewer-administered is administered by two or more different\n PROs only) interviewers\n\n\nValidity Content validity Evidence that the instrument measures the \u2022 Derivation of all items\n concept of interest including evidence from \u2022 Qualitative interview schedule\n qualitative studies that the items and domains \u2022 Interview or focus group transcripts\n of an instrument are appropriate and \u2022 Items derived from the transcripts\n comprehensive relative to its intended \u2022 Composition of patients used to develop content\n measurement concept, population, and use. \u2022 Cognitive interview transcripts to evaluate patient\n Testing other measurement properties will understanding\n not replace or rectify problems with content\n validity.\n Construct validity Evidence that relationships among items, \u2022 Strength of correlation testing a priori hypotheses\n domains, and concepts conform to a priori (discriminant and convergent validity)\n hypotheses concerning logical relationships \u2022 Degree to which the PRO instrument can distinguish\n that should exist with measures of related among groups hypothesized a priori to be different\n concepts or scores produced in similar or (known groups validity)\n diverse patient groups\nAbility to detect Evidence that a PRO instrument can identify \u2022 Within person change over time\nchange differences in scores over time in individuals \u2022 Effect size statistic\n or groups (similar to those in the clinical\n trials) who have changed with respect to the\n measurement concept\n\n\n\n\n 11\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 17 of 44\n\n Contains Nonbinding Recommendations\n\n\n\n D. Content Validity\n\nContent validity is the extent to which the instrument measures the concept of interest. Content\nvalidity is supported by evidence from qualitative studies that the items and domains of an\ninstrument are appropriate and comprehensive relative to its intended measurement concept,\npopulation, and use. Content validity is specific to the population, condition, and treatment to be\nstudied. For PRO instruments, items, domains, and general scores reflect what is important to\npatients and comprehensive with respect to patient concerns relevant to the concept being\nassessed. Documentation of patient input in item generation as well as evaluation of patient\nunderstanding through cognitive interviewing can contribute to evidence of content validity.\nEvidence of other types of validity (e.g., construct validity) or reliability (e.g., consistent scores)\nwill not overcome problems with content validity because we evaluate instrument adequacy to\nmeasure the concept represented by the labeling claim. It is important to establish content\nvalidity before other measurement properties are evaluated.\n\nWhen evaluating the utility of an existing instrument or developing a new PRO instrument,\nsponsors are encouraged to support the adequacy of the instrument\u2019s content validity by\ndocumenting the following development processes and instrument attributes.\n\n 1. Item Generation\n\nItem generation should include input from the target patient population to establish the items that\nreflect the concept of interest and contribute to its evaluation. The population will help generate\nitem wording, evaluate the completeness of item coverage, and perform initial assessment of\nclarity and readability. PRO instrument items can be generated from literature reviews,\ntranscripts from focus groups, or interviews with patients, clinicians, family members,\nresearchers, or other sources. We may review whether appropriate individuals and sources were\nused and how information gleaned from those sources was used in the PRO instrument\ndevelopment process. We will also review whether open-ended patient interviews provide a full\nunderstanding of the patient\u2019s perspective of the concept of interest.\n\nItem generation generally incorporates the input of a wide range of patients with the condition of\ninterest to represent variations in severity and in population characteristics such as age, sex,\nethnicity, and language groups in accordance with the anticipated clinical trial design.\n\nWithout adequate documentation of patient input, a PRO instrument\u2019s content validity is likely to\nbe questioned. We will review documentation to determine that the items cover all aspects of the\nconcept important to patients, and that saturation has been reached. Saturation is reached at the\npoint when no new relevant or important information emerges and collecting additional data will\nnot likely add to the understanding of how patients perceive the concept of interest and the items\nin the questionnaire.\n\nDocumentation provided to the FDA to support content validity should include all item\ngeneration techniques used, including any theoretical approach; the populations studied; source\nof items; selection, editing, and reduction of items; cognitive interview summaries or transcripts;\n\n\n 12\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 18 of 44\n\n Contains Nonbinding Recommendations\n\npilot testing; importance ratings; and quantitative techniques for item evaluation. Table 1 lists\ncommon reasons for changing items.\n\nIf items are not generated in all language groups included in the clinical trials, the\nappropriateness of the content should be addressed in cognitive interviewing in each language\ngroup tested. An item tracking matrix may be helpful to document the changes or deletions in\nitems and the reasons for those changes.\n\nWith existing instruments, it cannot be assumed that the instrument has content validity if\npatients were not involved in instrument development. New qualitative work similar to that\nconducted when developing a new instrument can provide documentation of content validity for\nexisting instruments if patient interviews or focus groups are conducted using open-ended\nmethods to elicit patient input. Such qualitative testing of existing instruments is particularly\nimportant if a review of the instrument content gives cause for concern. For example, if\nsymptoms known to be common to the population to be studied in the clinical trial are missing\nfrom a measure meant to capture important symptoms in that population, we will question the\ninstrument\u2019s content validity. We cannot provide recommendations for the number or size of the\nindividual patient interviews or focus groups for establishing content validity. The sample size\ndepends on the completeness of the information obtained from analysis of the transcripts.\nGenerally, the number of patients is not as critical as interview quality and patient diversity\nincluded in the sample in relation to intended clinical trial population characteristics.\n\nItems that ask patients to respond hypothetically may cause patients to respond on the basis of\ntheir desired condition rather than on their actual condition and therefore are not recommended\nfor clinical trials. For example, in assessing the concept ability to perform daily activities, it is\nmore appropriate to ask whether or not the patient performed specific activities (and if so, with\nhow much difficulty) than whether or not the patient perceived that he or she can perform daily\nactivities, because patients may report they are able to perform a task even when they never do\nthe task.\n\nWhen using multi-item instruments, it is important that all items be relevant to most of the\npatients in the clinical trial. Using the example in the previous paragraph, it would be severely\ndisadvantageous to use a measure with items that include activities most of the clinical trial\npatients would not perform. Doing so would yield a bias toward the null, or a tendency to show\nno effect of treatment, even if the treatment were effective. In such cases, a negative response\n(or indication of little to no activity) is not useful. Use of not applicable response options creates\nproblems with scoring. Skip patterns may create difficulties in administration.\n\n 2. Data Collection Method and Instrument Administration Mode\n\nSponsors should consider the data collection method and all procedures and protocols associated\nwith the instrument administration mode, including instructions to interviewers, instructions for\nself-administration, or instructions for supervising self-administration. We will review data\nquality control procedures specific to the data collection method or instrument administration\nmode along with case report forms or screen shots of electronic PRO instruments.\nAdministration modes can include self-administration, interview, or a combination of both. Data\n\n\n 13\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 19 of 44\n\n Contains Nonbinding Recommendations\n\ncollection methods can include paper-based, computer-assisted, and telephone-based\nassessments. We intend to review the comparability of data obtained when using multiple data\ncollection methods or administration modes within a single clinical trial to determine whether the\ntreatment effect varies by method or mode. If a patient diary or some other form of unsupervised\ndata entry is used, we plan to review the clinical trial protocol to determine what steps are taken\nto ensure that patients make entries according to the clinical trial design and not, for example,\njust before a clinic visit when their reports will be collected.\n\n 3. Recall Period\n\nSponsors should also evaluate the rationale and the appropriateness of the recall period for a\nPRO instrument. To this end, it is important to consider patient ability to validly recall the\ninformation requested. The choice of recall period that is most suitable depends on the\ninstrument\u2019s purpose and intended use; the variability, duration, frequency, and intensity of the\nconcept measured; the disease or condition\u2019s characteristics; and the tested treatment. When\nevaluating PRO-based claims, we intend to review the clinical trial protocol to determine what\nsteps were taken to ensure that patients understood the instrument recall period. In many cases,\nwhat is of real interest is not the integrated effect over a short time period (e.g., 2-week period),\nbut the effect at regular intervals (e.g., 2, 4, and 6 weeks), similar to how measurements might be\nmade every 2 weeks in a blood pressure trial. In that case, patients can be asked to report on\nrecent status. Note also that any problems created by differential recall are likely to add noise\nand obscure treatment effects.\n\nPRO instruments that call for patients to rely on memory, especially if they must recall over a\nlong period of time, compare their current state with an earlier period, or average their response\nover a period of time, are likely to undermine content validity. Response is likely to be\ninfluenced by the patient\u2019s state at the time of recall. For these reasons, items with short recall\nperiods or items that ask patients to describe their current or recent state are usually preferable.\nIf detailed recall of experience over a period of time is necessary, we recommend the instrument\nuse appropriate methods and techniques for enhancing the validity and reliability of\nretrospectively reported data (e.g., ask patients to respond based on their worst (or best)\nexperience over the recall period or make use of a diary for data collection).\n\n 4. Response Options\n\nIt is also important to consider whether the response options for each item are consistent with its\npurpose and intended use. Table 3 describes some of the various types of item response options\nthat are typically seen in PRO instruments.\n\n\n\n\n 14\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 20 of 44\n\n Contains Nonbinding Recommendations\n\n\n Table 3. Response Option Types\n Type Description\n Visual analog A line of fixed length (usually 100 mm) with words that anchor the scale at the extreme ends\n scale (VAS) and no words describing intermediate positions. Patients are instructed to indicate the place\n on the line corresponding to their perceived state. The mark\u2019s position is measured as the\n score.\n Anchored or A VAS that has the addition of one or more intermediate marks positioned along the line with\n categorized reference terms assigned to each mark to help patients identify the locations between the\n scale\u2019s ends (e.g., half-way).\n VAS\n Likert scale An ordered set of discrete terms or statements from which patients are asked to choose the\n response that best describes their state or experience.\n Rating scale A set of numerical categories from which patients are asked to choose the category that best\n describes their state or experience. The ends of rating scales are anchored with words but the\n categories are numbered rather than labeled with words.\n Recording of Specific events are recorded as they occur using an event log that can be included in a patient\n events as they diary or other reporting system (e.g., interactive voice response system).\n occur\n Pictorial scale A set of pictures applied to any of the other response option types. Pictorial scales are often\n used in pediatric questionnaires but also have been used for patients with cognitive\n impairments and for patients who are otherwise unable to speak or write.\n Checklist Checklists provide a simple choice between a limited set of options, such as Yes, No, and\n Don\u2019t know. Some checklists ask patients to place a mark in a space if the statement in the\n item is true. Checklists are reviewed for completeness and nonredundancy.\n\n\nItem response options generally are considered appropriate when:\n\n \u2022 Wording used in responses is clear and appropriate (e.g., anchoring a scale using the term\n normal assumes that patients understand what is normal for the general population).\n\n \u2022 The item response options are appropriate for the intended population. For example,\n patients with visual impairment may find a VAS difficult to complete.\n\n \u2022 Responses offer a clear distinction between choices (e.g., patients may not distinguish\n between intense and severe if both are offered as response choices to describe their pain).\n\n \u2022 Instructions to patients for completing items and selecting responses for the items are\n adequate.\n\n \u2022 The number of response options is justified empirically (e.g., using qualitative research,\n initial instrument testing, or existing literature).\n\n \u2022 Responses for an item are appropriately ordered and represent similar intervals.\n\n \u2022 Responses for items avoid potential ceiling or floor effects (e.g., it may be necessary to\n introduce more responses to capture worsening or improvement so that fewer patients\n respond at the response continuum top or bottom).\n\n \u2022 Responses do not bias the direction of responses (e.g., bias exists if possible responses\n are weighted toward the severity spectrum\u2019s mild end with two severity options for mild\n and only one each for moderate and severe).\n\n\n 15\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 21 of 44\n\n Contains Nonbinding Recommendations\n\n\n\n 5. Instrument Format, Instructions, and Training\n\nResults obtained using a PRO instrument can vary according to the instructions given to patients\nor the training given to the interviewer or persons supervising PRO data collection during a\nclinical trial. Sponsors should consider all PRO instrument instructions and procedures\ncontained in publications and user manuals provided by developers, including procedures for\nreviewing completed questionnaires and procedures used to avoid missing data or clarify\nresponses.\n\nIt is important that the PRO instrument format used in the clinical trial be consistent with the\nformat that is used during the instrument development process. Format refers to the exact\nquestionnaire, diary, or interview script appearance used to collect the PRO data. Format is\nspecific to the administration mode and the data collection method. We plan to review the\nspecific format used in the clinical trial including the order and numbering of items, the\npresentation of response options in single response or grid formats, the grouping of items,\npatterns for skipping questions, and all instructions to interviewers or patients.\n\nWe recommend that the user manual provided by a developer during the PRO instrument\ndevelopment process specify how to incorporate the instrument into a clinical trial in a way that\nminimizes administrator burden, patient burden, missing data, and poor data quality. The user\nmanual should explain to investigators and interviewers critical principles of PRO\nadministration.\n\n 6. Patient Understanding\n\nWhen the initial and subsequent drafts of an instrument are prepared, sponsors are encouraged to\nexamine all items and procedures in a pilot test of whether patients understand the items and\ninstructions included in the PRO instrument. This examination should include documentation\nthat the concepts represented in the PRO instrument\u2019s conceptual framework are confirmed, that\nthe response options and recall period are appropriately comprehended, and that the instrument\u2019s\nreadability is adequate for the intended population. The FDA\u2019s evaluation of these procedures is\nlikely to include a review of a cognitive interviewing report containing the script used in patient\ncognitive interviews, the interview transcripts, the readability test used (if applicable), the\nusability testing process description (if applicable), the cognitive interviews analysis, and the\nactions taken to delete or modify items, response scales, or patient instructions in response to the\ncognitive interview or pilot test results. Evidence from the patient cognitive interview studies\n(i.e., the interview schedule, transcript, and listing of all concepts elicited by a single item) can\nbe used to determine when a concept is adequately captured. Repeating cognitive interviews can\nhelp confirm content validity.\n\n 7. Scoring of Items and Domains\n\nFor each item, numerical scores generally should be assigned to each answer category based on\nthe most appropriate scale of measurement for the item (e.g., nominal, ordinal, interval, or ratio\n\n\n\n\n 16\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 22 of 44\n\n Contains Nonbinding Recommendations\n\nscales). We will review the distribution of item responses to ensure that the response choices\nrepresent appropriate intervals.\n\nA scoring algorithm creates a single score from multiple items. We will review the evidence that\nthe summary score is appropriate. Equally weighted scores for each item are appropriate when\nthe responses to the items are independent. If two items are dependent, their collected\ninformation is less than two independent items and they are over-weighted when they are treated\nas two equally weighted items. Over-weighting also may be a concern when the number of\nresponse options or the values associated with response options varies by item. The same\nweighting concerns apply with added complexity when combining domain scores into a single\ngeneral score. Using qualitative research or defined statistical techniques, sponsors should\njustify the method chosen to combine items to create a score or to combine domain scores to\ncreate a general score.\n\nWhen empirically determined patient preference ratings are used to weight items or domains, we\nintend to review the composition of samples and the process used to determine the preference\nweights. Because preference weights are often developed for use in resource allocation (e.g., as\nin cost-effectiveness analysis that may use predetermined community weights), it is tempting to\nuse those same weights in the clinical trial setting to demonstrate treatment benefit. However,\nthis practice is discouraged unless the preference weights\u2019 relationship to the intended clinical\ntrial population is known and found adequate and appropriate.\n\nTotal scores combining multiple domains should be supported by evidence that the total score\nrepresents a single albeit complex concept. As described earlier in section III.C., Conceptual\nFramework of a PRO Instrument, the instrument\u2019s final conceptual framework documents the\nconcept represented by each score. If a score is intended to support a targeted claim, the concept\nmeasured will match the targeted claim language. Generally, we discourage claims expressed in\nterms of domain or instrument titles because they often do not represent the concept measured.\n\n 8. Respondent and Administrator Burden\n\nUndue physical, emotional, or cognitive strain on patients generally decreases the quality and\ncompleteness of PRO data. Factors that can contribute to respondent burden include the\nfollowing:\n\n \u2022 Length of questionnaire or interview\n\n \u2022 Formatting\n\n \u2022 Font size too small to read easily\n\n \u2022 New instructions for each item\n\n \u2022 Requirement that patients consult records to complete responses\n\n\n\n\n 17\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 23 of 44\n\n Contains Nonbinding Recommendations\n\n\n \u2022 Privacy of the setting in which the PRO is completed (e.g., not providing a private space\n for patients to complete questionnaires containing sensitive information about their\n sexual performance or substance abuse history)\n\n \u2022 Inadequate time to complete questionnaires or interviews\n\n \u2022 Literacy level too high for population\n\n \u2022 Questions that patients are unwilling to answer\n\n \u2022 Perception by patients that the interviewer wants or expects a particular response\n\n \u2022 Need for physical help in responding (e.g., turning pages, holding a pen, assistance with a\n telephone or computer keyboard)\n\nThe degree of respondent burden that is tolerable for instruments in clinical trials depends on the\nfrequency and timing of PRO assessments in a protocol and on patient cognition, illness severity,\nor treatment toxicity. For example, if the questionnaire contains instructions to skip one or more\nquestions based on response to a previous question, respondents may fail to understand what to\ndo and make errors in responding or find the assessment too complicated to complete. Sponsors\nshould consider missing data and the refusal rate as possible indications of inappropriate\nrespondent burden or inappropriate items or response options.\n\n E. Reliability, Other Validity, and Ability to Detect Change\n\nOnce the instrument\u2019s content validity has been established, we intend to consider the following\nadditional measurement properties during FDA review of a PRO instrument: reliability, construct\nvalidity, and ability to detect change. We plan to review the measurement properties that are\nspecific to the documented PRO instrument\u2019s conceptual framework, confirmed scoring\nalgorithm, administration procedures, and questionnaire format in light of the clinical trial\u2019s\nobjectives, design, enrolled population, and statistical analysis plan (SAP). We also plan to\nreview whether the population and medical conditions included in any sample used to develop or\ntest a PRO instrument are appropriate for the planned clinical trials.\n\nIn addition, an adequate study to evaluate any specific measurement property of a PRO\ninstrument should be designed to test a prespecified hypothesis. For example, if the study\ncompares a new PRO measure to an existing measure of the same concept administered during\nthe same interview or within a short time of each other to establish construct validity, the study\nshould be designed to test the hypothesized level of correlation and the results should be\ndiscussed in light of that hypothesis.\n\n 1. Reliability\n\nBecause clinical trials measure change over time, the adequacy of a PRO instrument for use in a\nclinical trial depends on its reliability or ability to yield consistent, reproducible estimates of true\ntreatment effect.\n\n\n 18\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 24 of 44\n\n Contains Nonbinding Recommendations\n\n\n\nWe will review documentation of tests to determine if reproducibility (e.g., test-retest reliability)\nhas been demonstrated. Test-retest is most informative when the time interval chosen between\nthe test and retest is long enough in stable patients to minimize memory effects. The time\ninterval chosen depends on the variability of the state or experience being evaluated and on the\npotential for change in the condition or population over time that reflects actual change in the\ncondition rather than variability in stable patients. Test-retest reliability can be tested over a\nvariety of periods to satisfy different study protocols or even in different intervals between visits\nin the same protocol. We acknowledge that for remitting and relapsing or episodic diseases, test-\nretest reliability may be difficult or impossible to establish.\n\nInternal consistency reliability tests (e.g., Cronbach\u2019s alpha) to determine agreement among\nresponses to different questions, in the absence of test-retest reliability, may not constitute\nsufficient evidence of reliability for clinical trial purposes. However, as is true for other\nimperfections in testing, in general, flaws in reliability tend to increase the beta (Type II) error,\nand instruments demonstrating poor reliability are unlikely to give a false positive result.\n\nWhen PRO instruments are interviewer-administered, we will review inter-interviewer\nreproducibility. Inter-interviewer reproducibility depends on instrument administration\nstandardization and interviewer training on this standard.\n\n 2. Other Validity\n\nIn addition to content validity (discussed in section III.D., Content Validity), we will evaluate\nevidence of construct validity, and if appropriate, criterion validity.\n\nConstruct validity is determined by evidence that relationships among items, domains, and\nconcepts conform to a priori hypotheses concerning logical relationships that should exist with\nother measures or characteristics of patients and patient groups.\n\nWe will review the construct validity of an instrument to determine whether the documented\nrelationships between results gathered using the instrument and results gathered using other\nmeasures are consistent with pre-existing hypotheses concerning those relationships (i.e.,\ndiscriminant and convergent validity). We will also review evidence that the instrument can\ndifferentiate between clinically distinct groups (i.e., known groups validity).\n\nAs stated earlier, single-item questions about general concepts are not useful to support claims;\nhowever, they can be useful to help assess the construct validity of multi-item measures of the\nsame concept and to determine whether important items or domains of a general concept are\nmissing. For example, when results using single-item general questions do not correlate with\nresults using a multi-item questionnaire of the same general concept, this may be evidence that\nthe questionnaire is not capturing all the important domains of the general concept.\n\nCriterion validity is the extent to which the scores of a PRO instrument are related to a known\ngold standard measure of the same concept. In rare cases, we will also review the criterion\nvalidity of an instrument if a criterion measure is purported for the PRO concept assessed (e.g.,\n\n\n 19\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 25 of 44\n\n Contains Nonbinding Recommendations\n\ncomparing a new sleep scale to a clinical measure of polysomnography). However, for most\nPROs, criterion validity testing is not possible because the nature of the concept to be measured\ndoes not allow for a criterion measure to exist. This is true for any symptom measure where the\nsymptom is known only to the patient. If a criterion measure is used, sponsors should provide\nrationale and support for that criterion. We will review the extent to which the PRO measure is\ncorrelated with the criterion measure as well as the sensitivity, specificity, and predictive value\nof the criterion measure.\n\n 3. Ability to Detect Change\n\nWe will review an instrument\u2019s ability to detect change using data that compare change in PRO\nscores to change in other similar measures that indicate that the patient\u2019s state has changed with\nrespect to the concept of interest. A review of the ability to detect change includes evidence that\nthe instrument is equally sensitive to gains and losses in the measurement concept and to change\nat all points within the entire range expected for the clinical trial population.\n\nWhen patient experience of a concept is predicted to change, the values for the PRO instrument\nmeasuring that concept should change. If there is clear evidence that patient experience relative\nto the concept has changed, but the PRO scores do not change, then either the ability to detect\nchange is inadequate or the PRO instrument\u2019s validity should be questioned. If there is evidence\nthat PRO scores are affected by changes that are not specific to the concept of interest, the PRO\ninstrument\u2019s validity may be questioned.\n\nThe ability of an instrument to detect change influences the sample size for evaluating the\neffectiveness of treatment. The extent to which the PRO instrument\u2019s ability to detect change\nvaries by important patient subgroups (e.g., sex, race, or age) can affect clinical trial results. If\nimportant subgroup differences in ability to detect change are known, these documented\ndifferences can be taken into account in assessing results. In general, an inability to detect\nchange tends to support the null hypothesis of no treatment effect.\n\n F. Instrument Modification\n\nThe adequacy of an instrument\u2019s development and testing is specific to its intended application\nin terms of population, condition, and other aspects of the measurement context for which the\ninstrument was developed. When a PRO instrument is modified, sponsors generally should\nprovide evidence to confirm the new instrument\u2019s adequacy. That is not to say that every small\nchange in application or format necessitates extensive studies to document the final version\u2019s\nmeasurement properties. Additional qualitative work may be adequate depending on the type of\nmodification made. Examples of changes that can alter the way that patients respond to the same\nset of questions include:\n\n \u2022 Changing an instrument from paper to electronic format\n\n \u2022 Changing the timing of or procedures for PRO instrument administration within the clinic\n visit\n\n\n\n 20\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 26 of 44\n\n Contains Nonbinding Recommendations\n\n\n \u2022 Changing the application to a different setting, population, or condition\n\n \u2022 Changing the order of items, item wording, response options, or recall period or deleting\n portions of a questionnaire\n\n \u2022 Changing the instructions or the placement of instructions within the PRO instrument\n\nA small nonrandomized study may be adequate to compare the distribution of responses between\nversions of a questionnaire with different formats (e.g., changing a response scale from vertical\nto horizontal). If the PRO instrument will be used in a significantly different patient population\n(e.g., a different disease or age group), we may recommend using qualitative studies to confirm\ncontent validity in the new population. A small randomized study to ascertain the measurement\nproperties in the new population may minimize the risk that the instrument will not perform\nadequately.\n\n G. PRO Instruments Intended for Specific Populations\n\nAs previously mentioned, if multiple versions of an instrument will be used in a clinical trial,\ndocumentation should exist that the content validity and other measurement properties of those\nversions are similar to each other. Measurement of PRO concepts in children and adolescents, in\npatients who have cognitive impairment or are unable to communicate because of serious illness,\nand across culture or language groups introduces challenges in addition to those already\nmentioned. These challenges are discussed below.\n\n 1. Children and Adolescents\n\nIn general, the review issues related to the development process for pediatric PRO instruments\nare similar to the issues detailed for adults. Additional review issues for PRO instruments\napplied in children and adolescents include age-related vocabulary, language comprehension,\ncomprehension of the health concept measured, and duration of recall. Instrument development\nwithin fairly narrow age groupings is important to account for developmental differences and to\ndetermine the lower age limit at which children can understand the questions and provide reliable\nand valid responses that can be compared across age categories. We discourage proxy-reported\noutcome measures for this population (i.e., reports by someone who is not the patient responding\nas if that person were the patient). For patients who cannot respond for themselves (e.g., infant\npatients), we encourage observer reports that include only those events or behaviors that can be\nobserved. For example, observers cannot validly report an infant\u2019s pain intensity but can report\ninfant behavior thought to be caused by pain.\n\n 2. Patients Cognitively Impaired or Unable to Communicate\n\nWe discourage proxy-reported outcome measures for this population. For patients who cannot\nrespond for themselves (e.g., cognitively impaired), we encourage observer reports that include\nonly those events or behaviors that can be observed.\n\n\n\n\n 21\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 27 of 44\n\n Contains Nonbinding Recommendations\n\n 3. Culture or Language Subgroups\n\nBecause many development programs are multinational, application of PRO instruments to\nmultiple cultures or languages is common in clinical trials. Regardless of whether the instrument\nwas developed concurrently in multiple cultures or languages or whether a fully developed\ninstrument was adapted or translated to new cultures or languages, we recommend that sponsors\nprovide evidence that the content validity and other measurement properties are adequately\nsimilar between all versions used in the clinical trial. We will review the process used to\ntranslate and culturally adapt the instrument for populations that will use them in the trial.\n\n\nIV. CLINICAL TRIAL DESIGN\n\nThe same clinical trial design principles that apply to other endpoint measures also apply to\nPROs. Therefore, this section is not a comprehensive overview of those principles but rather\nfocuses primarily on issues unique to PRO endpoints.\n\n A. General Protocol Considerations\n\nIf the PRO measurement goal is to support labeling claims, PRO concept measurement should be\nstated as a specific clinical trial objective or hypothesis. It is important that the case report form\nin the protocol include the exact format and version of the specific PRO instrument to be\nadministered. If an electronic version of the instrument will be used, the protocol can include\nscreen shots or other similar instrument representations. In the process of considering the new\ndrug application (NDA)/biologics license application (BLA)/medical device premarket approval\n(PMA) or NDA/BLA/PMA supplement, we intend to compare both the planned and actual PRO\ninstrument used and its analysis.\n\n 1. Blinding and Randomization\n\nOpen-label clinical trials, where patients and investigators are aware of assigned therapy, are\nrarely adequate to support labeling claims based on PRO instruments. Patients who know they\nare in an active treatment group may overestimate benefit whereas patients who know they are\nnot receiving active treatment may underreport any improvement actually experienced. For the\nsame reasons, to prevent influencing patient perceptions, PRO instruments administered during a\nclinic visit should be administered before other clinical assessments or procedures.\n\nIn blinded clinical trials, patients should be blinded to treatment assignment throughout the trial.\nIf the treatment has obvious effects, such as adverse events, the clinical trial may be at risk for\nunintentional unblinding. In these situations, sponsors can use PRO instrument administration\ntechniques that may minimize the effects of possible unblinding, such as using response options\nthat ask for current status, not giving patients access to previous responses, and using instruments\nthat include many items about the same concept.\n\nSuspicion of inadvertent unblinding can be a problematic review consideration for the FDA\nwhen assessing PRO endpoints. Therefore, when PRO instruments are included in a clinical\n\n\n 22\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 28 of 44\n\n Contains Nonbinding Recommendations\n\ntrial, we encourage sponsors to include a single item during or at the end of the trial to ask\npatients to identify the clinical trial arm in which they believe they participated.\n\nThe effect of intentional unblinding is important to consider in the interpretation of clinical trial\nresults. There are certain situations, such as in the evaluation of some medical devices or\nadministration of identifiable treatment regimens, where blinding is not feasible and other\nsituations where there is no reasonable control group (and therefore no randomization). When a\nPRO instrument appears useful in assessing patient benefit in those situations, we encourage\nsponsors to confer with the appropriate review division.\n\n 2. Clinical Trial Quality Control\n\nThe quality of a clinical trial can be optimized at the design stage by specifying in the protocol\nprocedures to minimize inconsistencies in trial conduct. We recommend a standardized order by\nwhich PRO and other clinical assessments are administered. Other examples of standardized\ninstructions and processes that can appear in the protocol include:\n\n \u2022 Training and instructions to patients for self-administered PRO instruments\n\n \u2022 Interviewer training and interview format for PRO instruments administered in an\n interview format\n\n \u2022 Instructions for the clinical investigators regarding patient supervision, timing and order\n of questionnaire administration during or outside the office visit, processes and rules for\n questionnaire review for completeness, and documentation of how and when data are\n filed, stored, and transmitted to or from the clinical trial site\n\n \u2022 Plans for confirmation of the instrument\u2019s measurement properties using clinical trial\n data\n\n 3. Handling Missing Data\n\nSometimes patients fail to report for visits, fail to complete questionnaires, or withdraw from a\nclinical trial before its planned completion. The resulting missing data can introduce bias and\ninterfere with the ability to compare effects in the test group with the control group because only\na subset of the initial randomized population contributes, and these patient groups may no longer\nbe comparable. Missing data is a major challenge to the success and interpretation of any\nclinical trial. The clinical trial protocol should describe how missing data will be handled in the\nanalysis.\n\nThe protocol can increase the likelihood that a clinical trial will still be informative by\nestablishing backup plans for gathering all treatment-related reasons for patients failing to report\nat scheduled times or withdrawing from a treatment or the clinical trial and by trying to minimize\npatient dropouts before trial completion. Patients should remain in the clinical trial, even if they\nhave discontinued treatment, and should continue to provide PRO data. The protocol should also\n\n\n\n 23\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 29 of 44\n\n Contains Nonbinding Recommendations\n\nestablish a process by which PRO measurement is obtained before or shortly after patient\nwithdrawal from treatment should early withdrawal be unpreventable.\n\n B. Frequency of Assessments\n\nThe frequency of PRO assessment should correspond with the specific research questions being\naddressed, length of recall asked by the instrument\u2019s response options, demonstrated instrument\nmeasurement properties, the disease or condition\u2019s natural history, the treatment\u2019s nature, and\nplanned data analysis. Some diseases, conditions, or clinical trial designs may necessitate more\nthan one baseline assessment and several PRO assessments during treatment.\n\n C. Clinical Trial Duration\n\nThe duration of PRO assessment depends on the PRO research questions being posed. It is\nimportant to consider whether the clinical trial\u2019s duration is of adequate length to support the\nproposed claim and assess a durable outcome in the disease or condition being studied.\nGenerally, duration of follow-up with a PRO assessment should be the same as for other\nmeasures of effectiveness. However, the clinical trial duration appropriate for the PRO-related\nobjective may not be the same duration as for other endpoints.\n\n D. Design Considerations for Multiple Endpoints\n\nA single hierarchy of endpoints as diagrammed in an endpoint model (see Figures 1 and 2 in\nsection III.A., Endpoint Model) is determined by the trial\u2019s stated objectives and the clinical\nrelevance and importance of each specific measure independently and in relationship to each\nother. We consider any endpoints that are not part of the prespecified hierarchy of primary and\nkey secondary endpoints to be exploratory. Endpoints included for economic evaluation that are\nnot intended for labeling claims should be designated as such, and will be regarded as\nexploratory. A PRO measurement can be the clinical trial\u2019s primary endpoint measure, a co-\nprimary endpoint measure in conjunction with another PRO measure, other clinical endpoints or\nphysician-rated measurements, or a secondary endpoint measure whose analysis is considered\naccording to a hierarchical sequence. It is critical that the clinical trial protocol define the\nendpoint measures and the criteria for the statistical analysis and interpretation of results,\nincluding a specification of the conditions for a positive clinical trial conclusion, because\ndetermination of these criteria and conditions after data are unblinded will not be credible.\nSponsors should avoid separate consideration of PRO endpoints from the clinical trial\u2019s primary\nobjectives in terms of clinical trial design or data analysis. Sponsors also should avoid cherry\npicking or post hoc selective picking of PRO endpoint results for inclusion in proposed labeling.\n\n E. Planning for Clinical Trial Interpretation Using a Responder Definition\n\nRegardless of whether the primary endpoint for the clinical trial is based on individual responses\nto treatment or the group response, it is usually useful to display individual responses, often\nusing an a priori responder definition (i.e., the individual patient PRO score change over a\npredetermined time period that should be interpreted as a treatment benefit). The responder\ndefinition is determined empirically and may vary by target population or other clinical trial\n\n\n 24\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 30 of 44\n\n Contains Nonbinding Recommendations\n\ndesign characteristics. Therefore, we will evaluate an instrument\u2019s responder definition in the\ncontext of each specific clinical trial.\n\nThe empiric evidence for any responder definition is derived using anchor-based methods.\nAnchor-based methods explore the associations between the targeted concept of the PRO\ninstrument and the concept measured by the anchors. To be useful, the anchors chosen should be\neasier to interpret than the PRO measure itself. For example, the number of incontinence\nepisodes collected in incontinence diaries has been used to determine a responder definition for\nPRO instruments assessing the annoyance of incontinence. A 50 percent reduction in\nincontinence episodes might be proposed as the anchor for defining a responder on the PRO\ninstrument. Confirmation of this anchor approach in early clinical trials can provide the basis for\nthe proposed responder definition in the confirmatory trials.\n\nAnother anchor-based approach to defining responders makes use of patient ratings of change\nadministered at different periods of time or upon exit from a clinical trial. These numerical\nratings range from worse to the same and better. The difference in the PRO score for persons\nwho rate their condition the same and better or worse can be used to define responders to\ntreatment. Patient ratings of change are less useful as anchors when patients are not blinded to\ntreatment assignment.\n\nAnother set of approaches to defining a responder are distribution-based methods that use, for\nexample, the between-person standard deviation or the standard error of measurement to define a\nmeaningful change on a scale. Distribution-based methods can be used to categorize these\nchanges as small, moderate, and large and often can be combined with anchor-based estimates to\nprovide confidence in the responder definition. Distribution-based methods for determining\nclinical significance of particular score changes should be considered as supportive and are not\nappropriate as the sole basis for determining a responder definition.\n\nAlternatively, it is possible to present the entire distribution of responses for treatment and\ncontrol group, avoiding the need to pick a responder criterion. Whether the individual responses\nare meaningful represents a judgment, but that problem is present with almost all endpoints\nexcept survival. Such cumulative distribution displays show a continuous plot of the percent\nchange from baseline on the X-axis and the percent of patients experiencing that change on the\nY-axis. This display type may be preferable to attempting to provide categorical definitions of\nresponders. A variety of responder definitions can be identified along the cumulative\ndistribution of response curve.\n\nGuidance on interpretation considerations for a clinical trial\u2019s SAP is found in section V.E.,\nInterpretation of Clinical Trial Results.\n\n\n\n\n 25\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 31 of 44\n\n Contains Nonbinding Recommendations\n\n\n F. Specific Concerns When Using Electronic PRO Instruments\n\nWhen PRO instruments are used, sponsors must ensure that FDA regulatory requirements are\nmet for sponsor and investigator record keeping, maintenance, and access. 6 These\nresponsibilities are independent of the method used to record clinical trial data and, therefore,\napply to all types of PRO data including electronic PRO data. Sponsors are responsible for\nproviding investigators with all information to conduct the investigation properly, for monitoring\nthe investigation, for ensuring that the investigation is conducted in accordance with the\ninvestigational plan, and for permitting the FDA to access, copy, and verify records and reports\nrelating to the investigation.\n\nThe principal record keeping requirements for clinical investigators include the preparation and\nmaintenance of adequate and accurate case histories (including the case report forms and\nsupporting data), record retention, and provision for the FDA to access, copy, and verify records\n(i.e., source data verification). The investigator\u2019s responsibility to control, access, and maintain\nsource documentation can be satisfied easily when paper PRO instruments are used, because the\npatient usually returns the diary to the investigator who either retains the original or a certified\ncopy as part of the case history. The use of electronic PRO instruments, however, may pose a\nproblem if direct control over source data is maintained by the sponsor or the contract research\norganization and not by the clinical investigator. We consider the investigator to have met his or\nher responsibility when the investigator retains the ability to control and provide access to the\nrecords that serve as the electronic source documentation for the purpose of an FDA inspection.\nThe clinical trial protocol, or a separate document, should specify how the electronic PRO source\ndata will be maintained and how the investigator will meet the regulatory requirements.\n\nIn addition, the FDA has previously provided guidance to address the use of computerized\nsystems to create, modify, maintain, archive, retrieve, or transmit clinical data to the FDA and to\nclarify the requirements and application of 21 CFR part 11. 7,8 Because electronic PRO data\n(including data gathered by personal digital assistants or phone-based interactive voice recording\nsystems) are part of the case history, electronic PRO data should be consistent with the data\nstandards described in that guidance. Sponsors should plan to establish appropriate system and\nsecurity controls, as well as cyber-security and system maintenance plans that address how to\nensure data integrity during network attacks and software updates.\n\nSponsors also should avoid the following:\n\n \u2022 Direct PRO data transmission from the PRO data collection device to the sponsor,\n clinical investigator, or other third party without an electronic audit trail that documents\n all changes to the data after it leaves the PRO data collection device.\n\n6\n For the principal record keeping requirements for clinical investigators and sponsors developing drugs and\nbiologics, see 21 CFR 312.50, 312.58, 312.62, and 312.68. For medical devices, see 21 CFR 812.140 and 812.145.\n7\n See the guidance for industry Computerized Systems Used in Clinical Investigations\n(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).\n8\n See the guidance for industry Part 11, Electronic Records; Electronic Signatures \u2014 Scope and Application\n(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).\n\n\n 26\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 32 of 44\n\n Contains Nonbinding Recommendations\n\n\n\n \u2022 Source document control by the sponsor exclusively.\n\n \u2022 Clinical investigator inability to maintain and confirm electronic PRO data accuracy.\n The data maintained by the clinical investigator should include an audit trail to capture\n any changes made to the electronic PRO data at any point in time after it leaves the\n patient\u2019s electronic device.\n\n \u2022 The existence of only one database without backup (i.e., risk of data corruption or loss\n during the trial with no way to reconstitute or verify the data).\n\n \u2022 Ability of any entity other than the investigator (and/or site staff designated by the\n investigator) to modify the source data.\n\n \u2022 Loss of adverse event data.\n\n \u2022 Premature or unplanned access to unblinded data.\n\n \u2022 Inability of an FDA investigator to inspect, verify, and copy the data at the clinical site\n during an inspection.\n\n \u2022 An insecure system where records are easily altered.\n\n \u2022 Direct PRO data transmission of important safety information to sponsors, clinical\n research organizations, and/or third parties, without ensuring the timely transmission of\n the data to the clinical investigator responsible for the patients.\n\n\nV. DATA ANALYSIS\n\nIncorporating PRO instruments as clinical trial endpoint measures introduces challenges in the\nanalysis of clinical trial data. The most important of these challenges are discussed in the\nfollowing sections.\n\n A. General Statistical Considerations\n\nThe statistical analysis considerations for PRO endpoints are not unlike statistical considerations\nfor any other endpoint used in medical product development.9 Every protocol should describe\nthe principal data analysis features in the statistical section with a detailed elaboration of the\nanalysis in an SAP. We intend to determine the adequacy of clinical trial data to support claims\nin light of the prespecified method for endpoint analysis. We usually view unplanned or post\nhoc statistical analyses conducted after unblinding as exploratory and, therefore, unable to serve\nas the basis of a labeling claim of effectiveness.\n\n9\n See the ICH guidance for industry E9 Statistical Principles for Clinical Trials\n(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).\n\n\n 27\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 33 of 44\n\n Contains Nonbinding Recommendations\n\n\n\n B. Statistical Considerations for Using Multiple Endpoints\n\nPROs in a clinical trial, like non-PRO clinical endpoints, can be primary or secondary endpoints.\nPrimary endpoints are those endpoints on which the main benefit of a clinical trial\u2019s test\ntreatment is judged rigorously. Primary endpoints are used to determine the clinical trial sample\nsize and are the endpoints that will be tested statistically. They are clinically meaningful but\nmay not be the most important endpoint because choice of clinical trial endpoints is a complex\nevolution of expected effect size, expected number of events, and other factors.\n\nThere are often multiple endpoints that would be of clinical interest. Analysis of multiple\nendpoints, where an effect on any of the endpoints will be considered evidence of effectiveness,\ncan inflate the probability of false positive findings known as the Type I error rate, an inflation\nthat can be controlled by a prospectively planned multiplicity adjustment. It is common to\nanalyze secondary endpoints only after success on a primary endpoint. This can be done using a\nsequential analysis, testing additional endpoints in a defined sequence each at the usual alpha =\n0.05 level of statistical significance. The analyses cease when a failure occurs. It is important\nthat the clinical trial protocol specify all primary and secondary endpoints. The SAP should\ndescribe the planned primary analysis in detail noting whether the endpoint will be analyzed as a\ncontinuous variable (mean scores), dichotomous variable (success or failure), or some graded\nresponse; the primary and secondary endpoints; adjustments for multiplicity to control the\noverall Type I error rate; and the specific statistical methods planned. Sponsors should provide\nthe FDA with the clinical trial\u2019s SAP for review.\n\nCases arise in clinical trials where a clinically meaningful treatment benefit depends on having\ntwo or more primary endpoints achieving statistical significance at a specified alpha level (e.g.,\nalpha = 0.05). For example, a clinical trial may identify two endpoints with a decision rule that\neach should show that the treatment is better than control. Such a decision rule does not require\nmultiplicity adjustment because the maximum Type I error rate (alpha) is actually reduced.\nHowever, this type of decision rule will increase the Type II error. Therefore, we recommend\nsizing the trial carefully for this situation.\n\nThere is no single best statistical procedure for multiplicity adjustment because the choice of\nprocedure depends upon the clinical trial\u2019s objectives, the most important endpoints, the decision\nrule for declaring treatment benefit, and other considerations. Some of the statistical procedures\nthat can be useful for a more efficient analysis approach include methods that prespecify a\nsequence or order of testing or a hierarchy of comparisons that should first be satisfied before\nothers are considered for testing as described above. These methods can be less conservative\nthan the conventional nonhierarchical type methods, such as Bonferroni, the step-down or step-\nup tests, and prospective alpha allocations schemes, which ignore the hierarchy of comparisons\nor their families. These conventional type methods should be used when a restriction on the\norder of testing is not warranted.\n\nA multidomain PRO measure may successfully support a labeling claim based on one or a subset\nof the domains measured if an a priori analysis plan prespecifies the domains that will be\ntargeted as endpoints and the method of analysis that will adjust for the multiplicity of tests for\n\n\n 28\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 34 of 44\n\n Contains Nonbinding Recommendations\n\nthe specific claim. The use of domain subsets as clinical trial endpoints presupposes that the\nPRO instrument was adequately developed and validated to measure the subset of domains\nindependently from the other domains.\n\n C. Statistical Considerations for Composite Endpoints\n\nFor a PRO instrument with multiple domains, combining the scores to calculate a general score\ncreates a composite endpoint. Composite endpoints have a few advantages (e.g., they can reduce\nmultiplicity problems), but their use for confirmatory clinical trials for specific claims of\ntreatment benefit poses many difficulties and challenges.\n\nRules for interpretation of composite endpoints depend on substantial experience with the\nmeasure in the clinical trial setting. Therefore, development of a composite endpoint at the time\nthe confirmatory clinical trial protocol is written depends on special considerations and\nsubstantial empirical evidence of the following: the components are of similar importance to\npatients, the more important and less important components are equally likely to occur with\nsimilar frequency, and the components are likely to have roughly similar treatment effects.\nTherefore, we discourage the use of a composite endpoint for confirmatory clinical trials when\nlarge variations are predicted to exist between its components.\n\nMultiplicity problems arise when the multiple individual components of a composite endpoint\nare intended as possible claims. In general, individual components of a composite endpoint will\nnot be adequate to support a labeling claim for the components unless the components are\nprespecified in the protocol as separate endpoints and all prespecified components are reported in\nlabeling as suggested in current guidance. 10 The components of a composite endpoint will be\nshown in labeling to convey what drove a favorable result. Sequential testing approaches can be\nused to test the components of a composite. The components are tested only when there is a\nstatistically significant treatment benefit for the composite.\n\n D. Statistical Considerations for Patient-Level Missing Data\n\nWhen the amount of missing data becomes large, clinical trial results can be inconclusive. As\ndescribed in section IV., Clinical Trial Design, we encourage prespecified procedures in the\nclinical trial protocol to avoid missing data. We also encourage prespecified procedures for\nobtaining data on each patient at the time of early withdrawal from the clinical trial. If a\nmeasurement is taken at the time of withdrawal, this information can be handled according to\nrules established in the SAP. In clinical trials of terminal illness, it is critical to plan ahead for\nhow missing data because of death will be handled. Missing data may occur because of the\ntreatment received or the underlying disease and can introduce bias in the analysis of treatment\ndifferences and conclusions about treatment effect.\n\n\n\n\n10\n See the guidance for industry Clinical Studies Section of Labeling for Human\nPrescription Drug and Biological Products \u2014 Content and Format\n(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).\n\n\n 29\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 35 of 44\n\n Contains Nonbinding Recommendations\n\nEven with the best planning, data may be missing at the end of the clinical trial. The SAP should\naddress plans for how the statistical analyses will handle missing data when evaluating treatment\nbenefit and when considering patient success or patient response.\n\n 1. Missing Items within Domains\n\nAt a specific patient visit, a domain measurement may be missing some, but not all, items. One\napproach to handling this type of missing data is to define rules that specify the number of items\nthat can be missing and still consider the domain as adequately measured. Rules for handling\nmissing data should be specific to each PRO instrument and usually should be determined during\nthe instrument development process. The SAP should specify all rules for handling missing data.\nFor example, the SAP can specify the proportion of items that can be missing before a domain is\ntreated as missing.\n\n 2. Missing Entire Domains or Entire Measurements\n\nWe will consider a variety of statistical strategies to deal with missing data because of a patient\u2019s\nearly termination before planned completion of a trial. No single method is generally considered\nas preferred. All of these strategies are imperfect, as they involve strong or weak assumptions\nabout what caused data to be missing, assumptions that usually cannot be verified from the data.\nMethods of missing data imputation should take the patient population, disease progression, and\nrespondent burden into account. How to impute the missing data for a PRO endpoint and any\nrelated supportive endpoints should be addressed in the protocol and the SAP. In addition, the\nsensitivity analyses in analyzing the PRO endpoints should be proposed in the protocol and the\nSAP to assess the robustness of statistical estimation for endpoints with the missing data\nimputed. We recommend that in the protocol the sponsor propose two or more sensitivity\nanalyses with different methods for missing data imputation.\n\n E. Interpretation of Clinical Trial Results\n\nBecause statistical significance can sometimes be achieved for small changes in PRO measures\nthat may not be clinically meaningful (i.e., do not indicate treatment benefit), we encourage\nsponsors to avoid proposing labeling claims based on statistical significance alone.\n\nTo demonstrate treatment benefit, we find it informative to examine the cumulative distribution\nfunction (CDF) of responses between treatment groups to characterize the treatment effect and\nexamine the possibility that the mean improvement reflects different responses in patient subsets.\nTo interpret the CDF, sponsors can apply the responder definition along the CDF curve at each\nlevel of response (see section IV.E., Planning for Clinical Trial Interpretation Using a Responder\nDefinition).\n\nInterpretation of PRO endpoints follows similar considerations as for all other endpoint types\nused to evaluate treatment benefit of a medical product.\n\n\n\n\n 30\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 36 of 44\n\n Contains Nonbinding Recommendations\n\n\n GLOSSARY\n\nAbility to detect change \u2014 Evidence that a PRO instrument can identify differences in scores\nover time in individuals or groups who have changed with respect to the measurement concept.\n\nClaim \u2014 A statement of treatment benefit. A claim can appear in any section of a medical\nproduct\u2019s FDA-approved labeling or in advertising and promotional labeling of prescription\ndrugs and devices.\n\nCognitive interviewing \u2014 A qualitative research tool used to determine whether concepts and\nitems are understood by patients in the same way that instrument developers intend. Cognitive\ninterviews involve incorporating follow-up questions in a field test interview to gain a better\nunderstanding of how patients interpret questions asked of them. In this method, respondents are\noften asked to think aloud and describe their thought processes as they answer the instrument\nquestions.\n\nConcept \u2014 The specific measurement goal (i.e., the thing that is to be measured by a PRO\ninstrument). In clinical trials, a PRO instrument can be used to measure the effect of a medical\nintervention on one or more concepts. PRO concepts represent aspects of how patients function\nor feel related to a health condition or its treatment.\n\nConceptual framework of a PRO instrument \u2014 An explicit description or diagram of the\nrelationships between the questionnaire or items in a PRO instrument and the concepts measured.\nThe conceptual framework of a PRO instrument evolves over the course of instrument\ndevelopment as empiric evidence is gathered to support item grouping and scores. We review\nthe alignment of the final conceptual framework with the clinical trial\u2019s objectives, design, and\nanalysis plan.\n\nConstruct validity \u2014 Evidence that relationships among items, domains, and concepts conform\nto a priori hypotheses concerning logical relationships that should exist with other measures or\ncharacteristics of patients and patient groups.\n\nContent validity \u2014 Evidence from qualitative research demonstrating that the instrument\nmeasures the concept of interest including evidence that the items and domains of an instrument\nare appropriate and comprehensive relative to its intended measurement concept, population, and\nuse. Testing other measurement properties will not replace or rectify problems with content\nvalidity.\n\nCriterion validity \u2014 The extent to which the scores of a PRO instrument are related to a known\ngold standard measure of the same concept. For most PROs, criterion validity cannot be\nmeasured because there is no gold standard.\n\nDomain \u2014 A subconcept represented by a score of an instrument that measures a larger concept\ncomprised of multiple domains. For example, psychological function is the larger concept\ncontaining the domains subdivided into items describing emotional function and cognitive\nfunction.\n\n\n 31\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 37 of 44\n\n Contains Nonbinding Recommendations\n\n\n\nEndpoint \u2014 The measurement that will be statistically compared among treatment groups to\nassess the effect of treatment and that corresponds with the clinical trial\u2019s objectives, design, and\ndata analysis. For example, a treatment may be tested to decrease the intensity of symptom Z.\nIn this case, the endpoint is the change from baseline to time T in a score that represents the\nconcept of symptom Z intensity.\n\nEndpoint model \u2014 A diagram of the hierarchy of relationships among all endpoints, both PRO\nand non-PRO, that corresponds to the clinical trial\u2019s objectives, design, and data analysis plan.\n\nHealth-related quality of life (HRQL) \u2014 HRQL is a multidomain concept that represents the\npatient\u2019s general perception of the effect of illness and treatment on physical, psychological, and\nsocial aspects of life. Claiming a statistical and meaningful improvement in HRQL implies: (1)\nthat all HRQL domains that are important to interpreting change in how the clinical trial\u2019s\npopulation feels or functions as a result of the targeted disease and its treatment were measured;\n(2) that a general improvement was demonstrated; and (3) that no decrement was demonstrated\nin any domain.\n\nInstrument \u2014 A means to capture data (i.e., a questionnaire) plus all the information and\ndocumentation that supports its use. Generally, that includes clearly defined methods and\ninstructions for administration or responding, a standard format for data collection, and well-\ndocumented methods for scoring, analysis, and interpretation of results in the target patient\npopulation.\n\nItem \u2014 An individual question, statement, or task (and its standardized response options) that is\nevaluated by the patient to address a particular concept.\n\nItem tracking matrix \u2014 A record of the development (e.g., additions, deletions, modifications,\nand the reasons for the changes) of items used in an instrument.\n\nMeasurement properties \u2014 All the attributes relevant to the application of a PRO instrument\nincluding the content validity, construct validity, reliability, and ability to detect change. These\nattributes are specific to the measurement application and cannot be assumed to be relevant to all\nmeasurement situations, purposes, populations, or settings in which the instrument is used.\n\nPatient-reported outcome (PRO) \u2014 A measurement based on a report that comes directly from\nthe patient (i.e., study subject) about the status of a patient\u2019s health condition without amendment\nor interpretation of the patient\u2019s response by a clinician or anyone else. A PRO can be measured\nby self-report or by interview provided that the interviewer records only the patient\u2019s response.\n\nProxy-reported outcome \u2014 A measurement based on a report by someone other than the patient\nreporting as if he or she is the patient. A proxy-reported outcome is not a PRO. A proxy report\nalso is different from an observer report where the observer (e.g., clinician or caregiver), in\naddition to reporting his or her observation, may interpret or give an opinion based on the\nobservation. We discourage use of proxy-reported outcome measures particularly for symptoms\nthat can be known only by the patient.\n\n\n 32\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 38 of 44\n\n Contains Nonbinding Recommendations\n\n\n\nQuality of life \u2014 A general concept that implies an evaluation of the effect of all aspects of life\non general well-being. Because this term implies the evaluation of nonhealth-related aspects of\nlife, and because the term generally is accepted to mean what the patient thinks it is, it is too\ngeneral and undefined to be considered appropriate for a medical product claim.\n\nQuestionnaire \u2014 A set of questions or items shown to a respondent to get answers for research\npurposes. Types of questionnaires include diaries and event logs.\n\nRecall period \u2014 The period of time patients are asked to consider in responding to a PRO item\nor question. Recall can be momentary (real time) or retrospective of varying lengths.\n\nReliability \u2014 The ability of a PRO instrument to yield consistent, reproducible estimates of true\ntreatment effect.\n\nResponder definition \u2014 A score change in a measure, experienced by an individual patient over\na predetermined time period that has been demonstrated in the target population to have a\nsignificant treatment benefit.\n\nSaturation \u2014 When interviewing patients, the point when no new relevant or important\ninformation emerges and collecting additional data will not add to the understanding of how\npatients perceive the concept of interest and the items in a questionnaire.\n\nScale \u2014 The system of numbers or verbal anchors by which a value or score is derived for an\nitem. Examples include VAS, Likert scales, and rating scales.\n\nScore \u2014 A number derived from a patient\u2019s response to items in a questionnaire. A score is\ncomputed based on a prespecified, validated scoring algorithm and is subsequently used in\nstatistical analyses of clinical trial results. Scores can be computed for individual items,\ndomains, or concepts, or as a summary of items, domains, or concepts.\n\nSign \u2014 Any objective evidence of a disease, health condition, or treatment-related effect. Signs\nare usually observed and interpreted by the clinician but may be noticed and reported by the\npatient.\n\nSymptom \u2014 Any subjective evidence of a disease, health condition, or treatment-related effect\nthat can be noticed and known only by the patient.\n\nTarget product profile (TPP) \u2014 A clinical development program summary in the context of\nlabeling goals where specific types of evidence (e.g., clinical trials or other sources of data) are\nlinked to the targeted labeling claims or concepts.\n\nTreatment benefit \u2014 The effect of treatment on how a patient survives, feels, or functions.\nTreatment benefit can be demonstrated by either an effectiveness or safety advantage. For\nexample, the treatment effect may be measured as an improvement or delay in the development\nof symptoms or as a reduction or delay in treatment-related toxicity. Measures that do not\n\n\n 33\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 39 of 44\n\n Contains Nonbinding Recommendations\n\ndirectly capture the treatment effect on how a patient survives, feels, or functions are surrogate\nmeasures of treatment benefit.\n\nUsability testing \u2014 A formal evaluation with documentation of respondents\u2019 abilities to use the\ninstrument, as well as comprehend, retain, and accurately follow instructions.\n\n\n\n\n 34\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 40 of 44\n\n Contains Nonbinding Recommendations\n\n\n APPENDIX: INFORMATION ON A PRO INSTRUMENT\n REVIEWED BY THE FDA\n\nThe following topics represent areas that should be addressed in PRO documents provided to the\nFDA for review. The extent of background information provided in each section will vary\ndepending upon the PRO instrument used. Some sections may be less relevant for a particular\nPRO instrument application than others, or may be less complete for discussions in early stages\nof medical product development. Refer to the content of this guidance for additional information\nconcerning the types of evidence needed in each of the following areas.\n\nIf the PRO information is provided electronically, it should be placed in section 5.3.5.3 of the\nelectronic common technical document. 11\n\nI. Instrument (review cannot begin without a copy of the proposed instrument):\n\n A. Exact version of the instrument proposed or used in the clinical trial (protocol) under\n review and all instructions for use. Include screen shots or interviewer scripts, if\n relevant.\n\n B. Prior versions, if relevant.\n\n C. Instructions for use: An instrument user manual can be provided as Appendix A and\n referenced here.\n 1. Administration timing, method (e.g., paper or pencil, electronic), and mode (e.g.,\n self-, clinician-, or interviewer-administered)\n 2. The scoring algorithm\n 3. Training method and materials used for questionnaire administration\n a. Patient training \u2014 summarize here and include a copy of all materials in\n Appendix A1\n b. Investigator training \u2014 summarize here and include a copy of all materials in\n Appendix A2\n c. Other training \u2014 summarize here and include a copy of all materials in Appendix\n A3\n\nII. Targeted Claims or Target Product Profile (TPP) 12\n\n Include language describing all specific targeted labeling claims related to all clinical trial\n endpoint measures, both PRO and non-PRO, and specific to:\n\n\n\n11\n See the ICH guidance for industry M2 eCTD: Electronic Common Technical Document Specification\n(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).\n12\n See the draft guidance for industry and review staff Target Product Profile \u2014 A Strategic Development\nProcess Tool. When final, this guidance will represent the FDA\u2019s current thinking on this topic.\nFor the most recent version of a guidance, check the FDA Drug guidance Web page at\nhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.\n\n\n 35\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 41 of 44\n\n Contains Nonbinding Recommendations\n\n\n \u2022 Disease or condition with stage, severity, or category, if relevant\n \u2022 Intended population (e.g., age group, sex, other demographics)\n \u2022 Data analysis plan\n\nIII. Endpoint Model\n\n A. Relationships (known and hypothesized) among all clinical trial endpoints, both PRO and\n non-PRO. These endpoints can include physiologic/lab/physical, caregiver, or clinician-\n reported measures in addition to PROs.\n\n B. Hierarchy of all PRO and non-PRO endpoints intended to support claims corresponding\n with the planned data analyses.\n\nIV. The PRO Instrument\u2019s Conceptual Framework\n\n Diagram of hypothesized (proposed) or final PRO instrument conceptual framework showing\n relationship of items to domains and domains to total score. Ensure that the PRO\n instrument\u2019s conceptual framework corresponds to the clinical trial endpoints described in\n the clinical trial protocol and proposed as labeling claims.\n\nV. Content Validity Documentation\n\n Evidence that instrument captures all of the most clinically important concepts and items, and\n that items are complete, relevant (appropriate), and understandable to the patient. This\n evidence applies to both existing and newly created instruments and is specific to the planned\n clinical trial population and indication. Documentation includes:\n\n A. Literature review and documentation of expert input\n\n B. Qualitative study protocols, interview guides, and summary of results for:\n 1. Focus group testing (include transcripts in Appendix C1)\n 2. Open-ended patient interviews (include transcripts in Appendix C2)\n 3. Cognitive interviews (include transcripts in Appendix C3)\n\n C. Origin and derivation of items with chronology of events for item generation,\n modification, and finalization\n\n Item tracking matrix for versions tested with patients showing items retained and items\n deleted providing evidence of saturation. Summarize here and include complete\n materials under Appendix B.\n\n D. Qualitative study summary that supports content validity for:\n 1. Item content\n 2. Response options\n 3. Recall period\n 4. Scoring\n\n\n 36\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 42 of 44\n\n Contains Nonbinding Recommendations\n\n\n\n E. Summary of qualitative studies demonstrating how item pool was generated, reduced,\n and finalized. Specify type of study (i.e., focus group, patient interview, or cognitive\n interview) and characteristics of study population. Include full transcripts and datasets in\n Appendix C.\n\nVI. Assessment of Other Measurement Properties\n\n Assuming content validity is established in the intended population and application, evidence\n that the instrument is reliable, valid, and able to detect change. The same version of the\n instrument to be used in the clinical trial should be used to assess measurement properties.\n\n A. Protocols for instrument testing\n\n B. Summary of testing results for each domain or summary score proposed as support for\n claims:\n 1. Reliability (internal; test-retest)\n 2. Construct validity (convergent, discriminant, known-groups)\n 3. Ability to detect change\n\nVII. Interpretation of Scores\n\n A. Summary of the logic and methods used to interpret the clinical meaningfulness of\n clinical trial results\n\n B. Responder definition (i.e., definition of meaningful within-person change specific to the\n clinical trial population)\n\nVIII. Language Translation and Cultural Adaptation\n\n A. Process used to translate and culturally adapt the instrument for populations that will use\n them in the trial\n\n B. Description of patient testing, language- or culture-specific concerns, and rationale for\n decisions made to create new versions.\n\n C. Copies of translated or adapted versions\n\n D. Evidence that content validity and other measurement properties are comparable between\n the original and new instruments\n\nIX. Data Collection Method\n\n A. Process used to develop data collection methods (e.g., electronic, paper) intended for use\n in the clinical trial\n\n\n\n\n 37\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 43 of 44\n\n Contains Nonbinding Recommendations\n\n If electronic data collection is used to assess PRO endpoints, evidence that procedures for\n maintenance, transmission, and storage of electronic source documents comply with\n regulatory requirements.\n\n B. Evidence that content validity and other measurement properties are comparable among\n all data collection methods\n\n C. User manual for each additional data collection method\n\nX. Modifications\n\n Any change in the original instrument (e.g., wording of items, response options, recall\n period, use in a new population or indication)\n\n A. Rationale for and process used to modify the instrument\n\n B. Copy of original and new instruments\n\n C. Evidence that content validity and other measurement properties are comparable between\n the original and modified instruments (including use in a new indication or population)\n\nXI. PRO-Specific Plans Related to Clinical Trial Design and Data Analysis\n\n A. Clinical trial protocol. Ensure in the protocol that:\n \u2022 Each PRO endpoint is stated as a specific clinical trial objective and multiplicity\n concerns are addressed\n \u2022 The clinical trial will be adequately blinded\n \u2022 Procedures for training are well-described for:\n \u2212 Patients\n \u2212 Interviewers\n \u2212 Clinical investigators\n \u2022 Plans for instrument administration are consistent with instrument\u2019s user manual\n \u2022 Plans for PRO instrument scoring are consistent with those used during instrument\n development\n \u2022 Procedures include assessment of PRO endpoint before or shortly after a patient\n withdraws from the clinical trial\n \u2022 Frequency and timing of PRO assessments are appropriate given patient population,\n clinical trial design and objectives, and demonstrated PRO measurement properties\n \u2022 Clinical trial duration is adequate to support PRO objectives\n \u2022 Plans are included for handling missing data\n \u2022 Plans are included for a cumulative distribution function comparison among treatment\n groups\n \u2022 Data collection, data storage, and data handling and transmission of procedures,\n including electronic PROs, are specified\n\n\n\n\n 38\n\f Case 1:24-cv-03529-CM Document 23-6 Filed 08/23/24 Page 44 of 44\n\n Contains Nonbinding Recommendations\n\n B. Statistical analysis plan (SAP). Ensure the SAP includes:\n \u2022 Plans for multiplicity adjustment\n \u2022 Plans for handling missing data at both the instrument and patient level\n \u2022 Description of how between-group differences will be portrayed (e.g., cumulative\n distribution function)\n\nXII. Key References\n\n List and attach all relevant published and unpublished documents\n\nAppendix A \u2014 User Manual\n\n A1: Patient training\n\n A2: Investigator training\n\n A3: Other training\n\nAppendix B \u2014 Item Tracking Matrix\n\nAppendix C \u2014 Transcripts\n\n C1: Focus groups\n\n C2: Open-ended patient interviews\n\n C3: Cognitive interviews\n\n\n\n\n 39\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:21.089891-07:00","document_number":"23","attachment_number":6,"pacer_doc_id":"127036039506","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Report","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579230/","id":409579230,"tags":[],"absolute_url":"/docket/68511120/23/7/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.750957-07:00","date_modified":"2024-08-27T02:10:46.177417-07:00","sha1":"6ff714e733315d8cac6f54c6e096d1e271049b3e","page_count":16,"file_size":350097,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.7.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.7.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 1 of 16\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 2 of 16\n\n\n\n\nAnavex Life Sciences Corp.\nNasdaqGS:AVXL\nFQ1 2022 Earnings Call Transcripts\nWednesday, February 09, 2022 9:30 PM GMT\nS&P Global Market Intelligence Estimates\n -FQ1 2022- -FQ2 2022- -FY 2022- -FY 2023-\n\n CONSENSUS ACTUAL SURPRISE CONSENSUS CONSENSUS CONSENSUS\n\n EPS Normalized (0.16) (0.14) NM (0.18) (0.76) (0.65)\n\n Revenue (mm) 0.00 0.00 0.00 0.00 0.00 7.52\nCurrency: USD\nConsensus as of Feb-07-2022 3:09 PM GMT\n\n\n\n\n - EPS NORMALIZED -\n\n CONSENSUS ACTUAL SURPRISE\n\n FQ2 2021 (0.15) (0.12) NM\n\n FQ3 2021 (0.14) (0.14) NM\n\n FQ4 2021 (0.14) (0.15) NM\n\n FQ1 2022 (0.16) (0.14) NM\n\n\n\n\nCOPYRIGHT \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All rights reserved 1\nspglobal.com/marketintelligence\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 3 of 16\nContents\n\n\n\n\nTable of Contents\n\nCall Participants .................................................................................. 3\nPresentation .................................................................................. 4\nQuestion and Answer .................................................................................. 7\n\n\n\n\nCOPYRIGHT \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All rights reserved 2\nspglobal.com/marketintelligence\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 4 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\n\nCall Participants\nEXECUTIVES\n\nChristopher U. Missling\nPresident, CEO, Secretary &\nDirector\n\nClint Tomlinson\nVP of Corporate\n\nSandra Boenisch\nPrincipal Financial Officer &\nTreasurer\n\nANALYSTS\n\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research\nDivision\n\nSoumit Roy\nJonesTrading Institutional\nServices, LLC, Research Division\n\nTom Bishop\nBI Research\n\nXu Zou\n\n\n\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 3\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 5 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\n\nPresentation\nClint Tomlinson\nVP of Corporate\nGood afternoon. Welcome to the Anavex Life Sciences Fiscal 2022 First Quarter Conference Call. My\nname is Clint Tomlinson, and I will be your host for today's call. [Operator Instructions] Please note\nthat this conference is being recorded. The call will be available for replay on Anavex's website at\nwww.anavex.com.\n\nWith us today is Dr. Christopher Missling, President and Chief Executive Officer; and Sandra Boenisch, our\nPrincipal Financial Officer.\n\nBefore we begin, please note that during this conference call, the company will make some projections\nand forward-looking statements. These statements are only predictions based on current information and\nexpectations and involve a number of risks and uncertainties. We encourage you to review the company's\nfilings with the SEC.\n\nThis includes, without limitation, the company's Forms 10-K and 10-Q, which identify the specific factors\nthat may cause actual results or even events to differ materially from those described in these forward-\nlooking statements. These factors may include, without limitation, risks inherent in the development\nand/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory\napprovals, need and ability to obtain future capital and maintenance of intellectual property rights.\n\nAnd with that, I would like to turn the call over to Dr. Missling.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nThank you, Clint, and we appreciate everyone joining us on today's conference call to review our most\nrecently reported financial results and to provide a business update. The first quarter marked significant\nprogress across our portfolio, highlighted by the positive top line results of the randomized placebo-\ncontrolled AVATAR Phase III study for the treatment of adult patients with Rett syndrome and the positive\ntop line results from the placebo-controlled Phase I study of ANAVEX 3-71, which is in development for\nthe treatment of neurodegenerative diseases, including FTD, frontotemporal dementia; and a clinical data-\ndriven evidence of efficacy and safety of our broad SIGMAR1 platform portfolio, which allows us to plan\nand to expand further into the rare disease space, including implementing expanded access for adult\npatients with Rett syndrome, an underserved population.\n\nAt the same time, we are advancing both ANAVEX 2-73 and ANAVEX 3-71 in the planned studies with a\ngoal to driving meaningful growth across our broad SIGMAR1 platform portfolio to deliver transformational\ntreatments for patients with both degenerative and developmental neurological disorders around the\nworld.\n\nStarting with our lead drug candidate, 2-73. We reported positive top line results from the second\nrandomized placebo-controlled AVATAR Phase III study for the treatment of adult patients with Rett\nsyndrome. The study met its primary and secondary efficacy and safety endpoints with consistent and\nclinically meaningful improvements in all efficacy measures of Rett syndrome symptoms.\n\nConvenient once-daily oral liquid doses of up to 30 milligram of ANAVEX 2-73 were also well tolerated with\ngood medication compliance. Based on the results of the AVATAR Phase III study and the prior successful\nU.S. Phase II study in adult patients with Rett syndrome, Anavex is now planning to meet with the FDA to\ndiscuss the approval pathway.\n\nTop line results from the placebo-controlled EXCELLENCE Phase II/III study for the treatment of pediatric\npatients with Rett syndrome are expected in second half of 2022. The extension of this expected -- or\nthe expected duration of enrollment is based on recent country and local government requirements for\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 4\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 6 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nchildren to have full COVID-19 vaccination prior to joining a clinical trial, which includes our pediatric\nEXCELLENCE trial.\n\nThis Phase II/III study in pediatric patients with Rett syndrome aged 5 to 17 will evaluate the safety and\nefficacy of 2-73 in approximately 84 patients over a 12-week treatment period, including ANAVEX 2-73\nspecific precision medicine biomarkers.\n\nRegarding our Alzheimer's disease program, top line results from the randomized placebo-controlled Phase\nIIb/III ANAVEX 2-73-AD-004 study for the treatment of Alzheimer's disease are also expected in the\nsecond half 2022. The 509 patients, late-stage Phase IIb/III study in patients with Alzheimer's disease\nis taking place at 52 sites across North America, Europe and Australia, using ADAS-Cog for cognition and\nADCS-ADL for activities of daily living and function as primary endpoints.\n\nThis clinical trial is measuring efficacy, tolerability and safety of 2 different once-daily oral 2-73 doses\nor placebo. The current data allows us to expand in parallel our Anavex platform pipeline using gene\nbiomarkers of response, applying precision medicine for neurological disorders with unmet medical needs,\nwhich are expected in 2022.\n\nThat includes the planned initiation of ANAVEX 2-73 imaging-focused Parkinson's disease clinical study;\na planned initiation of a potential pivotal Phase II/III study in Fragile X syndrome, the most frequent\ngenetic cause of autism spectrum disorder; and a planned initiation of a Phase II/III clinical trial for\nthe treatment of a new rare disease indication. As well, last month, Anavex reported positive top line\nresults from the placebo-controlled Phase I ANAVEX 3-71 clinical trial in development for the treatment of\nneurodegenerative diseases, including FTD, frontotemporal dementia, for which ANAVEX 3-71 has been\ngranted orphan drug designation by the FDA.\n\nThe study reached primary and secondary endpoints of safety with no serious adverse events or dose-\nlimiting toxicity observed. ANAVEX 3-71 was well tolerated in all cohorts receiving ANAVEX 3-71 in single\ndoses ranging from 5-milligram to 200-milligram daily with no serious adverse events and no significant\nlab abnormalities in any subject.\n\nBased on these results in ANAVEX 3-71's preclinical profile, we intend to advance 3-71 into a biomarker-\ndriven clinical development dementia program for the treatment of FTD, frontotemporal dementia,\nschizophrenias and Alzheimer's disease, evaluating longitudinal effect of treatment with ANAVEX 3-71. We\nbelieve that the results of these studies could serve as the basis for advancing into respective registration\nstudies in the U.S.\n\nAnd now I would like to direct the call to Sandra Boenisch, Principal Financial Officer of Anavex, for a brief\nfinancial summary of the recently reported quarter.\nSandra Boenisch\nPrincipal Financial Officer & Treasurer\nThank you, Christopher, and good afternoon to everyone on the call. Our cash position at December\n31, 2021, was $151.1 million, which we believe is sufficient cash runway to fund operations and clinical\nprograms beyond 2025.\n\nFor the first quarter, cash utilized in operations was $3.5 million. We reported a net loss of $10.9 million\nfor the quarter or $0.14 per share, inclusive of noncash compensation charges of $3.9 million compared\nto net loss of $7.9 million or $0.12 per share, inclusive of noncash compensation of $0.9 million for the\ncomparable quarter of fiscal 2021.\n\nOur research and development expenses for the first quarter of fiscal 2022 were $8.7 million as compared\nto $7.9 million for the first quarter of fiscal 2021. General and administrative expenses were $3.1 million\ncompared to $1.5 million for the comparable quarter of fiscal 2021.\n\nIn both cases, the increases are primarily related to an increase in noncash compensation charges of\n$1.7 million for research and development and $1.3 million for general and administrative expenses\n\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 5\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 7 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nperiod-over-period. These increases in noncash compensation are mainly driven by the addition of staff to\nmanage and support our clinical studies and development.\n\nThank you, and I'll turn it back over to Christopher.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nThank you, Sandra. Again, we look forward into 2022. We are very excited about the company's potential\nas we build on the successful completion of 2 important studies that allow us to confidently expand further\ninto the rare disease space and plan expanded access for adult patients with Rett syndrome, while we are\nlooking forward to further pivotal clinical trial readouts in pediatric Rett syndrome and Alzheimer disease\nand pipeline updates this year.\nI would like now to turn the call back to Clint for Q&A.\n\n\n\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 6\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 8 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\n\nQuestion and Answer\nClint Tomlinson\nVP of Corporate\n[Operator Instructions] And our first question is coming from Charles Duncan with Cantor Fitzgerald.\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research Division\nLet's see. Can you hear me?\nClint Tomlinson\nVP of Corporate\nWe can hear you.\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research Division\nOkay. Super. I had a couple of questions on the recent AVATAR readout, one on EXCELLENCE, and then I\nwanted to ask Sandra a little bit about the cash runway.\n\nSo regarding AVATAR, we were quite intrigued with recent results. But I guess I'm wondering if you had\nassessed just simply the change from baseline in RSBQ and CGI and if you intend to present that data\nhere in the near term. And then regarding the expanded access, is that part of an open-label extension\nstudy or open-label extension to the AVATAR study?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nRight. So get me -- first on the last question, the idea is expanded access is to provide not only for those\npatients which have been participating in the trials to give the drug for free so they can continue to enjoy\nthe treatment effect, but also those patients which are not part of the trial. So that is the definition of the\nexpanded access. So that's what we are considering and working towards.\n\nRegarding the first question, let me explain again the background of the response analysis. And the results\nof the animal studies for Rett syndrome and other neurodegenerative diseases indicated that ANAVEX\n2-73 has both symptomatic and disease-modifying effects on neurodevelopmental and neurodegenerative\ndiseases. And for that reason, the ANAVEX 2-73 analysis of the data should capture this kind of effect. And\nthis is done in the form of the way we have presented it as a response analysis with the RSBQ AUC.\n\nNow on top of that, we have seen and we've learned in the paper, which was quoted and explicitly\nmentioned also in the presentation of February 1, pointed out that RSBQ alone as a stand-alone has just\nso many flaws that has, for example, 200 percentage upswing and downswing and is not calibrated in a\nbaseline. So it's just not fair to use it.\n\nWhatever -- however, what we can say is that we make a reference of what is the CGI requirement of a\n1 point scale improvement, which is a 3 or less, which is a minimum improvement of clinical significance.\nAnd that represents a RSBQ change of average of 12.5 reduction of the RSBQ scale.\n\nSo knowing now that you have above average -- over 72% responder, which are better than 3 -- score\nof 3, so they can have also a score of 2, which we have seen in this study. So you can see that the RSBQ\naverage needs to be at least more than 12.5 delta. So I hope that helps to explain this a little bit better.\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research Division\nIt does, Christopher. I appreciate that, and definitely appreciate linking RSBQ to clinical benefit.\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 7\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 9 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nLet me turn to EXCELLENCE. I guess I'm wondering if you'll use the same evaluation as was used in\nAVATAR because I think clin trials has it a little bit different, and you might correct that.\n\nAnd then the second thing about EXCELLENCE is that in terms of the patient enrollment to date, can you\ngive us some color on the number of patients enrolled? And when during the second half of '22 you would\nanticipate that study to read out?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nYes. So the enrollment is going well. It's just that we learned that because of the COVID vaccines have\nbeen approved around the world and also have been approved for children, which are younger than 18,\nand the requirement is now that all these participants want to and need to and it's a fair proposition to get\nvaccinated.\n\nThe protocol, however, requires that you have to be on a constant medication several weeks, I think it's\n6 or 8 weeks in advance, before joining a trial. So that means that you have to get the first dose of the\nvaccine but also the second one. And in time -- and then you have to allow for some time to pass by to\nbe on a stable new indication -- new medication, and vaccine is a new medication. So what it does, it\nshifts a little bit out the time line to finish the last patients in this trial. The -- what was the other question,\nCharles? I just...\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research Division\nYes. I just -- I was just wondering if you can provide some color on the number of patients enrolled thus\nfar.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nWe are doing well from our perspective. I'd like to just mention that right now, we are very comfortable\nwith the time frame during second half '22 that gives us amply -- ample time to complete the study with\nthis additional required vaccination regimen. So this is sufficient for us at this point to share.\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research Division\nOkay. And you may narrow the time frame from, say, second half to a little bit more granularity in the\nfuture as your enrollment progresses?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nExactly right. Yes. And in regards to the ClinicalTrials.gov, I would like to make, again, a statement here\nthat the ClinicalTrials.gov is not what we want to refer as to company communication. It will be updated\neventually. So I'd like to -- you to be aware of that. So the company communication is -- has priority over\nClinicalTrials.gov, but it will be updated when we have finalized the study outcome. And then we will also\nupdate the ClinicalTrials.gov. Right now, it might not be completely up to date. So I want to make sure\npeople understand that.\nCharles Cliff Duncan\nCantor Fitzgerald & Co., Research Division\nOkay. Last quick question for Sandra. I think you mentioned $151 million go through '25. I assume that's\nconsidering only the current spend and that you are not contemplating an NDA filing or commercial prep\nfor that runway and that the runway may change if you end up being involved in an NDA filing and/or\ncommercialization?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 8\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 10 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nYes. If I can maybe start first. So we have over $150 million in cash, which is a really incredibly large sum\nof money. And when you calculate our average cash utilization in the past was very consistent in the range\nof $2 million per month to $2.5 million. And now in the last quarter, we averaged $2.3 million, I think.\n\nSo this exactly right will be the cash utilization. If we do have additional plans, which are marketing the\ndrug, of course, there will be a difference in that regard. So in this regard to the cash utilization is right\nnow continuing what we have planned, which is the several studies, which we mentioned we are planning\nto do and executing the studies which are ongoing. So that is the assumption of the calculation.\nClint Tomlinson\nVP of Corporate\nThe next question is coming from Soumit Roy at Jones Research.\nSoumit Roy\nJonesTrading Institutional Services, LLC, Research Division\nCongrats on this quarter and the data. One question, Chris, I wanted to understand or get your take on,\nhow do you think FDA would look at 2 drugs being filed so close to each other with 2 different endpoints?\nCurious if you would make any comment if you think they would ask Acadia to file it RSBQ AUC?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nIt's an excellent question. I would like to speak just on our data. We really think that, as I mentioned\nbefore, every drug needs to be looked at in its uniqueness, and you want to analyze it with the drug effect\nin mind. And that's what we've done.\n\nAnd on top of it came the paper on the RSBQ, which really has extremely high variability and baseline\ninconsistency. And again, I'm not speaking here out of line. It's really in this paper from 2020, which came\naround the time when we finished our first study in the U.S. study. And that's what we learned from that\nto adjust to this.\n\nAnd then the guidelines of the FDA guidance are really specific, what to do in those cases. If you have a\nbaseline -- if you have an endpoint, which has not a totally reliability feature, then you can use what is\ncalled the anchoring and use the response analysis.\n\nBut that requires -- it's very important, and we probably should highlight it stronger that this endpoint in\nquestion needs to be correlating with the CGI. And if it doesn't correlate, you cannot use this anchoring\nmethod. So -- and you are then left with a poor outcome.\nBut since we tested the correlation, and it should correlate because the difference between the 2\nmeasures are the RSBQ is assessed by the parents, and the CGI are assessed by the physician. And while\nthey measure different things, they both should basically see a positive change independently of each\nother. And so that means they should eventually correlate to a certain extent. And they do in our studies,\nand they did in those studies, which is a good thing.\n\nAnd so once you have established a correlation, then the FDA guidelines really explicitly say, please use\nthis anchor-based method because you just also take care of what the FDA is always concerned about not\nclinically -- not statistical significance, but clinically meaningfulness. And by doing this, we basically raised\nthe bar for us, for the drug. But we also did it to make it easier to appreciate the drug effect because now\nyou can be assured that everybody who's a responder also has to have an improvement, which is clinically\nmeaningful.\n\nSo we made it for the FDA easier. That's why I think the guidance is very clear because they want to make\nsure that you just don't have an average statistical improvement of a certain percentage and/or score,\nbut it doesn't mean anything to anybody. Nobody can confirm that it is beneficial. The physician cannot\nassess it or confirm it. The patient cannot confirm it, and the parents cannot confirm it, but it's statistically\nsignificant. So it doesn't help anybody.\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 9\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 11 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nSo by using this approach of the CGI anchored RSBQ, you'll see we were able to raise the bar, make it\neasy to interpret. So it's the analogy of what we just also mentioned on the 1st of February of the story\nof the way skin diseases are assessed in rash or other features that you have to raise -- reduce a certain\namount, a minimum amount. For example, in rash, it's at 75% or even 90% before being considered even\nthat the drug works. And this bar is what we have here included. And that allows for just more fair and\nproper assessment of the drug -- of the effect of the drug.\nSoumit Roy\nJonesTrading Institutional Services, LLC, Research Division\nChris, that really helps. One last question is, if you can remind us if there is any formulation difference\nbetween the adult Rett trial and the pediatric one? And if you could talk about if the liquid versus pills you\nsee any advantage you have versus your peers?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nYes. So we have for the Rett trials consistent liquid formulation across all trials, all 3 trials in the program.\nSo the U.S. study, the AVATAR and the EXCELLENCE, have exactly the same formulation. It's a liquid\nformulation once daily orally, they take the amount of drug they need. And so there's no difference.\n\nWhat maybe you are referring to is the formulation for the Parkinson's disease, dementia study and the\nAlzheimer disease study. So in those cases, we have a once-daily solid capsule formulation or pill. And that\nis obviously also at different doses, and that is taken in a solid form.\n\nAnd the reason why we formulated or developed a formulation of liquid formulation of the drug was we\nlearned very early on that patients with Rett syndrome sometimes either cannot swallow capsules or pills\nor they have not even the ability to take food or a liquid the normal way. They have a pouch, where they\nhave basically getting that injected. So you need to have a formulation which allows to do that, and a\nliquid formulation is exactly suitable for that.\nClint Tomlinson\nVP of Corporate\nThe next call is coming from Tom Bishop at BI Research.\nTom Bishop\nBI Research\nCan you hear me?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nYes.\nTom Bishop\nBI Research\nOkay. If memory serves me, on another call, you estimated that, I think, that the total Rett market could\nbe as much as $2 billion to $5 billion. And I was just wondering if my recollection is correct. And was that\nfor the U.S. or the world? And maybe even if you can tell us something about the adult Rett population\nversus the pediatric.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nRight. So the number, I don't think we mentioned it, but is back-on-the-envelope calculation, which I just\nwant to point out here. So on average, there are 11,000 patients assumed in the U.S., so let's simplify\n10,000. And a rare disease pricing per year could be easily in the range, and I'm not saying that this is\nthe price of the drug for Rett patients, but it could be in the range of $200,000 to $500,000 per year per\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 10\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 12 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\npatient. And if you calculate and multiply this by 10,000, so the total revenue per year could be sales in\nthe range of $2 billion to $5 billion. I think that's probably the calculation was made. So that would be\naddressing only U.S. market at this point.\n\nIf you also now look at specific to adult patients with Rett, we estimate this is around about 50% of the\npatients in the -- of adult patients compared to the total patient amount. So you basically would assume\nthat the adult Rett population would be around about half of that.\nTom Bishop\nBI Research\nOkay. And then there's the whole world to boot.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nAnd then there's whole world. We have -- obviously, the markets are large. What we have seen is that the\nmarket sizes are in the range of, I would say -- what have we seen in -- an estimate Fragile X, Europe is\n13,000, Asia is 37,000 and global 350,000.\nTom Bishop\nBI Research\nWas that Fragile X or Rett?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nYes, this is -- sorry, this is Rett syndrome only. So Rett syndrome, Europe is 11 -- 13,000. These are\nall quoted references from the national foundations or respective information. And Asia's 37,000 Rett\nsyndrome patients and global 350,000 patients with Rett syndrome. Fragile X is larger. It's around about 6\nto 7x the size of Rett syndrome.\nTom Bishop\nBI Research\nOkay. I note that the quarterly commentary, again, skips over Parkinson's disease dementia and the\nphysical aspect as well. And I'm wondering why that is. And what's the status?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nNo. We want to update when we have the updates. So the PDD study was really successful, and it\nallowed us to move into now 2 directions. And we stated that. One is to plan a potentially pivotal study\nin Parkinson's alone given the strong UPDRS signal as well as in UPDRS in Parkinson's disease dementia\ngiven the strong cognitive improvement.\n\nWe are now discussing with the respective experts designs of such studies. And then we go with these\ndesigns to the FDA, to the agency and ask for their input on how to execute those studies, and that's right\nnow taking place. So once we have feedback, we will come back and revert back on this.\nTom Bishop\nBI Research\nGood. Okay. And when do you estimate the last patient will complete the last observation in the 48-week\nAlzheimer's trial? I understand that's fully enrolled at 509,000 -- 509 patients already, right?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\n\n\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 11\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 13 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nYes, 509 patients. So we expect the last patient to be finished around probably summertime. And so I\nthink then we have to clean data and do data lock, and then we have the data. So that's right now the\nexpected time lines.\nTom Bishop\nBI Research\nCould you just describe the various steps of activities after the trial is over and the cleaning and eventually\nthen blinding the trial and crunching the numbers? I mean how long do these -- what are these various\nsteps? I think it would help everybody a little bit. And how long roughly -- a time range roughly do they\ntake?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nRight. So the key bulk of the time is the data cleanup. So you have to be aware that a clinical trial once\nit's data locked, what it's called, you cannot go in there anymore. You cannot even change a comma. It's\nlike locked as the word says.\n\nSo what you want to do, you want to double, triple, quadruple check every entry, that all the entries are\nin there, that all items are explained, that there's no missing cell or whatever, like an Excel spreadsheet.\nSo this -- everything needs to be checked and double checked and triple checked. And that often takes\nseveral months.\n\nAnd once it's done, it's locked and then the time from lock to the unblinded data is very short. It's 2\nweeks because then the CRO does that, and they do quality control themselves to double check that\nthe outcome is truly what they have -- the calculation is provided, and they double check with their own\ninternal control. And then they give it to us. So this is around about how it works.\nTom Bishop\nBI Research\nOkay. That's helpful. And there have been a lot of estimates of how big the revenue opportunity would be\nfor a drug that works on Alzheimer's disease, and I must confess to have made some myself in the U.S.\nand the world. And for the U.S., I think it sounds to me like many think that could be around $10 billion\nannually. But I'm more interested in what your thoughts are on that market potential size.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nYes. I mean, it's certainly not out of reach or unreasonable. I remember when the data or the approval\nfrom Biogen was announced that the stock jumped to $30 billion. So if that is the expectation of net\npresent value of a successful trial -- potential successful drug can then go to market, then so be it.\n\nAnd I think it's really like a measure of price times patients which are eligible. And then you have to make\nthe math from that point of view. But certainly, it's a largest unmet need. There's no doubt about that.\nTom Bishop\nBI Research\nI noticed that same $20 billion increase in the market cap of Biogen temporarily, anyway.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nWe have here another question if there is no other question. I was wondering if you could comment on a\ncouple of items. Will you consider initiating further trials in Angelman syndrome, perhaps a basket trial\nwith multiple gene-related disorders.\n\nAnd so the answer to that question is we are planning already -- so let me ask this -- answer this. So\nwe want to basically bring home the Rett franchise first, and we're very close to that. And after that, we\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 12\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 14 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nwant to tackle these other indications, which we have preclinical data, information which is a conductive of\nmoving into a clinical trials, which includes Angelman syndrome.\n\nBut also, as I mentioned, I think, on the last call that we are planning to use a quasi-basket trial for\nFragile X because Fragile X is a very heterogeneous population. And we just wanted to make sure we're\naddressing the right population for the cohort. And what we do, we do a quasi -- planning a quasi-basket\ntrial in Fragile X. So each cohort will be addressed and will be homogeneous. We are assessed by how well\nthey do with our drug. So we're already basically utilizing this basket-like trial designs to feature in our\nnext trial. Clint, are there any more questions do you see?\nXu Zou\nOkay. Can you hear me?\nClint Tomlinson\nVP of Corporate\nPlease go ahead, yes.\nXu Zou\nOkay. This is Xu on for Yun. Congratulations on this quarter's progress. And I just want to take 1 step\nback about the Rett syndrome clinical manifestation because Rett syndrome, that has pretty wide range of\nclinical manifestation. So do you consider Rett syndrome primarily central nervous related or both central\nand peripheral? Because a lot of multiple clinical trials have been using RSBQ and CGI as their primary\nendpoint. But some experts believe RSBQ focus too much on behavior changes, but motor functions for\nRett syndrome patients are also important. So are you marrying any like motor function-related endpoints\nin the trial?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nExcellent question. And that's another reason why the RSBQ is basically not a bad endpoint, but just\nneeds to be put in the right perspective, and as a stand-alone, not sufficiently validated to represent the\nfull features of Rett pathology.\n\nSo the answer to that is twofold. Yes, we did see a signal also in movement features. We noticed that in\nthe quality-of-life assessment that there were some activities noticed in that regard, and the quality of life\nalso captures movement.\nAnd also, for example, family cohesion. So is the family more happy to deal with things? And can the\npatient do things by itself? And we also heard from some investigators that there were the ability of\nmoving the legs again which were not able to move before.\n\nAnd to come to the question about the periphery versus central nervous system, I think this is a complex\ndisease. And as we learn more about it, we also have to appreciate that the fact that we have seen in\nthe periphery by measuring blood biomarkers of pathology like the GABA and the LAAA, which responded\nnicely and were in line with the outcome of the patient benefit.\n\nSo these are also CNS-related features, but they were measured in the periphery. So we cannot exclude\nthat the periphery effect also is involved. But ultimately, we know that the key feature of the drug is really\non CNS. And we have seen that confirmed with the target engagement study we did prior with the PET\nscan sigma-1 ligand.\n\nSo we definitely know that the key target point is in the brain. But again, I would not exclude that there is\nalso potential periphery effect, but the key target is definitely the CNS.\nXu Zou\nIt's helpful. So regarding your interaction with the regulators, have you already scheduled a meeting with\nthe FDA? Or when should we expect to see?\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 13\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 15 of 16\nANAVEX LIFE SCIENCES CORP. FQ1 2022 EARNINGS CALL | FEB 09, 2022\n\n\n\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nYes. So the way it works, we have to send to the FDA clinical trial reports, and they're required to be put\ntogether. So it's not just the slides which we have. So in that right now is on the high pressure is taking\nplace. So once we have those slides, those documents done together, which are clinical study reports, the\nformal report, then we will submit them and then request the meeting.\nXu Zou\nOkay. So do you expect the feedback to be before the readout of EXCELLENCE study?\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nThis is very likely because we said second half of 2022, so we expect that to be the case, yes.\nXu Zou\nOkay. Sure. Second follow-up, your -- you just mentioned your basket study for 3-71 for 3 different\nindications. Just can you give us more color on like 3 different indications, how do you plan to recruit the\npatients and how to measure efficacy, this indication have very different endpoint or clinical duration like\n[indiscernible] change very quickly. So do you have any prioritization or just give me color on that.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nRight. So I think it was a bit of like maybe explained too quickly. We refer to Fragile X where we will\ninclude Fragile X patients. These are all Fragile X patients, but they have different features which are\nnot identical. So they have to homogenize them to make them more consistent in their feature. We\ngroup them in distinct groups of Fragile X. And it could be certain behavior prevalent -- certain cognitive\nimpairment prevalences and so forth. So that's what I was referring to do across the basket trial. So we\nwill measure the same endpoint, which is Fragile X-related endpoints.\n\nWhen it comes to ANAVEX 3-71, which we are planning in Alzheimer in frontotemporal dementia and also\nschizophrenia, this will be not basket trial. It will be in a program, call it. There will be trials which will be\ndone separately because schizophrenia, for example, requires a relatively short study duration, run about\n6 weeks, for example. In the FTD and Alzheimer study require longer studies, at least 6 months. So you\nsee already from that angle that they are not -- that they cannot be put in one trial together.\nClint Tomlinson\nVP of Corporate\nThat's all the questions, Dr. Missling.\nChristopher U. Missling\nPresident, CEO, Secretary & Director\nSo then we'd like to thank everybody. And again, as we look forward into 2022, we're very excited about\nthe company's potential as we build on a successful completion of the 2 important studies that allow us to\nconfidently expand further into the rare disease space and plan expanded access for adult patients with\nRett syndrome, and while we're looking forward to further pivotal clinical trial readout in pediatric Rett\nsyndrome and in Alzheimer's disease as well as pipeline updates this year. So with that, thank you very\nmuch.\nClint Tomlinson\nVP of Corporate\nThank you, ladies and gentlemen. And that concludes today's conference call. We appreciate you\nparticipating. You can now disconnect.\n\n\nCopyright \u00a9 2024 S&P Global Market Intelligence, a division of S&P Global Inc. All Rights reserved.\nspglobal.com/marketintelligence 14\n\f Case 1:24-cv-03529-CM Document 23-7 Filed 08/23/24 Page 16 of 16\nANAVEX LIFE SCIENCES CORP. 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All Rights reserved.\nspglobal.com/marketintelligence 15\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:21.841160-07:00","document_number":"23","attachment_number":7,"pacer_doc_id":"127036039507","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Earnings Call","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579231/","id":409579231,"tags":[],"absolute_url":"/docket/68511120/23/8/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.793234-07:00","date_modified":"2024-08-27T02:10:46.286221-07:00","sha1":"7ae6d83bd1acc5c9c37d886624609ce21c3ddb5d","page_count":8,"file_size":165040,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.8.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.8.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 1 of 8\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 2 of 8\n\n\n\n\nFile Name:\n\nANAVEX LIFE SCIENCES CORP.\nQ1 2023 Earnings Call\nFebruary 7, 2023\n\nLEGEND:\n\n[UI]: Unintelligible\n[PH]: Phonetic\n\nCORPORATE PARTICIPANTS\n\nClint Tomlinson\nVice President -Operations Anavex Life Sciences Corp.\n\nChristopher U. Missling\nPresident, Chief Executive Officer & Director Anavex Life Sciences Corp.\n\nSandra Boenisch\nPrincipal Financial Officer & Treasurer Anavex Life Sciences Corp.\n\nOTHER PARTICIPANTS\n\nSoumit Roy\nAnalyst\nJonesTrading Institutional Services LLC\n\nYun Zhong\nAnalyst\nBTIG LLC\n\nMANAGEMENT DISCUSSION SECTION\n\nClint Tomlinson\nGood morning everyone, and welcome to the Anavex Life Sciences Fiscal 2023 First\nQuarter Conference Call. My name is Clint Tomlinson, and I will be your host for today's\ncall. At this time, all participants are in a listen-only mode. Later, we will conduct a\nquestion-and-answer session. During this session, if you\u2019d like to ask a question, use the\nQ&A box or please raise your hand. Note that this conference is being recorded. The call\nwill be available for replay on Anavex's website at www.anavex.com.\n\nWith us today is Dr. Christopher Missling, President and Chief Executive Officer\u037e and\nSandra Boenisch, Principal Financial Officer. Before we begin, please note that during this\nconference call, the company will make some projections and forward-looking statements.\nThese statements are only predictions based on current information and expectations and\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 3 of 8\n\n\n\n\ninvolve a number of risks and uncertainties. We encourage you to review the company's\nfilings with the SEC. This includes, without limitation, the company's Forms 10-K and 10-\nQ, which identify the specific factors that may cause actual results or events to differ\nmaterially from those described in these forward-looking statements.\n\nThese factors may include, without limitation, the risks inherent in the development and/or\ncommercialization of potential products, uncertainty in the results of clinical trials or\nregulatory approvals, need and ability to obtain future capital, and maintenance of\nintellectual property rights. And with that, I would like to turn the call over to Dr. Missling.\n\nChristopher U. Missling\nThank you, Clint. We appreciate everyone joining us on today's conference call to review\nour most recently reported financial results and to provide a business update. We are\nexcited with the continued advancement of our lead product candidate, ANAVEX 2-73, in\nAlzheimer's disease and Rett syndrome, as we maintain our attention on execution across\neach of our clinical programs and overall business operations.\n\nWe were very pleased to present top-line data of the randomized, double-blind, placebo-\ncontrolled Phase 2b/3 study for the treatment of early Alzheimer's disease at the CTAD\nCongress 2022 on December 1.\n\nThe trial met both core primary and secondary endpoints, showing statistically significant\nreduction of clinical decline as measured by those endpoints. We are excited about the data\nand plan to submit the data for publication in a peer-reviewed medical journal in the near\nterm. As a reminder, Alzheimer's disease represents a growing burden to healthcare\nsystems and societies worldwide. This disease is often multifactorial and complex in\nnature. We believe that our precision medicine platform, the novel central nervous system\nmechanism, improved the chance of clinical success.\n\nWe are pleased by the results of the placebo-controlled Phase 2b/3 study Alzheimer's\ndisease trial, which data suggests that ANAVEX 2-73, blarcamesine, an orally-available\nsmall molecule activator of the upstream SIGMAR1 receptor, is pivotal to restoring neural\ncell homeostasis and promoting new plasticity, and might be at the forefront of biomarker-\nguided, pathway-based, targeted precision medicine drug development.\n\nWe look forward to presenting the complete dataset of the study as well as the other long-\nterm study data of the other programs, including Parkinson's disease, dementia and Rett\nsyndrome. With a deep portfolio of promising therapies, we believe that Anavex remains\nwell-positioned to address the urgent needs of patients affected by neurodegenerative and\nrare neurodevelopmental diseases.\n\nGoing back to the Rett Syndrome program, we announced recently on February 2nd last\nweek the completion of enrollment of the randomized placebo-controlled EXCELLENCE\nPhase 2/3 study for the treatment of pediatric patients with Rett syndrome. We expect to\nannounce top-line results from the study in the second half of this year.\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 4 of 8\n\n\n\n\nIn Parkinson's disease dementia, we are planning to announce data from the 48-week open\nlabel extension of the previously successfully completed Phase 2 study. In other\nindications, recent communication with the FDA confirms our strategy to advance\nANAVEX 2-73 for the treatment of Fragile X syndrome. We plan to initiate this trial soon,\nand we\u2019ll share more details about this clinical program in the near term, as it becomes\navailable. Further, pipeline expansion of the Anavex platform using gene biomarkers of\nresponse, applying precision medicine to neurological disorders is expected, including\nplanned initiation of an ANAVEX 2-73 imaging-focused Parkinson's disease clinical\nstudy, sponsored by the Michael J. Fox Foundation, the planned initiation of a Phase 2/3\nclinical trial for the treatment of a new rare disease indication, and the planned initiation of\nan ANAVEX 3-71 Phase 2 clinical trial for schizophrenia.\n\nAnd last but not least, we expect several clinical publications involving ANAVEX 2-73\nand ANAVEX 3-71 and a Rett syndrome Burden of Illness study.\n\nAnd now I would like to direct the call to Sandra Boenisch, Principal Financial Officer of\nAnavex, for a brief financial summary of the recently reported quarter.\n\nSandra Boenisch\nThank you, Christopher, and good morning to everyone. We continue to demonstrate\noperating fiscally responsibly. During our first fiscal quarter, general and administrative\nexpenses were $3.3 million, compared to $3.1 million for the comparable quarter of fiscal\n2022. Our research and development expenses for the quarter were $12.1 million, as\ncompared to $8.7 million for the comparable quarter of fiscal 2022. Overall, we reported a\nnet loss of $13 million or $0.17 per share, inclusive of $5.3 million in non-cash\ncompensation items.\n\nOur cash position at December 31, 2022, was $103.6 million. During the quarter, we\nutilized cash and cash equivalents of $5.8 million to fund our operations. At our current\ncash utilization rate, we believe we have sufficient cash runway to fund operations and\nclinical programs beyond the next four years, consistent with guidance in previous quarters.\n\nThe increase in research and development expenses over the comparable period is\nprimarily related to the expansion of our team and an associated increase in compensation\nand non-cash charges period over period, as well as costs associated with our Phase 2b/3\nstudy, Anavex 2-73-AD-004, and the manufacture of additional clinical trial supply for\nupcoming pipeline programs. Thank you, and now back to you, Christopher.\n\nChristopher U. Missling\nThank you, Sandra. This is an exciting time for the company, and we remain on track for\ncompletion and readout of ongoing clinical trials and initiation of additional biomarker-\ndriven precision medicine clinical trials as planned.\n\nI would like now to turn the call back to Clint for Q&A.\n\nQ&A\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 5 of 8\n\n\n\n\nClint Tomlinson\nThank you, Christopher. We will now begin the Q&A session. If you have a question, raise\nyour hand or please put it in the Q&A box. The first question is going to come from Soumit\nRoy at Jones Research. I think you can go ahead, Soumit.\n\nSoumit Roy Q\nHi, everyone. Congratulations on the progress. Could you give us a little color on what\nkind of details on the Alzheimer's data we are going to expect? Are we going to see some\nMRI data, or time course of how the reduction in the cognitive decline has occurred, or\nsomething like that?\n\nChristopher U. Missling A\nYeah, so several items will be in the paper, in the publication. Of course, we made sure\nthat the study has a lot of biomarkers and additional measures of endpoints. So among them\nis MRI, which is a very important marker of pathology, which is the most accurate \u2013 it\u2019s a\npicture of the brain and it's very well-described that the brain atrophy moves in this\npathology aggressively. So that will be part of the analysis, as well as additional biomarkers\nof pathology like A-beta and tau, as well as the biomarker which is specific to ANAVEX,\nwhich is the SIGMAR1 variant analysis, which was clearly pre-specified, which you\nremember we noted that patients with a wild-type SIGMAR1 receptor did much better\ncompared to those who had the variant. But because the variant carriers were in the\nminority, often that signal overall was not affecting the significance of all patients, but it\nwas notable that there was a better outcome in patients with the wild-type SIGMAR1\ncarrier status in previous studies. So we are looking forward to seeing how this plays out\nin this study as well.\n\nBut then, also, we will see the response to the endpoints of the study depending on doses,\nas well as over the period of time, because we measure every three months the time points\nof this area within this study. And then we will see additional endpoints, which have been\nincluded in this study, like quality of life, sleep quality, and other behavioral measures\nwhich are related to the Alzheimer's pathology.\n\nSoumit Roy Q\nThank you for the detail. That was really helpful. Should we expect the data to come out\nfirst half of this year, or are you going to be more like second half should be our\nexpectation?\n\nChristopher U. Missling A\nWe actually try to do this as soon as possible because we want to share that also with the\nagencies, the FDA and Europe. So we are really keen to do that as soon as possible. But at\nthis point in time, it's too premature to give guidance on the timing, but you can be assured\nwe\u2019ll do that as soon as possible.\n\nSoumit Roy\nGreat, thank you so much for taking the questions and congrats on all the progress.\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 6 of 8\n\n\n\n\nChristopher U. Missling\nThank you.\n\nClint Tomlinson\nThe next call comes from Yun Zhong at BTIG. I think you can go ahead, Zhong.\n\nYun Zhong Q\nHi. Good morning. Thank you very much for taking questions. So, Christopher, can you\ntalk about your plan for the regulatory discussion with the FDA on the Alzheimer's\nindication? Have you started any [Technical Difficulty] talk to the FDA?\n\nChristopher U. Missling\nSorry, a bit of cut off.\n\nClint Tomlinson\nI\u2019m sorry, can you ask that again? We had a \u2013 we had a glitch.\n\nYun Zhong Q\nOkay, no problem. So yeah, I was wondering your plan for the discussion with the FDA.\nHave you started anything, or do you have to wait for additional data to be available before\nyou can start that conversation with the FDA?\n\nChristopher U. Missling A\nThat's correct. The FDA engages when you have data, and that's exactly where we are. So\nthe data means a complete data set as far as possible. And that's what we want to \u2013 that's\nwhy we are so keen to complete that, as I just mentioned, because that's how you can\nengage with the FDA as well as with the European EMA agency.\n\nYun Zhong Q\nOkay. And then switching to the Rett syndrome study, I believe the press release\nannouncing over enrollment had the language that with the FDA's input, you are using the\nprimary endpoint. So I wanted to confirm that the primary endpoint is RSBQ AUC, similar\nto or the same to the one used in the AVATAR study. And so has the FDA agreed that the\nAUC, the modified RSBQ scale can be an appropriate endpoint for Rett syndrome study?\n\nChristopher U. Missling A\nWe have it described in clinicaltrials.gov, and it was also never changed in\nclinicaltrials.gov for the EXCELLENCE study. It is - the RSBQ is primary endpoint and\nthe CGI-I is key secondary endpoint. This is over the course of the trial.\n\nYun Zhong Q\nIs that the same endpoint that was used in the AVATAR study?\n\nChristopher U. Missling A\nIt's slightly different. So it's actually the measurement over time from beginning to end of\ntrial.\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 7 of 8\n\n\n\n\nYun Zhong Q\nNot AUC?\n\nChristopher U. Missling A\nNot AUC.\n\nYun Zhong Q\nNot AUC.\n\nChristopher U. Missling A\nExactly, yes. Because the study is large enough that it can carry the signal by itself without\nAUC.\n\nYun Zhong Q\nOkay, great. So the last question, I believe the original plan is to initiate all those studies\nthat you talked about by year-end last year. And I understand that the focus was on the\nAlzheimer's disease program. But are there any specific reasons for the delay, or also are\nyou able to provide any specifics in terms of timing? When do you expect to initiate those\nstudies?\n\nChristopher U. Missling A\nYes, we were very ambitious last year when we made those plans. And the attention to\ndetail required really to finance and work on the specific protocol. Because it's easy to start\nany trial. It's more difficult to finish a trial successfully, and that's what we're aiming for.\nSo I think we should appreciate that initiating a trial is not difficult. It's about making the\ntrial successful and meaningful for \u2013 for when it's going. And so when you look at each\ntrial, there's always things to consider, and you learn to improve it as you go before you\nreally start it. And we didn't want to rush it. So that's why we want to say we want to do\nthis with the right timing. But obviously, we will catch up very nicely now with all these\ntrials which we planned to do, and they are still on track to be executed.\n\nYun Zhong\nOkay, great. Thank you very much.\n\nChristopher U. Missling\nYou're welcome.\n\nClint Tomlinson\nI don't see any further questions at this time. Christopher?\n\nChristopher U. Missling\nGood. Thank you. Again, we are very much looking forward and we're very excited about\nthe company's potential as we build on biomarker-driven precision medicine studies with\nsignificant unmet medical need and economic burden. And we're looking forward to\nupcoming data readouts in Parkinson's dementia and Alzheimer's disease with complete\n\f Case 1:24-cv-03529-CM Document 23-8 Filed 08/23/24 Page 8 of 8\n\n\n\n\ndata set, as well as Parkinson's dementia open label extension and the pediatric Rett\nsyndrome study. Thank you very much.\n\nClint Tomlinson\nAll right. Thank you, ladies and gentlemen. This concludes today's conference. We\nappreciate you participating and you may now disconnect.\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:23.148019-07:00","document_number":"23","attachment_number":8,"pacer_doc_id":"127036039508","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Transcript","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579232/","id":409579232,"tags":[],"absolute_url":"/docket/68511120/23/9/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.835357-07:00","date_modified":"2024-08-27T02:16:49.194768-07:00","sha1":"485631865fd386dd872d373af517ed25c5f87c7c","page_count":4,"file_size":699789,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.9.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.9.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-9 Filed 08/23/24 Page 1 of 4\n\f Case 1:24-cv-03529-CM Document 23-9 Filed 08/23/24 Page 2 of 4\nJun 6, 2023\n\n\nCompletion of ANAVEX\u00ae2-73 (blarcamesine)\nEXCELLENCE Phase 2/3 Rett Syndrome Clinical\nTrial\n\n\n\n\nNEW YORK \u2013 June 6, 2023\nAnavex Life Sciences Corp. (\u201cAnavex\u201d or the \u201cCompany\u201d) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company\ndeveloping differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders\nincluding Alzheimer\u2019s disease, Parkinson\u2019s disease, Rett syndrome and other central nervous system (CNS) disorders,\ntoday announced the completion of dosing of all participants of the placebo-controlled EXCELLENCE Phase 2/3 study\nANAVEX\u00ae2-73-RS-003 in pediatric patients with Rett syndrome. The Company expects to announce topline results\nfrom this study in the second half of this year.\n\n\nANAVEX\u00ae2-73 (blarcamesine) is an orally available, small-molecule activator of the sigma-1 receptor (SIGMAR1) which,\ndata suggest, is pivotal to restoring cellular homeostasis and promoting neuroplasticity. [1]\n\n\nThe completion of the randomized, placebo-controlled EXCELLENCE Phase 2/3 study ANAVEX\u00ae2-73-RS-003 for the\ntreatment of 92 pediatric patients with Rett syndrome ages \u2265 5 years to 17 (inclusive) was preceded by the successful\ncompletion of both placebo-controlled Phase 2 U.S. (ANAVEX\u00ae2-73-RS-001) [2], and Phase 3 AVATAR (ANAVEX\u00ae2-\n73-RS-002)[3] studies in adult patients with Rett syndrome.\n\n\nThe multi-center, double-blind clinical EXCELLENCE study (ANAVEX\u00ae2-73-RS-003)[4] in pediatric patients is\nmeasuring safety, tolerability, and efficacy of daily oral ANAVEX\u00ae2-73 (blarcamesine) doses or placebo. After\n\f Case 1:24-cv-03529-CM Document 23-9 Filed 08/23/24 Page 3 of 4\ncompleting the double-blind study, eligible participants are able to join a voluntary open-label extension study of\nANAVEX\u00ae2-73 (blarcamesine).\n\n\nIn communication with the FDA, the Company received the Agency\u2019s input on the study endpoints, which were utilized\nin this clinical study. The Rett Syndrome Behavior Questionnaire (RBSQ) total score and Clinical Global Impression\nImprovement Scale (CGI-I) score are co-primary endpoints in the statistical analysis plan with specified linear mixed-\neffects models for repeated measures (MMRM) as the primary analysis methods.\n\n\nANAVEX\u00ae2-73 (blarcamesine) had previously received Fast Track designation, Rare Pediatric Disease designation and\nOrphan Drug designation from the FDA for the treatment of Rett syndrome.\n\n\n\u201cWe would like to thank the investigators and clinical site coordinators as well as all the participating families for their\ndedication to this clinical study completed with ANAVEX\u00ae2-73 (blarcamesine)\u201d, said Christopher U. Missling, PhD,\nPresident and Chief Executive Officer of Anavex. \u201cRett syndrome is a devastating, non-inherited genetic post-natal\nprogressive neurodevelopmental disorder that occurs almost exclusively in girls and leads to severe impairments,\naffecting nearly every aspect of the child\u2019s life, hence we continue our fast-paced development program of ANAVEX\u00ae2-\n73 (blarcamesine) in Rett syndrome.\u201d\n\n\nAbout Rett Syndrome\nRett syndrome is a rare, non-inherited genetic postnatal progressive neurodevelopmental disorder that occurs almost\nexclusively in girls and leads to severe impairments, affecting nearly every aspect of the child\u2019s life: their ability to speak,\nwalk, eat and even breathe easily. The hallmark of Rett syndrome is near constant repetitive hand movements while\nawake. It is characterized by normal early growth and development (6 to 18 months) followed by a slowing of\ndevelopment, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems\nwith walking, seizures and intellectual disability. There is currently no cure for Rett syndrome and treatment of the\ndisorder is symptomatic. Management of symptoms is done through a multidisciplinary approach utilizing medication for\nmotor difficulties, breathing irregularities and control of seizures through anticonvulsant drugs. Rett syndrome is\ncaused by mutations in the MECP2 gene and strikes all racial and ethnic groups and occurs worldwide in approximately\none in every 10,000 to 15,000 live female births.\n\n\n\nAbout Anavex Life Sciences Corp.\nAnavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the\ndevelopment of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders,\nincluding Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases,\npain, and various types of cancer. Anavex's lead drug candidate, ANAVEX\u00ae2-73 (blarcamesine), has successfully\ncompleted a Phase 2a and recently a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study\nin Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome.\nANAVEX\u00ae2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and\nmuscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's\ndisease. ANAVEX\u00ae2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in\nanimal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox\nFoundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study\n\f Case 1:24-cv-03529-CM Document 23-9 Filed 08/23/24 Page 4 of 4\nto develop ANAVEX\u00ae2-73 for the treatment of Parkinson's disease. ANAVEX\u00ae3-71, which targets sigma-1 and M1\nmuscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the\nmajor hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau\npathologies. In preclinical trials, ANAVEX\u00ae3-71 has shown beneficial effects on mitochondrial dysfunction and\nneuroinflammation. Further information is available at www.anavex.com. You can also connect with the company on\nTwitter, Facebook, Instagram, and LinkedIn.\n\n\nForward-Looking Statements\nStatements in this press release that are not strictly historical in nature are forward-looking statements. These\nstatements are only predictions based on current information and expectations and involve a number of risks and\nuncertainties. Actual events or results may differ materially from those projected in any of such statements due to\nvarious factors, including the risks set forth in the Company\u2019s most recent Annual Report on Form 10-K filed with the\nSEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the\ndate hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life\nSciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after\nthe date hereof.\n\n\nFor Further Information:\nAnavex Life Sciences Corp.\nResearch & Business Development\nToll-free: 1-844-689-3939\nEmail: info@anavex.com\n\n\nInvestors:\nAndrew J. Barwicki\nInvestor Relations\nTel: 516-662-9461\nEmail: andrew@barwicki.com\n\n\n[1]Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as\nTherapeutic Targets.\n[2] ClinicalTrials.gov Identifier: NCT03758924\n[3] ClinicalTrials.gov Identifier: NCT03941444\n[4] ClinicalTrials.gov Identifier: NCT04304482\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:23.810417-07:00","document_number":"23","attachment_number":9,"pacer_doc_id":"127036039509","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Press Release","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579233/","id":409579233,"tags":[],"absolute_url":"/docket/68511120/23/10/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.879270-07:00","date_modified":"2024-08-27T02:13:17.910232-07:00","sha1":"a84a662a560fef9f8c86442cbfb325e18cf993a6","page_count":4,"file_size":638106,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.10_1.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.10.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-10 Filed 08/23/24 Page 1 of 4\n\f Case 1:24-cv-03529-CM Document 23-10 Filed 08/23/24 Page 2 of 4\nJun 12, 2023\n\n\nAnavex Life Sciences Reports Publication in\nMedical Journal for Continued Commitment to\nImprove RSBQ\n Rett Syndrome Caregiver Outcome Measure\n\n\n\n\nNEW YORK \u2013 June 12, 2023\nAnavex Life Sciences Corp. (\u201cAnavex\u201d or the \u201cCompany\u201d) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company\ndeveloping differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders\nincluding Alzheimer\u2019s disease, Parkinson\u2019s disease, Rett syndrome and other central nervous system (CNS) disorders,\ntoday announced the publication of a relevant new peer-reviewed study in the American Journal on Intellectual and\nDevelopmental Disabilities, entitled \u2018Rett Syndrome Behaviour Questionnaire in Children and Adults With Rett Syndrome:\nPsychometric Characterization and Revised Factor Structure\u2019.[1]\n\n\nThe study reports distribution of scores and other statistical features of the Rett Syndrome Behaviour Questionnaire\n(RSBQ) in more than 600 children and adults with Rett syndrome. It also re-examines the structure of the questionnaire,\nspecifically the grouping of questions (items) into different subscales. This evaluation led authors to propose some\nchanges to the organization of the questions (i.e., revised subscales). The study, which represents the largest ever\nanalysis of the RSBQ and the first report of the instrument in adults with Rett Syndrome, was the result of an\ninternational collaboration including anonymized databases from the United States, Australia, United Kingdom, and\nDenmark. The ultimate goal of the project was to provide reference values and other metrics of the RSBQ for its clinical\napplication and implementation in research studies. The study was partially funded by a grant from the International\n\f Case 1:24-cv-03529-CM Document 23-10 Filed 08/23/24 Page 3 of 4\nRett Syndrome Foundation (IRSF). All analyses performed in the study are available to the community through a website\nhosted by IRSF.\n\n\nThe RSBQ was developed by a British team of clinicians and researchers to better delineate behavioral problems in\nchildren with Rett syndrome. Over the course of the following two decades, the use of the RSBQ has been expanded to\nobservational studies in adults with Rett syndrome and efficacy assessments. The RSBQ\u2019s implementation as global\noutcome measures in FDA-regulated clinical trials is the result of its comprehensive nature since the questionnaire\nincludes not only behaviors but also behavior-related symptoms. Indeed, most regulated trials include as co-primary\nefficacy endpoints the RSBQ, as a caregiver measure, and the Clinical Global Impression of Improvement (CGI-I) as an\ninvestigator assessment. For all these reasons, this psychometric study is timely and significant, providing additional\nsupport for the use of the RSBQ in children and adults as well as reference values and revised subscales for its improved\nuse.\n\n\nIn the EXCELLENCE Phase 2/3 ANAVEX\u00ae2-73-RS-003 Rett syndrome pediatric clinical trial, the characterized Rett\nSyndrome Behaviour Questionnaire (RBSQ), together with the Clinical Global Impression Improvement Scale (CGI-I),\nrepresent the co-primary efficacy endpoints of the study.\n\n\n\u201cThis paper is a further demonstration of Anavex\u2019s involvement as part of the team of clinicians and commitment to the\nrare disease and especially to the Rett syndrome community,\u201d said Christopher U Missling, PhD, President and Chief\nExecutive Officer of Anavex. \"We are looking forward to the topline data from the EXCELLENCE Phase 2/3\nANAVEX\u00ae2-73-RS-003 Rett syndrome pediatric clinical trial in the second half of 2023.\u201d\n\n\nThe paper can be accessed online at: https://pubmed.ncbi.nlm.nih.gov/37104862/.\n\n\nAbout Rett Syndrome\nRett syndrome is a devastating, non-inherited genetic post-natal progressive neurodevelopmental disorder that occurs\nalmost exclusively in girls and leads to severe impairments, affecting nearly every aspect of the child\u2019s life: their ability to\nspeak, walk, eat and easily breathe. The hallmark of Rett syndrome is near constant repetitive hand movements while\nawake. The disease is characterized by normal early growth and development (6 to 18 months) followed by a slowing of\ndevelopment, loss of purposeful use of the hands, distinctive hand movements, autistic features, slowed brain and head\ngrowth, ataxia, seizures and intellectual disability.\nRett syndrome is caused by mutations in the MECP2 gene and strikes all racial and ethnic groups. The disease occurs\nworldwide in approximately one in every 10,000 to 15,000 live births. The population of patients with Rett syndrome is\nestimated to be approximately 11,000 patients in the U.S. There is currently no cure for Rett syndrome.\n\n\nAbout Anavex Life Sciences Corp.\nAnavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the\ndevelopment of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders,\nincluding Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases,\npain, and various types of cancer. Anavex's lead drug candidate, ANAVEX\u00ae2-73 (blarcamesine), has successfully\ncompleted a Phase 2a and recently a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study\nin Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome.\nANAVEX\u00ae2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and\n\f Case 1:24-cv-03529-CM Document 23-10 Filed 08/23/24 Page 4 of 4\nmuscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's\ndisease. ANAVEX\u00ae2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in\nanimal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox\nFoundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study\nto develop ANAVEX\u00ae2-73 for the treatment of Parkinson's disease. ANAVEX\u00ae3-71, which targets sigma-1 and M1\nmuscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the\nmajor hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau\npathologies. In preclinical trials, ANAVEX\u00ae3-71 has shown beneficial effects on mitochondrial dysfunction and\nneuroinflammation. Further information is available at www.anavex.com. You can also connect with the company on\nTwitter, Facebook, Instagram, and LinkedIn.\n\n\nForward-Looking Statements\nStatements in this press release that are not strictly historical in nature are forward-looking statements. These\nstatements are only predictions based on current information and expectations and involve a number of risks and\nuncertainties. Actual events or results may differ materially from those projected in any of such statements due to\nvarious factors, including the risks set forth in the Company\u2019s most recent Annual Report on Form 10-K filed with the\nSEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the\ndate hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life\nSciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after\nthe date hereof.\n\n\nFor Further Information:\nAnavex Life Sciences Corp.\nResearch & Business Development\nToll-free: 1-844-689-3939\nEmail: info@anavex.com\n\n\nInvestors:\nAndrew J. Barwicki\nInvestor Relations\nTel: 516-662-9461\nEmail: andrew@barwicki.com\n\n\n[1] Oberman LM, Leonard H, Downs J, Cianfaglione R, Stahlhut M, Larsen JL, Madden KV, Kaufmann WE. Rett\nSyndrome Behaviour Questionnaire in Children and Adults With Rett Syndrome: Psychometric Characterization and\nRevised Factor Structure. Am J Intellect Dev Disabil. 2023 May 1;128(3):237-253. doi: 10.1352/1944-7558-\n128.3.237.PMID: 37104862.\n\f","ocr_status":2,"date_upload":"2024-08-26T13:25:46.963127-07:00","document_number":"23","attachment_number":10,"pacer_doc_id":"127036039510","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Press Release","acms_document_guid":""},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579234/","id":409579234,"tags":[],"absolute_url":"/docket/68511120/23/11/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:51:07.921075-07:00","date_modified":"2024-08-27T02:10:46.593403-07:00","sha1":"fff7d67a13ee62af2b819bec9b6d45b64294e5bf","page_count":6,"file_size":1806913,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.11.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.23.11.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"Case 1:24-cv-03529-CM Document 23-11 Filed 08/23/24 Page 1 of 6\n\f Case 1:24-cv-03529-CM Document 23-11 Filed 08/23/24 Page 2 of 6\nAug 8, 2023\n\n\nAnavex Life Sciences Reports Fiscal 2023 Third\nQuarter Financial Results\nOn track to release top-line data of potentially pivotal ANAVEX\u00ae2-73-RS-003 Phase 2/3 EXCELLENCE pediatric clinical trial in\n the second half of 2023\n\n\n Newly available preliminary efficacy results of surrogate biomarkers from the ANAVEX\u00ae2-73-AD-004 study in Alzheimer\u2019s\n disease with convenient oral treatment to be released in the second half of 2023\n\n\n Company to host a webcast today at 8:30 a.m. Eastern Time\n\n\n\n\nNEW YORK \u2013 August 8, 2023\n\nAnavex Life Sciences Corp. (\u201cAnavex\u201d or the \u201cCompany\u201d) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company\ndeveloping differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders\n\f Case 1:24-cv-03529-CM Document 23-11 Filed 08/23/24 Page 3 of 6\nincluding Alzheimer\u2019s disease, Parkinson\u2019s disease, Rett syndrome and other central nervous system (CNS) diseases,\ntoday reported financial results for its fiscal quarter ended June 30, 2023.\n\n\n\u201cWe are very excited to be entering an important phase of the Company, with several key data readouts based on\ninnovative science at Anavex with ANAVEX\u00ae2-73 (blarcamesine), an orally available, small-molecule activator of the\nupstream sigma-1 receptor (SIGMAR1), involved in restoring neural cell homeostasis and promoting neuroplasticity,\u201d\nsaid Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. \u201cWe remain focused on execution as\nwe prepare for a pivotal year ahead of us potentially involving a digital \u2018Healthcare Sales Marketing\u2019 pharma platform\nand also making meaningful advances in our other neurodevelopmental and neurodegenerative precision medicine\nportfolio, including schizophrenia and Parkinson\u2019s disease.\u201d\n\n\nKey Near Term Pipeline Updates:\n Rett syndrome: Top-line data of potentially pivotal ANAVEX\u00ae2-73-RS-003 Phase 2/3 EXCELLENCE\n pediatric clinical trial. Company expects to announce topline results from this study in the second half of 2023.\n Alzheimer\u2019s disease: Full data ANAVEX\u00ae2-73-AD-004, including newly available preliminary results of\n surrogate biomarkers of pivotal Phase 2b/3 clinical trial. The Company intends to discuss these findings with\n regulatory authorities in the context of the ongoing clinical development of ANAVEX\u00ae2-73 in this indication,\n with the goal of providing a much-needed treatment to the millions of patients living with Alzheimer\u2019s disease\n with a convenient once-daily oral treatment. Company expects to announce data in the second half of 2023.\n Parkinson\u2019s disease: Initiation of ANAVEX\u00ae2-73 pivotal clinical trial.\n Parkinson\u2019s disease: Initiation of ANAVEX\u00ae2-73 imaging-focused clinical trial.\n Fragile X: Initiation of potentially pivotal ANAVEX\u00ae2-73 Phase 2/3 clinical trial.\n Schizophrenia: Initiation of ANAVEX\u00ae3-71 Phase 2 clinical trial.\n New Rare disease: Initiation of potentially pivotal ANAVEX\u00ae2-73 Phase 2/3 clinical trial.\n Publications: Several clinical publications involving ANAVEX\u00ae2-73, ANAVEX\u00ae3-71 and Rett syndrome\n Burden of Illness study.\n\n\nRecent Business Highlights:\n On August 7, 2023, the Company announced a peer-reviewed publication in Clinical Pharmacology in Drug\n Development, findings from the ANAVEX\u00ae3-71 first-in-human study which achieved its cardiovascular safety\n objectives. The publication is entitled, \u2018Concentration-QTc Relationship from a Single Ascending Dose Study of\n ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for\n the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease\u2019.\n On June 28, 2023, the Company announced that long-term clinical study results from the U.S. ANAVEX\u00ae2-\n 73-RS-001 clinical trial demonstrate disease-modifying effect of ANAVEX\u00ae2-73 (blarcamesine) for adult\n patients with Rett syndrome.\n On June 27, 2023, the Company announced a strategic partnership with Partex N.V. Group, the first Data-to-\n Drugs digital pharma platform in which Partex will implement AI-based \u2018Healthcare Sales Marketing\u2019 in\n preparation for Anavex\u2019s late-stage drug pipeline.\n\f Case 1:24-cv-03529-CM Document 23-11 Filed 08/23/24 Page 4 of 6\n On June 12, 2023, the Company announced the publication of a relevant new peer-reviewed study in the\n American Journal on Intellectual and Developmental Disabilities, entitled \u2018Rett Syndrome Behaviour\n Questionnaire in Children and Adults With Rett Syndrome: Psychometric Characterization and Revised\n Factor Structure.\u2019 In the EXCELLENCE Phase 2/3 ANAVEX\u00ae2-73-RS-003 Rett syndrome pediatric clinical\n trial, the characterized Rett Syndrome Behaviour Questionnaire (RBSQ), together with the Clinical Global\n Impression Improvement Scale (CGI-I), represents the co-primary efficacy endpoints of the study.\n On June 6, 2023, the Company announced the completion of dosing of all participants of the placebo-\n controlled EXCELLENCE Phase 2/3 clinical trial ANAVEX\u00ae2-73-RS-003 in pediatric patients with Rett\n syndrome.\n On June 1, 2023, the Company announced that it was awarded a new U.S. Patent No. 11,661,405 entitled\n \u201cCRYSTAL FORMS OF TETRAHYDRO-N,N-DIMETHYL-2,2-DIPHENYL-3-FURANMETHANAMINE\n HYDROCHLORIDE, PROCESSES OF MAKING SUCH FORMS, AND THEIR PHARMACEUTICAL\n COMPOSITIONS\u201d from the United States Patent and Trademark Office (USPTO), expanding Anavex\u2019s patent\n coverage of certain crystal forms of ANAVEX\u00ae2-73 (blarcamesine) compositions, processes of preparation,\n and uses thereof.\n\n\nFinancial Highlights:\n Cash and cash equivalents of $154.8 million at June 30, 2023 compared to $149.2 million at fiscal year end\n September 30, 2022.\n General and administrative expenses for the quarter of $3.2 million compared to $3.2 million for the\n comparable quarter of fiscal 2022.\n Research and development expenses for the quarter of $10.3 million compared to $9.3 million for the\n comparable quarter of fiscal 2022.\n Net loss for the quarter of $11.3 million, inclusive of $3.9 million in non-cash items, or $0.14 per share,\n compared to a net loss of $12.4 million, inclusive of $4.0 million in non-cash items, or $0.16 per share for the\n comparable quarter of fiscal 2022.\nThe financial information for the quarter ended June 30, 2023, should be read in conjunction with the Company\u2019s\ninterim condensed consolidated financial statements, which will appear on EDGAR, www.sec.gov and will be available on\nthe Anavex website at www.anavex.com.\n\n\nWebcast / Conference Call Information:\nThe live webcast of the conference call will be available on Anavex\u2019s website at www.anavex.com.\n\n\nThe conference call can be also accessed by dialing 1 929 205 6099 for participants in the U.S. using the Meeting ID#\n891 9995 1143 and reference passcode 511901. A replay of the conference call will also be available on Anavex\u2019s\nwebsite for up to 30 days.\n\n\nAbout Anavex Life Sciences Corp.\nAnavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the\ndevelopment of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders,\n\f Case 1:24-cv-03529-CM Document 23-11 Filed 08/23/24 Page 5 of 6\nincluding Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases,\npain, and various types of cancer. Anavex's lead drug candidate, ANAVEX\u00ae2-73 (blarcamesine), has successfully\ncompleted a Phase 2a and recently a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study\nin Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome.\nANAVEX\u00ae2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and\nmuscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's\ndisease. ANAVEX\u00ae2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in\nanimal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox\nFoundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study\nto develop ANAVEX\u00ae2-73 for the treatment of Parkinson's disease. ANAVEX\u00ae3-71, which targets sigma-1 and M1\nmuscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the\nmajor hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau\npathologies. In preclinical trials, ANAVEX\u00ae3-71 has shown beneficial effects on mitochondrial dysfunction and\nneuroinflammation. Further information is available at www.anavex.com. You can also connect with the company on\nTwitter, Facebook, Instagram and LinkedIn.\n\n\nForward-Looking Statements\nStatements in this press release that are not strictly historical in nature are forward-looking statements. These\nstatements are only predictions based on current information and expectations and involve a number of risks and\nuncertainties. Actual events or results may differ materially from those projected in any of such statements due to\nvarious factors, including the risks set forth in the Company\u2019s most recent Annual Report on Form 10-K filed with the\nSEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the\ndate hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life\nSciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after\nthe date hereof.\n\n\nFor Further Information:\nAnavex Life Sciences Corp.\nResearch & Business Development\nToll-free: 1-844-689-3939\nEmail: info@anavex.com\n\n\nInvestors:\nAndrew J. Barwicki\nInvestor Relations\nTel: 516-662-9461\nEmail: andrew@barwicki.com\n\fCase 1:24-cv-03529-CM Document 23-11 Filed 08/23/24 Page 6 of 6\n\f","ocr_status":2,"date_upload":"2024-08-26T06:01:25.332065-07:00","document_number":"23","attachment_number":11,"pacer_doc_id":"127036039511","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":2,"description":"Exhibit Press Release","acms_document_guid":""}],"date_created":"2024-08-23T20:48:28.078384-07:00","date_modified":"2025-12-22T08:34:03.464034-08:00","date_filed":"2024-08-23","time_filed":"23:41:44","entry_number":23,"recap_sequence_number":"2024-08-23.003","pacer_sequence_number":104,"description":"DECLARATION of Theodore L. Kornobis in Support re: 22 MOTION to Dismiss .. Document filed by Anavex Life Sciences Corporation, Christopher U. Missling. (Attachments: # 1 Exhibit Form 10-K, # 2 Exhibit Form 10-K, # 3 Exhibit Press Release, # 4 Exhibit Transcript, # 5 Exhibit Presentation, # 6 Exhibit Report, # 7 Exhibit Earnings Call, # 8 Exhibit Transcript, # 9 Exhibit Press Release, # 10 Exhibit Press Release, # 11 Exhibit Press Release).(Kornobis, Theodore) (Entered: 08/23/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/400348515/","id":400348515,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/409579209/","id":409579209,"tags":[],"absolute_url":"/docket/68511120/22/downing-v-anavex-life-sciences-corporation/","date_created":"2024-08-23T20:48:28.044557-07:00","date_modified":"2025-12-22T08:34:03.439418-08:00","sha1":"746591126cd525285b8f1ee1d44ceb35697495fd","page_count":2,"file_size":138916,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.22.0.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.22.0.pdf","ia_upload_failure_count":null,"thumbnail":"recap-thumbnails/gov.uscourts.nysd.621044/409579209.thumb.1068.png","thumbnail_status":1,"plain_text":" Case 1:24-cv-03529-CM Document 22 Filed 08/23/24 Page 1 of 2\n\n\n\n\nUNITED STATES DISTRICT COURT\nSOUTHERN DISTRICT OF NEW YORK\n\n-------------------------------x\nKENNETH DOWNING, Individually and on\nbehalf of All Others Similarly Situated,\n Case No. 1:24-cv-03529-CM\n Plaintiff,\n\n -vs.-\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n-------------------------------x\n\n NOTICE OF DEFENDANTS\u2019 MOTION TO DISMISS\n\n PLEASE TAKE NOTICE that, upon the accompanying Memorandum of Law in Support\n\nof Defendants\u2019 Motion to Dismiss, the Declaration of Theodore L. Kornobis and accompanying\n\nexhibits, and all other papers and proceedings herein, Defendants Anavex Life Sciences\n\nCorporation and Chistopher U. Missling (together \u201cDefendants\u201d) will move this Court, before the\n\nHonorable Colleen McMahon, United States District Judge for the Southern District of New York,\n\non a date and time to be set by the Court, for an Order dismissing the Complaint (Dkt. No. 1) with\n\nprejudice pursuant to Rule 12(b)(6) of the Federal Rules of Civil Procedure. The basis for the\n\nmotion is set forth in the accompanying memorandum of law.\n\n\n\n\n319990824.1\n\f Case 1:24-cv-03529-CM Document 22 Filed 08/23/24 Page 2 of 2\n\n\n\n\n Dated: August 23, 2024 Respectfully submitted,\n\n\n /s/ Theodore L. Kornobis\n Theodore L. Kornobis\n Stephen G. Topetzes (pro hac vice pending)\n K&L Gates LLP\n 1601 K Street NW\n Washington, DC 20006-1600\n Phone: (202) 778-9000\n Email: ted.kornobis@klgates.com\n stephen.topetzes@klgates.com\n\n Attorneys for Defendant Anavex Life Sciences\n Corporation and Christopher U. 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Anavex Life Sciences Corporation waiver sent on 6/10/2024, answer due 8/9/2024. 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For the reasons stated at the June 13, 2024, court conference: The motion to appoint Kenneth Downing to serve as lead plaintiff is DENIED. The motion to appoint Quintessa Huey to serve as lead plaintiff and appoint Levi & Korsinky as lead counsel is GRANTED. The motion to consolidate these cases is DENIED. Submitted by: Adam King. (Court Reporter Nicole Dimasi). (mde) Modified on 6/25/2024 (mde).","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/393653332/","id":393653332,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/402727848/","id":402727848,"tags":[],"absolute_url":"","date_created":"2024-06-13T14:10:46.027010-07:00","date_modified":"2024-06-13T14:10:46.030361-07:00","sha1":"","page_count":null,"file_size":null,"filepath_local":null,"filepath_ia":"","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"","ocr_status":null,"date_upload":null,"document_number":"","attachment_number":null,"pacer_doc_id":"","is_available":false,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Pretrial Conference - Initial","acms_document_guid":""}],"date_created":"2024-06-13T14:10:46.019507-07:00","date_modified":"2024-06-13T14:10:46.019516-07:00","date_filed":"2024-06-13","time_filed":"16:11:01","entry_number":null,"recap_sequence_number":"2024-06-13.001","pacer_sequence_number":null,"description":"","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/392630595/","id":392630595,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/401678645/","id":401678645,"tags":[],"absolute_url":"/docket/68511120/17/downing-v-anavex-life-sciences-corporation/","date_created":"2024-06-03T16:09:53.613811-07:00","date_modified":"2025-12-22T08:34:03.149302-08:00","sha1":"dbf9e74fe852090d3899802a48aa7f7fbf121ad9","page_count":22,"file_size":310373,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.17.0.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.17.0.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":" UNITED STATES DISTRICT COURT\n SOUTHERN DISTRICT OF NEW YORK\n\nJONATHAN BLUM, Individually and on behalf\nof All Others Similarly Situated, Case No.: 1:24-cv-01910\n\n Plaintiff, CLASS ACTION\n\n v.\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n\nKENNETH DOWNING, Individually and on\nbehalf of All Others Similarly Situated, Case No.: 1:24-cv-03529\n Plaintiff,\n CLASS ACTION\n v.\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n\n\n\n MEMORANDUM OF LAW IN FURTHER SUPPORT OF MOTION OF KENNETH\n DOWNING FOR CONSOLIDATION OF RELATED ACTIONS, APPOINTMENT AS\nLEAD PLAINTIFF, AND APPROVAL OF SELECTION OF LEAD COUNSEL, AND IN\n OPPOSITION TO COMPETING LEAD PLAINTIFF MOTION\n\f TABLE OF CONTENTS\n\n Page\n\nTABLE OF AUTHORITIES .......................................................................................................... ii\n\nPRELIMINARY STATEMENT .................................................................................................... 1\n\nARGUMENT .................................................................................................................................. 5\n\nI. Consolidation of the Related Actions is Appropriate, and the Failure to\n Consolidate Will Result in the Needless Waste of Resources ............................................ 5\n\nII. The Broader Period of Alleged Fraud Pled in the Downing Complaint Should be the\n Operative Class Period, as it is Neither \u201cImplausible\u201d Nor \u201cObviously Frivolous\u201d .......... 7\n\nIII. Movant Downing Should Be Appointed Lead Plaintiff ................................................... 12\n\n A. Downing Has the Largest Financial Interest ......................................................... 12\n\n B. Downing Satisfies the Requirements of Rule 23 .................................................. 13\n\n 1. Downing Is Typical................................................................................... 14\n\n 2. Downing Is Adequate ............................................................................... 14\n\nIV. Movant Downing\u2019s Selection of Counsel Should Be Approved ...................................... 15\n\n\n\n\n i\n\f TABLE OF AUTHORITIES\n\nCases Page(s)\n\nAtanasio v. Tenaris S.A.,\n 331 F.R.D. ................................................................................................................................. 13\n\nBevinal v. Avon Prod., Inc.,\n No. 19-cv-1420(CM), 2019 WL 2497739 (S.D.N.Y. June 3, 2019)........................................... 2\n\nBo Young Cha v. Kinross Gold Corp.,\n No. 12-cv-1203 (PAE), 2012 WL 2025850 (S.D.N.Y. May 31, 2012) ...................................... 2\n\nCarlyle Aviation Mgmt. v. Frontier Airlines, Inc.,\n No. 23-cv-4774 (PAE), 2024 WL 168079 (S.D.N.Y. Jan. 16, 2024) ......................................... 6\n\nCity of Riviera Beach Gen. Emps. Ret. Sys. v. Macquarie Infrastructure Corp.,\n No. 18-cv-3608 (VSB), 2019 WL 364570 (S.D.N.Y. Jan. 30, 2019) ....................................... 13\n\nFaig v. Bioscrip, Inc.,\n No. 13-cv-06922 (AJN), 2013 WL 6705045 (S.D.N.Y. Dec. 19, 2013) .................................. 14\n\nGlavan v. Revolution Lighting Techs., Inc.,\n No. 19-cv-980 (JPO), 2019 WL 3406582 (S.D.N.Y. July 29, 2019) ........................................ 13\n\nHom v. Vale, S.A.,\n No. 15-CV-9539 (GHW), 2016 WL 880201 (S.D.N.Y. Mar. 7, 2016) .................................... 10\n\nIn re BP, PLC Sec. Litig.,\n 758 F. Supp. 2d 428 (S.D. Tex. 2010) ........................................................................................ 8\n\nIn re Centerline Holding Co. Sec. Litig.,\n No. 08-cv-1026(SAS), 2008 WL 1959799 (S.D.N.Y. May 5, 2008) ......................................... 8\n\nIn re Doral Fin. Corp. Sec. Litig.,\n 414 F. Supp. 2d 398 (S.D.N.Y. 2006) ......................................................................................... 7\n\nIn re Drexel Burnham Lambert Grp., Inc.,\n 960 F.2d 285 (2d Cir. 1992) ...................................................................................................... 14\n\nIn re Elan Corp. Sec. Litig.,\n No. 08-cv-8761 (AKH), 2009 WL 1321167 (S.D.N.Y. May 11, 2009) ..................................... 4\n\nIn re Initial Pub. Offering Sec. Litig.,\n 214 F.R.D. 117 (S.D.N.Y. 2002)............................................................................................... 14\n\nJanbay v. Canadian Solar, Inc.,\n 272 F.R.D. 112 (S.D.N.Y. 2010)................................................................................................. 7\n\n\n\n ii\n\fJohnson v. Celotex Corp.,\n 899 F.2d 1281 (2d Cir.1990) ....................................................................................................... 5\n\nKaplan v. Gelfond,\n 240 F.R.D. 88 (S.D.N.Y. 2007)............................................................................................... 6, 7\n\nKemp v. Universal Am. Fin. Corp.,\n Case No. 05-CV-9883-JFK, 2006 WL 1190691 (S.D.N.Y. May 1, 2006) ............................... 12\n\nKhunt v. Alibaba Grp. Holding Ltd.,\n 102 F. Supp. 3d 523 (S.D.N.Y. 2015) ......................................................................................... 5\n\nKux-Kardos v. VimpelCom, Ltd.,\n 151 F. Supp. 3d 471 (S.D.N.Y. 2016) ......................................................................................... 5\n\nLucas v. United States Oil Fund, LP,\n No. 20-cv-4740 (PGG), 2020 WL 5549719 (S.D.N.Y. Sept. 16, 2020) ..................................... 8\n\nMay v. Barclays PLC,\n No. 23-cv-2583 (LJL), 2023 WL 5950689 (S.D.N.Y. Sept. 13, 2023)..................................... 13\n\nMcCormack v. Dingdong (Cayman) Ltd.,\n No. 22-CV-7273 (VSB), 2023 WL 3750162 (S.D.N.Y. June 1, 2023) .................................... 10\n\nMicholle v. Ophthotech Corp.,\n Case No. 17-cv-210 (VSB), 2018 WL 1307285 (S.D.N.Y. Mar. 13, 2018) ............................... 3\n\nMoshell v. Sasol Limited,\n No. 20-cv-1008 (JR), 2020 WL 2115410 (S.D.N.Y. Feb. 5, 2020) .......................................... 15\n\nOmdahl v. Farfetch Ltd.,\n No. 19-cv-8657(AJN), 2020 WL 3072291 (S.D.N.Y. June 10, 2020) ....................................... 6\n\nPlaut v. The Goldman Sachs Grp., Inc.,\n No. 18-cv-12084 (VSB), 2019 WL 4512774 (S.D.N.Y. Sept. 19, 2019) ................................. 14\n\nRagan v. AppHarvest, Inc.,\n No. 21-cv-7985 (LJL), 2021 WL 5909116 (S.D.N.Y. Dec. 13, 2021) ....................................... 3\n\nRauch v. Vale S.A.,\n 378 F. Supp. 3d 198 .................................................................................................................... 7\n\nSalinger v. Sarepta Therapeutics, Inc.,\n No. 19-cv-8122 (VSB), 2019 WL 6873807 (S.D.N.Y. Dec. 17, 2019) .................................... 14\n\nTurner v. ShengdaTech, Inc.,\n No. 11-1918 (TPG), 2011 WL 6110438 (S.D.N.Y. Dec. 6, 2011) ........................................... 10\n\nVillella v. Chem. & Mining Co. of Chile Inc.,\n\n\n iii\n\f No. 15-cv-2106 (ER), 2015 WL 6029950 (S.D.N.Y. Oct. 14, 2015) ......................................... 7\n\nStatutes\n\n15 U.S.C. \u00a7 78u\u20134(a)(3)(A)(ii) ..................................................................................................... 10\n15 U.S.C. \u00a7 78u-4(a)(3)(B) ........................................................................................................... 13\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(I) ................................................................................................. 12\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(I)(cc) ........................................................................................... 13\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II) ............................................................................................ 3, 13\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II)(aa) ......................................................................................... 15\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(v) ...................................................................................................... 15\n\nRules\n\nFed. R. Civ. P. 42 ................................................................................................................ 3, 5, 6, 7\nFed. R. Civ. P. 42(a) ....................................................................................................................... 5\n\n\n\n\n iv\n\f Proposed Lead Plaintiff Kenneth Downing (\u201cDowning\u201d or \u201cMovant\u201d) respectfully\n\n submits this Memorandum of Law in Further Support of Downing\u2019s Motion for Consolidation of\n\n Related Actions, Appointment as Lead Plaintiff, and Approval of Selection of Lead Counsel, and\n\n in Opposition to Competing Lead Plaintiff Motion, and states as follows.\n\n PRELIMINARY STATEMENT 1\n\n On March 13, 2024, Jonathan Blum initiated the above-captioned class action against\n\n Anavex Life Sciences Corporation (\u201cAnavex\u201d) and its senior executives, alleging a class period\n\n of February 1, 2022 through January 1, 2024 (\u201cBlum\u201d). On May 8, 2024, Downing initiated the\n\n above-captioned related class action against the same Defendants, alleging an expanded Class\n\n Period of June 21, 2021 through January 1, 2024 (\u201cDowning\u201d; together with Blum, the \u201cRelated\n\n Actions\u201d). For the reasons discussed herein, the broader class period alleged in Downing is the\n\n operative period for purposes of the instant motions for appointment of lead plaintiff.\n\n On May 13, 2024, Movant Downing timely filed his Motion for Consolidation of Related\n\n Actions, Appointment as Lead Plaintiff, and Approval of Selection of Lead Counsel (ECF No.\n\n 17) (\u201cDowning Motion\u201d). Also on that date, Quintess Huey (\u201cHuey\u201d or \u201cCompeting Movant\u201d)\n\n moved for appointment as lead plaintiff and approval of selection of counsel (ECF No. 13) (\u201cHuey\n\n Motion\u201d). Competing Movant Huey does not, however, seek consolidation of the Related\n\n Actions, and instead argues, without citation to any relevant authority, that the Related Actions \u2013\n\n despite alleging the same claims against the same defendants stemming from the same conduct\n\n during substantially overlapping class periods \u2013 should proceed separately. See ECF No. 14 at 3,\n\n\n\n\n1\n Unless otherwise indicated, all references to \u201cECF No. __\u201d are to docket entries in the first-filed\nBlum action, and all capitalized terms are defined in Downing\u2019s Motion and accompanying\nMemorandum of Law, see ECF Nos. 17 & 18.\n\n\n 1\n\f n. 2. 2 The Huey Motion should be denied; the Downing Motion should be granted, Downing\n\n should be appointed Lead Plaintiff, and the Blum and Downing actions should be consolidated.\n\n First, Downing suffered the largest loss in his transactions in Anavex in the operative\n\n Class Period under the preferred LIFO methodology, 3 as the following chart illustrates:\n\n Movant Losses (LIFO)\n\n Downing $216,243.88\n\n Huey $123,030.15\n\n Downing thus possesses the \u201clargest financial interest\u201d in this litigation \u2013 nearly double the\n\nloss claimed by Huey \u2013 and is presumptively the \u201cmost adequate plaintiff\u201d under the PSLRA. See\n\nBevinal v. Avon Prod., Inc., No. 19-cv-1420(CM), 2019 WL 2497739, at *1 (S.D.N.Y. June 3,\n\n2019) (the PSLRA \u201cestablishes a rebuttable presumption that \u2018the most adequate plaintiff in any\n\nprivate action arising under this chapter is the person or group of persons that:\u2019 (1) has either filed\n\nthe complaint or made a motion in response to the publication of notice; (2) has the largest financial\n\ninterest in the relief sought by the class; and (3) otherwise satisfies the requirements of Rule 23 of\n\nthe Federal Rules of Civil Procedure.\u201d) (McMahon, J.). Huey incorrectly implies that her losses\n\nare larger; they are not because Huey\u2019s losses are calculated based on the class period in the Blum\n\n\n\n2\n Competing Movant filed her Opposition to Competing Motion for Appointment as Lead Plaintiff\nand Approval of Selection of Counsel on May 28, 2024 (ECF No. 21), six days prior to the June\n3, 2024 deadline as prescribed by Section IV.M. of this Court\u2019s Individual Practices and\nProcedures, applicable to \u201cCases Governed by the Private Securities Litigation Reform Act\n(PSLRA)\u201d and specifying that \u201cOpposition to each such motion must be filed separately and must\nbe received by the court no later than fourteen (14) business days following the date on which such\nmotions are due.\u201d\n3\n LIFO is the preferred and most-widely-accepted methodology for calculating movants\u2019 losses.\nSee Bo Young Cha v. Kinross Gold Corp., No. 12-cv-1203 (PAE), 2012 WL 2025850, at *3\n(S.D.N.Y. May 31, 2012) (observing that \u201cthe overwhelming trend . . . nationwide has been to use\nLIFO\u201d). The movants\u2019 LIFO losses are taken from their respective filings.\n\n\n 2\n\fAction, not the Downing Action, which is the operative class period, as discussed more fully\n\nbelow.\n\n Second, Movant Downing satisfies the typicality and adequacy requirements of Fed. R.\n\nCiv. P. 23, and Huey has not offered any \u201cproof\u201d to the contrary. See infra, Section III.B.; see\n\nalso 15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II) (requiring \u201cproof\u201d to rebut presumption); Micholle v.\n\nOphthotech Corp., Case No. 17-cv-210 (VSB), 2018 WL 1307285, at *4 (S.D.N.Y. Mar. 13,\n\n2018).\n\n Third, Huey has demonstrated her inadequacy as a class representative by resisting\n\nconsolidation of the above-captioned Related Actions, which should plainly be consolidated\n\npursuant to Fed. R. Civ. P. 42, given the abundance of common questions of law and fact. It\n\nspeaks volumes that Huey cannot offer a single securities class action in support of her groundless\n\nand irresponsible assertion that these Related Actions should proceed independently of each\n\nother. See ECF No. 21 at 3 n.1.\n\n Fourth, Huey has also demonstrated her inadequacy as a class representative by refusing,\n\nin contravention of the applicable law, to apply the broader, more inclusive Downing Class\n\nPeriod. See Ragan v. AppHarvest, Inc., No. 21-cv-7985 (LJL), 2021 WL 5909116, at *7\n\n(S.D.N.Y. Dec. 13, 2021) (\u201cWhere there are two potential class periods, courts addressing lead\n\nplaintiff motions generally apply the longer class period.\u201d). Huey would have this Court believe\n\nthat the Downing Class Period \u2013 which expands the class period alleged in Blum from February 1,\n\n2022 through January 1, 2024 (the \u201cBlum Class Period\u201d) by just over seven months to June 21,\n\n2021 through January 1, 2024 \u2013 is \u201cimplausible\u201d and \u201cobviously frivolous.\u201d See ECF No. 21 at\n\n6. Huey\u2019s contention is baseless. To the contrary, the Downing Class Period seeks to protect a\n\ngreater number of Anavex investors and recover potentially significantly higher damages for the\n\n\n\n\n 3\n\f putative Class, while still premised on essentially the same facts and theory of liability, and\n\n against the same Defendants as alleged in Blum.\n\n Importantly, the conduct of Huey\u2019s counsel belies Huey\u2019s baseless contention that the\n\n Downing Class Period is somehow frivolous. Following the filing of the Downing complaint,\n\n Huey\u2019s counsel issued a press release advising Anavex investors that the operative Class Period\n\n was now the broader period alleged in Downing. 4 The press release encouraged investors to\n\n \u201cContact Levi & Korsinsky Before May 13, 2024 to Discuss Your Rights.\u201d See id. It strains\n\n credulity that Huey\u2019s counsel would issue a press release regarding the expanded Downing Class\n\n Period, encouraging prospective lead plaintiff movants to contact counsel \u2013 which it had no\n\n obligation to do under the PSLRA \u2013 only to contend that the Downing Class Period is\n\n \u201cimplausible\u201d and \u201cfrivolous.\u201d Indeed, despite its rhetoric, as discussed below, when representing\n\n other investors in other PSLRA cases, Huey\u2019s counsel has filed complaints that extended a class\n\n period during the PSLRA\u2019s 60-day period. See Exs. B-F.\n\n Regardless, it is well-settled that the longest, most inclusive class period governs the\n\n analysis of a lead plaintiff\u2019s financial interest, both because the most inclusive period\n\n encompasses more potential class members and because, at this preliminary stage of the litigation,\n\n merits-based determinations, including the appropriate dates encompassing the class period, are\n\n premature. For these reasons, the overwhelming majority of courts to consider this issue has\n\n adopted the most inclusive class period. This is because only patent frivolousness or\n\n implausibility permits otherwise. See In re Elan Corp. Sec. Litig., No. 08-cv-8761 (AKH), 2009\n\n\n4\n A copy of Levi & Korsinsky\u2019s press release advising Anavex investors of the class action lawsuit\nagainst Anavex with the class period of June 21, 2021 through January 1, 2024 is attached as\nExhibit (\u201cEx.\u201d) A to the Supplemental Declaration of Radha Nagamani Raghavan (\u201cSupp.\nRaghavan Decl.\u201d), submitted concurrently herewith. All exhibit references are to the Supp.\nRaghavan Decl.\n\n\n 4\n\f WL 1321167, at *1 (S.D.N.Y. May 11, 2009) (\u201cit is appropriate to use that more inclusive period\n\n for present purposes\u201d as long as the claims are not \u201cimplausible\u201d). Neither applies here.\n\n For the reasons set forth below: (i) the above-captioned Related Actions should be\n\n consolidated; (ii) Movant Downing, the \u201cmost adequate plaintiff,\u201d with losses of $216,243.88 \u2013\n\n by far the largest of any movant \u2013 should be appointed Lead Plaintiff; and (iii) Downing\u2019s\n\n selection of Berger Montague PC as Lead Counsel should be approved. The Huey Motion should\n\n be rejected.\n\n ARGUMENT\n\nI. Consolidation of the Related Actions is Appropriate, and the Failure to Consolidate\n Will Result in the Needless Waste of Resources\n\n As set forth in Movant Downing\u2019s opening papers, the PSLRA \u201crequires that courts\n\npresiding over putative securities class actions resolve questions of consolidation before\n\nappointing a lead plaintiff.\u201d Khunt v. Alibaba Grp. Holding Ltd., 102 F. Supp. 3d 523, 530\n\n(S.D.N.Y. 2015) (McMahon, J.). Rule 42 gives courts broad discretion to determine whether\n\nconsolidation is appropriate, and provides that a court may consolidate actions that \u201cinvolve a\n\ncommon question of law or fact.\u201d See Fed. R. Civ. P. 42(a); see also Johnson v. Celotex Corp.,\n\n899 F.2d 1281, 1284 (2d Cir.1990). Critically, as Competing Movant seems to ignore, actions\n\nneed not be identical for consolidation to be appropriate. See Kux-Kardos v. VimpelCom, Ltd.,\n\n151 F. Supp. 3d 471, 474\u201375 (S.D.N.Y. 2016) (citation omitted). Likewise, \u201cdifferences in . . .\n\nthe class period do not render consolidation inappropriate if the cases present sufficiently\n\ncommon questions of fact and law, and the differences do not outweigh the interests of judicial\n\neconomy served by consolidation.\u201d Id. at 475 (citation omitted).\n\n Huey argues against consolidation, asserting (in a cursory footnote) without explanation\n\nthat consolidation of the Related Actions would \u201crisk confusion and complicate the progression\n\n\n\n 5\n\fof the cases as they move forward.\u201d See ECF No. 21 at 3, n. 1. Huey\u2019s sole authority, Carlyle\n\nAviation Mgmt. v. Frontier Airlines, Inc., No. 23-cv-4774 (PAE), 2024 WL 168079 (S.D.N.Y.\n\nJan. 16, 2024), is inapposite. Carlyle is not a securities class action (it concerns a dispute over\n\nlease agreements) and does not even involve \u201cthe same events or transactions.\u201d See id. at *14.\n\nIndeed, one of the suits at issue focused on whether the defendant was obligated to cooperate\n\nunder the lease agreements, while the other involved questions of notice. See id. There is simply\n\nno comparison between that instance and the facts at bar.\n\n Here, the Related Actions, like the vast majority of securities class actions, are perfectly\n\nsuited for consolidation pursuant to Rule 42. The complaints in both Related Actions allege\n\nviolations of the Exchange Act against identical defendants, they present the same or similar\n\ntheories for recovery, and are based on substantially the same allegedly wrongful course of\n\nconduct \u2013 namely, Defendants\u2019 allegedly false and/or misleading statements or omissions\n\nregarding the primary and secondary endpoints by which Anavex evaluated its drug blarcamesine\n\nas a treatment for Rett syndrome. Both of the Related Actions plead that Defendants\u2019 \u201cstatements\n\nabout its research methods and analysis were false and misleading,\u201d and that \u201cDefendants misled\n\ninvestors by providing a materially flawed and inaccurate impression of the Company\u2019s research\n\nprogram and of blarcamesine\u2019s actual likelihood of success in the Rett syndrome trials.\u201d See ECF\n\nNo. 1 (Blum complaint), \u00b6 66; Downing ECF No. 1 (Downing Complaint), \u00b6 61. Inescapably, the\n\nRelated Actions bring identical causes of action based upon the same allegedly wrongful conduct\n\nby the same Defendants during substantially overlapping class periods. See Omdahl v. Farfetch\n\nLtd., No. 19-cv-8657(AJN), 2020 WL 3072291, at *1 (S.D.N.Y. June 10, 2020) (quoting Kaplan\n\nv. Gelfond, 240 F.R.D. 88, 91 (S.D.N.Y. 2007)) (\u201cTo be sure, there are differences between the\n\ntwo cases\u2026. However, \u2018[d]ifferences in causes of action, defendants, or the class period do not\n\n\n\n\n 6\n\frender consolidation inappropriate if the cases present sufficiently common questions of fact and\n\nlaw, and the differences do not outweigh the interests of judicial economy served by\n\nconsolidation.\u2019\u201d).\n\n Further, contemporaneous with the filing of the Downing complaint, Downing filed a\n\nRelated Case Statement which set forth the factual bases for relatedness. See Downing ECF No.\n\n8. The following day, May 10, 2024, the docket reflected that the Downing case was \u201cACCEPTED\n\nAS RELATED\u201d to the Blum action.\n\n Thus, the Related Actions satisfy Rule 42 and should be consolidated.\n\nII. The Broader Period of Alleged Fraud Pled in the Downing Complaint Should be the\n Operative Class Period, as it is Neither \u201cImplausible\u201d Nor \u201cObviously Frivolous\u201d\n\n It is well-settled that, pursuant to the PSLRA, the longest, most inclusive class period\n\ngoverns the lead plaintiff appointment process. See Rauch v. Vale S.A., 378 F. Supp. 3d 198, 209\n\nn. 11 (E.D.N.Y. 2019) (\u201cFor the purposes of appointing lead plaintiff in cases involving two\n\npotential class periods, courts use the longer class period in the analysis.\u201d); Kaplan v. Gelfond,\n\n240 F.R.D. 88, 93 (S.D.N.Y. 2007) (\u201cFor the purposes of this analysis, we use the longer class\n\nperiod with the earlier start date.\u201d); Janbay v. Canadian Solar, Inc., 272 F.R.D. 112, 119\n\n(S.D.N.Y. 2010) (\u201cUsing the longer Class Period\u201d to calculate competing lead plaintiffs\u2019\n\nfinancial interests.). The reasons for this are intuitive: the most inclusive period encompasses\n\nmore potential class members and increases potential damages that the class stands to recover.\n\nSee Villella v. Chem. & Mining Co. of Chile Inc., No. 15-cv-2106 (ER), 2015 WL 6029950, at\n\n*5 (S.D.N.Y. Oct. 14, 2015) (\u201cThe Court will use the longest-noticed Class Period . . . as it\n\nencompasses more putative class members.\u201d); In re Doral Fin. Corp. Sec. Litig., 414 F. Supp.\n\n2d 398, 402 (S.D.N.Y. 2006). Accordingly, here, the Downing Class Period (June 21, 2021\n\n\n\n\n 7\n\fthrough January 1, 2024, inclusive), not the Blum class period (February 1, 2022 through January\n\n1, 2024, inclusive) should govern.\n\n Courts disregard a class period \u201conly where the proposed class period is implausible or\n\nobviously frivolous.\u201d Lucas v. United States Oil Fund, LP, No. 20-cv-4740 (PGG), 2020 WL\n\n5549719, at *4 (S.D.N.Y. Sept. 16, 2020) (citation and quotations omitted) (emphasis added).\n\nSee In re Centerline Holding Co. Sec. Litig., No. 08-cv-1026(SAS), 2008 WL 1959799, at *3\n\n(S.D.N.Y. May 5, 2008) (\u201cFor purposes of determining the lead plaintiff, I hold that the proper\n\nstandard is that which is used to evaluate a motion to dismiss: the standard of plausibility.\u201d); see\n\nalso, In re BP, PLC Sec. Litig., 758 F. Supp. 2d 428, 433\u201335 (S.D. Tex. 2010) (\u201cFor purposes of\n\nselecting a lead plaintiff, the Court will use the longest noticed class period unless the factual\n\nallegations supporting that period are \u201c\u2018obviously frivolous.\u2019\u201d) (citations omitted).\n\n Competing Movant Huey claims that the Downing Class Period is \u201cimplausible\u201d and\n\n\u201cobviously frivolous\u201d (ECF No. 21 at 6), insisting that the class period can begin only on\n\nFebruary 1, 2022, because on that date, \u201cdefendants told the market it would use AVATAR\u2019s\n\nevaluation methods in its next study, EXCELLENCE.\u201d See id. But even the most cursory\n\nreference to the Downing complaint \u2013 which begins the Downing Class Period on June 21, 2021,\n\nthus expanding the two-year period by roughly seven months \u2013 reveals that the conduct alleged\n\ntherein relates directly to the conduct alleged in Blum, and is therefore neither \u201cfrivolous\u201d nor\n\n\u201cobviously implausible.\u201d In fact, as demonstrated below, the Blum complaint itself \u2013 which\n\nHuey\u2019s own counsel filed \u2013 demonstrates that the two complaints speak to the same conduct.\n\n The gravamen of the Blum complaint is that Anavex represented that it \u201cintended to use\n\nseveral \u2018Primary Outcome Measures\u2019 and \u2018Secondary Outcome Measures\u2019 to evaluate\u201d\n\nblarcamesine as a treatment for Rett\u2019s syndrome in adults (the AVATAR trial), but that\n\n\n\n\n 8\n\f\u201c[c]ontrary to the protocol described on [FDA-sponsored website] ClinicalTrials, when Anavex\n\nlater reported its trial results, the Company revealed that it used alternative measures to assess\n\nthe drug\u2019s success.\u201d ECF No. 1 at 2 (emphasis added). However, as the Blum complaint further\n\nalleges, \u201c[n]otwithstanding the backlash it received from the market and the substantial market\n\ncapitalization losses, Anavex would proceed to pull the same sleight of hand with its\n\n\u2018Excellence\u2019 Phase II/Phase III study, which investigated blarcamesine as treatment for pediatric\n\nRett syndrome patients.\u201d Id. at 3 (emphasis added). In other words, the Blum complaint alleges\n\nthat Anavex misrepresented its \u201coutcome measures\u201d for the EXCELLENCE study (which tested\n\nblarcamesine in children) after having done so for its AVATAR study (which tested blarcamesine\n\nin adults). The Downing complaint simply broadens the Class Period to include the\n\nmisrepresentations relating to that earlier AVATAR study. See Downing ECF No. 1 at 12-15\n\n(alleging investor losses arising from Defendants\u2019 alleged manipulation of the AVATAR study\n\nendpoints); id. at 17-18 (alleging investor losses arising from Defendants\u2019 alleged manipulation\n\nof the EXCELLENCE study endpoints). Not only is the Downing Class Period not \u201cobviously\n\nimplausible,\u201d it is, in fact, the stronger, more complete Class Period. As such, the Downing\n\nAction alleges additional actionable misstatements and potentially affords greater recovery to a\n\ngreater number of Anavex investors.\n\n It deserves mention that February 1, 2022, the first day of the Blum Class Period, is more\n\nproperly pled as a partial corrective disclosure of the truth (which is how it is alleged in\n\nDowning). According to the Downing complaint, the market reacted negatively when Anavex\u2019s\n\nmanipulation of the endpoints for the AVATAR trial was partially revealed on February 1, 2022.\n\nFollowing that news, Anavex shares fell more than 19%. See Downing ECF No. 1 \u00b654.\n\n\n\n\n 9\n\fFebruary 1, 2022 is, therefore, a less logical date to start a class period relating investor losses in\n\nAnavex than June 21, 2021.\n\n The Southern District of New York\u2019s decision in Turner v. ShengdaTech, Inc., No. 11-\n\n1918 (TPG), 2011 WL 6110438, at *3 (S.D.N.Y. Dec. 6, 2011), is instructive. There, a new\n\ncomplaint expanding the class period of a securities fraud class action by nearly two years was\n\nfiled on the very same day as the lead plaintiff motion deadline. See id., 2011 WL 6110438, at\n\n*2. A lead plaintiff movant argued that the notice of the first-filed action was insufficient because\n\nthe newly filed complaint \u201cso expands the Class Period of the first-filed case.\u201d Id. The Court\n\nrejected the challenge, declined to order the republication of notice, and applied the more\n\ninclusive class period, holding that, because the newly-filed action \u201cproceeds against the same\n\ndefendants as the first-filed [] action, relies on the same legal theories as that action, and concerns\n\nthe same type of securities as that action,\u201d potential lead plaintiffs \u201cwere adequately notified of\n\nthe nature of the claims . . . despite the shorter purported Class Period of that action.\u201d Id. at *3.\n\nThat reasoning applies here.\n\n Moreover, although not required, 5 after filing the Downing complaint, Movant Downing\n\npublished notice of the pendency of his complaint, alerting investors to the fact that the class\n\nperiod for the claims against Anavex had been broadened. See Ex. G. Thereafter, several law\n\nfirms which represent investors in securities class actions \u2013 including counsel for Huey \u2013 issued\n\n\n5\n See 15 U.S.C. \u00a7 78u\u20134(a)(3)(A)(ii) (\u201cIf more than one action on behalf of a class asserting\nsubstantially the same claim or claims arising under this chapter is filed, only the plaintiff or\nplaintiffs in the first filed action shall be required to cause notice to be published.\u201d); see also,\nTurner v. ShengdaTech, Inc., No. 11-1918 (TPG), 2011 WL 6110438, at *3 (S.D.N.Y. Dec. 6,\n2011) (\u201cCourts, however, disfavor republication of notice under PSLRA when a class period is\nextended beyond the period contained in the first-filed securities class action.\u201d); McCormack v.\nDingdong (Cayman) Ltd., No. 22-CV-7273 (VSB), 2023 WL 3750162, at *3 (S.D.N.Y. June 1,\n2023); Hom v. Vale, S.A., No. 15-CV-9539 (GHW), 2016 WL 880201, at *4 (S.D.N.Y. Mar. 7,\n2016).\n\n\n 10\n\fpress release notices informing Anavex investors of the expanded class period and their rights\n\nunder the PSLRA. See Exs. A, H-J. As discussed above, Huey\u2019s counsel published a press release\n\nregarding the Downing Class Period, indicating that \u201c[t]he lawsuit seeks to recover losses on\n\nbehalf of Anavex Life Sciences investors who were adversely affected by alleged securities fraud\n\nbetween June 21, 2021 and January 1, 2024.\u201d See Ex. A.\n\n Huey\u2019s challenge to the filing of the Downing complaint is further undermined by the fact\n\nthat, when representing other investors in other securities class actions, Huey\u2019s counsel has done\n\nprecisely what it challenges here. For example, in In re Humanigen, Inc. Securities Litigation,\n\nNo. 22-cv-05258 (D. N.J.), an initial complaint was filed on August 26, 2022 on behalf of\n\ninvestors who purchased Humanigen securities between May 28, 2021 and July 12, 2022,\n\ntriggering a lead plaintiff deadline of October 25, 2022. See Ex. B. Approximately one week\n\nprior to that deadline, on October 17, 2022, Huey\u2019s counsel, representing a Humanigen investor,\n\nfiled a related action which extended the class period by more than a year (May 16, 2020 through\n\nJuly 12, 2022). See Ex. C. However, Huey\u2019s counsel did not issue notice of the pendency of the\n\ncomplaint until October 20, 2022 \u2013 five days before the lead plaintiff motion deadline. See Ex. D.\n\n More recently, an investor filed an initial complaint against Paycom Software, Inc.\n\n(\u201cPaycom\u201d) on November 11. 2023, triggering a deadline to file lead plaintiff motions on January\n\n9, 2024. See Ex. E. The class period for the initial complaint was May 3, 2023 through November\n\n1, 2023. See id. Huey\u2019s counsel filed a subsequent securities class action complaint against\n\nPaycom four business days prior the expiration of the 60-day lead plaintiff motion deadline. See\n\nEx. F. Huey\u2019s counsel extended the class period of the initial complaint by more than one year\n\n(February 9, 2022 through November 1, 2023). See id.\n\n\n\n\n 11\n\f In sum, the Downing Class Period is neither \u201cimplausible\u201d nor \u201cobviously frivolous,\u201d and\n\nshould therefore govern in the lead plaintiff appointment process here. Huey\u2019s cursory attack on\n\nthe Downing Class Period is not well founded and inconsistent with the law and facts, and should\n\nbe rejected.\n\nIII. Movant Downing Should Be Appointed Lead Plaintiff\n\n Downing satisfies all criteria set forth under the PSLRA and deserves the presumption\n\nthat he is the \u201cmost adequate plaintiff.\u201d Accordingly, as this strong presumption in favor of\n\nMovant\u2019s appointment has not been rebutted \u2013 nor can it \u2013 Downing is entitled to appointment\n\nas Lead Plaintiff.\n\n A. Downing Has the Largest Financial Interest\n\n The PSLRA provides that there is a \u201crebuttable presumption \u2026 that the most adequate\n\nplaintiff \u2026 is the person or group of persons \u2026 that \u2026 has the largest financial interest in the\n\nrelief sought by the class.\u201d See 15 U.S.C.\u00a7 78u-4(a)(3)(B)(iii)(I); see also Kemp v. Universal Am.\n\nFin. Corp., Case No. 05-CV-9883-JFK, 2006 WL 1190691, at *2 (S.D.N.Y. May 1, 2006).\n\nDowning suffered losses of $216,243.88 during the Downing Class Period in connection with his\n\ntransactions in Anavex securities. By contrast, Huey fails to provide her losses during the Downing\n\nClass Period. However, counsel for Downing calculates Huey\u2019s losses during the Downing Class\n\nPeriod as $123,030.15. Therefore, of the two competing movants, Downing has the largest\n\nfinancial interest \u2013 more than double that of Huey.\n\n Huey only provides her losses during the original and superseded Blum Class Period.\n\nHowever, Huey\u2019s loss calculation during the Blum Class Period is wrong and less than that\n\nsubmitted to the Court. That is because Huey attached four \u201cAssignments\u201d to her Certification that\n\nassigned, \u201call rights, title, and interest of the Assignor[s] in any and all claims, demands, and causes\n\nof action of any kind\u201d to Huey. See ECF No. 15-1. In each Assignment, Huey agreed to \u201cremit any\n\n\n 12\n\fproceeds received as a result of [the] assignment to the Assignor.\u201d Such assignments have been\n\nheld to be \u201cinconsistent with the statutory structure and purpose of the PSLRA to adopt the notion\n\nthat [a lead plaintiff movant] would have the Court adopt here: that a party can achieve lead\n\nplaintiff status not by virtue of his own transactions during the proposed class period but by virtue\n\nof assignments of claims by other class members after the class period has ended and after litigation\n\nhas commenced.\u201d See May v. Barclays PLC, No. 23-cv-2583 (LJL), 2023 WL 5950689, at *14\n\n(S.D.N.Y. Sept. 13, 2023) (Liman, J.).\n\n Downing indisputably has \u201cthe largest financial interest in the relief sought by the [C]lass,\u201d\n\nand is thus the presumptive \u201cmost adequate plaintiff.\u201d Glavan v. Revolution Lighting Techs., Inc.,\n\nNo. 19-cv-980 (JPO), 2019 WL 3406582, at *2 (S.D.N.Y. July 29, 2019) (quoting 15 U.S.C. \u00a7 78u-\n\n4(a)(3)(B)); see also Atanasio v. Tenaris S.A., 331 F.R.D. at 27 (finding lead plaintiff movant with\n\nlargest approximate loss to have the largest financial interest under the Olsten criteria).\n\n B. Downing Satisfies the Requirements of Rule 23\n\n In addition to suffering the largest loss, Downing also satisfies the PSLRA\u2019s preliminary\n\nshowing of typicality and adequacy. See 15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(I)(cc); see also City of\n\nRiviera Beach Gen. Emps. Ret. Sys. v. Macquarie Infrastructure Corp., No. 18-cv-3608 (VSB),\n\n2019 WL 364570, at *4 (S.D.N.Y. Jan. 30, 2019) (\u201cA potential lead plaintiff must also make a\n\npreliminary showing that it satisfies the typicality and adequacy requirements of Rule 23.\u201d)\n\n(quotation and internal citations omitted). As Huey has not, or will not be able to, submit the\n\nrequired \u201cproof\u201d that Downing fails on typicality or adequacy grounds, Downing is entitled to\n\nappointment as Lead Plaintiff. 15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II) (evidentiary burden required to\n\nrebut presumption of most adequate plaintiff is \u201cproof\u201d); see also Macquarie Infrastructure Corp.,\n\n2019 WL 364570, at *7 (rejecting speculative arguments against presumptive lead plaintiff).\n\n\n\n\n 13\n\f 1. Downing Is Typical\n\n Downing is typical of the Class as a whole and not subject to any unique defenses which\n\nwould disqualify him. \u201cWith respect to typicality, courts consider whether the claims of the\n\nproposed lead plaintiff \u2018arise from the same conduct from which the other class members\u2019 claims\n\nand injuries arise.\u2019\u201d Plaut v. The Goldman Sachs Grp., Inc., No. 18-cv-12084 (VSB), 2019 WL\n\n4512774, at *3 (S.D.N.Y. Sept. 19, 2019) (quoting In re Initial Pub. Offering Sec. Litig., 214\n\nF.R.D. 117, 121 (S.D.N.Y. 2002)); see also In re Drexel Burnham Lambert Grp., Inc., 960 F.2d\n\n285, 291 (2d Cir. 1992)). Importantly, Rule 23 does not require the lead plaintiff to be identically\n\nsituated with all class members to satisfy the typicality requirement. See Plaut v. The Goldman\n\nSachs Grp., Inc., 2019 WL 4512774, at *3 (noting that \u201cclaims need not be identical\u201d); see also\n\nFaig v. Bioscrip, Inc., No. 13-cv-06922 (AJN), 2013 WL 6705045, at *3 (S.D.N.Y. Dec. 19, 2013)\n\n(same).\n\n Here, Downing\u2019s claims are typical to the class as a whole. Downing: (i) suffered losses\n\non his investment in Anavex securities; (ii) as a result of his reliance on Defendants\u2019 alleged\n\nmisstatements and/or omissions; (iii) therefore, the claims of Downing are based on the same\n\ncourse of events as the claims of the Class; and (iv) as a result thereof, Downing\u2019s claims will rely\n\nupon the same legal theories as the Class as a whole. Therefore, Downing satisfies the typicality\n\nrequirement. See Faig v. Bioscrip, Inc., Case No. 13-cv06922-AJN, 2013 WL 6705045, at *3\n\n(S.D.N.Y. Dec. 19, 2013).\n\n 2. Downing Is Adequate\n\n Downing also satisfies Rule 23\u2019s adequacy requirement. In analyzing a movant\u2019s adequacy,\n\n\u201ca court must consider whether the proposed lead plaintiff: (1) maintains claims that conflict with\n\nthose of the class; (2) has sufficient interest in the outcome of the case; and (3) has selected counsel\n\nthat is qualified, experienced, and generally able to conduct the litigation in question.\u201d Salinger v.\n\n\n 14\n\fSarepta Therapeutics, Inc., No. 19-cv-8122 (VSB), 2019 WL 6873807, at *3 (S.D.N.Y. Dec. 17,\n\n2019) (citation omitted).\n\n Downing readily satisfies the adequacy requirement. Downing is committed to pursuing\n\n the best recovery possible for himself and all other Class members. He incurred substantial losses\n\n in his Anavex investment during the Class Period and thus is highly motivated to maximize any\n\n recovery.\n\n Finally, Downing further demonstrated his adequacy through his selection of the law firm\n\nof Berger Montague, as proposed Lead Counsel for the Class. See Moshell v. Sasol Limited, No.\n\n20-cv-1008 (JR), 2020 WL 2115410, at *2 (S.D.N.Y. Feb. 5, 2020) (finding adequacy requirement\n\nsatisfied where movant selected \u201cfirm experienced in securities class action litigation\u201d).\n\n Based on the foregoing, Downing, as the movant with the largest financial interest who\n\nalso satisfies the typicality and adequacy requirements of Rule 23, is entitled to appointment as\n\nLead Plaintiff.\n\nIV. Movant Downing\u2019s Selection of Counsel Should Be Approved\n\n Subject to Court\u2019s approval, the PSLRA vests authority in the Lead Plaintiff to select and\n\nretain lead counsel. See 15 U.S.C. \u00a7 78u-4(a)(3)(B)(v). The Court should interfere with the Lead\n\nPlaintiff\u2019s selection only when necessary \u201cto protect the interests of the class.\u201d See 15 U.S.C.\n\n\u00a7 78u-4(a)(3)(B)(iii)(II)(aa).\n\n Here, Downing selected the law firm of Berger Montague to serve as Lead Counsel for the\n\nclass. As discussed in the memorandum of law submitted in support of Movants\u2019 Motion (ECF\n\nNo. 18 at 12), Berger Montague is highly experienced in securities litigation and the full range of\n\nclass actions, and has successfully prosecuted numerous cases \u2013 including through trial \u2013 on behalf\n\nof investors. See id.\n\n Accordingly, this Court can confidently approve Downing\u2019s selection of Lead Counsel.\n\n\n 15\n\f CONCLUSION\n\n In sum, for all of the foregoing reasons, and for the reasons set forth in Movant Downing\u2019s\n\nopening papers, Movant Downing\u2019s Motion should be granted, Competing Movant Huey\u2019s motion\n\nshould be denied in its entirety, and: (i) the Related Actions should be consolidated; (ii) Movant\n\nDowning should be appointed Lead Plaintiff; and (iii) Movant Downing\u2019s selection of Berger\n\nMontague PC as Lead Counsel should be approved.\n\nDated: June 3, 2024 Respectfully submitted,\n\n BERGER MONTAGUE PC\n\n /s/ Radha Nagamani Raghavan\n Radha Nagamani Raghavan\n Michael Dell\u2019Angelo\n Andrew D. Abramowitz\n James A. Maro\n 1818 Market Street, Suite 3600\n Philadelphia, PA 19103\n Tel: (215) 875-3000\n Email: rraghavan@bm.net\n mdellangelo@bm.net\n aabramowitz@bm.net\n jmaro@bm.net\n Counsel for Lead Plaintiff Movant Kenneth\n Downing and Proposed Lead Counsel for the Class\n\n SCHALL LAW FIRM\n Brian Schall\n Rina Restaino\n Brian England\n 2049 Century Park East, Suite 2460\n Los Angeles, CA 90067\n Tel: (310) 301-3335\n Email: brian@schallfirm.com\n rina@schallfirm.com\n briane@schallfirm.com\n\n Additional Counsel for Lead Plaintiff Movant\n Kenneth Downing\n\n\n\n\n 16\n\f CERTIFICATE OF SERVICE\n\n I hereby certify that on June 3, 2024, a true and correct copy of the foregoing document\n\nwas served by CM/ECF to the parties registered to the Court\u2019s CM/ECF system.\n\n\n /s/ Radha Nagamani Raghavan\n Radha Nagamani Raghavan\n\n\n\n\n 17\n\f","ocr_status":2,"date_upload":"2024-08-19T11:03:36.742508-07:00","document_number":"17","attachment_number":null,"pacer_doc_id":"127035574485","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Response in Support of Motion","acms_document_guid":""}],"date_created":"2024-06-03T16:09:53.580348-07:00","date_modified":"2025-12-22T08:34:03.122175-08:00","date_filed":"2024-06-03","time_filed":"18:56:21","entry_number":17,"recap_sequence_number":"2024-06-03.001","pacer_sequence_number":78,"description":"RESPONSE in Support of Motion re: 13 MOTION to Appoint Kenneth Downing to serve as lead plaintiff(s) . MOTION to Appoint Counsel . MOTION to Consolidate Cases 1:24-cv-01910 . . Document filed by Kenneth Downing..(Nagamani Raghavan, Radha) (Entered: 06/03/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/392630588/","id":392630588,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/401678638/","id":401678638,"tags":[],"absolute_url":"/docket/68511120/18/downing-v-anavex-life-sciences-corporation/","date_created":"2024-06-03T16:09:51.018670-07:00","date_modified":"2025-12-22T08:34:03.201536-08:00","sha1":"","page_count":null,"file_size":null,"filepath_local":null,"filepath_ia":"","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"","ocr_status":null,"date_upload":null,"document_number":"18","attachment_number":null,"pacer_doc_id":"127035574509","is_available":false,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Declaration in Support of Motion","acms_document_guid":""}],"date_created":"2024-06-03T16:09:50.974055-07:00","date_modified":"2025-12-22T08:34:03.177813-08:00","date_filed":"2024-06-03","time_filed":"18:59:09","entry_number":18,"recap_sequence_number":"2024-06-03.002","pacer_sequence_number":83,"description":"DECLARATION of Radha Nagamani Raghavan in Support re: 13 MOTION to Appoint Kenneth Downing to serve as lead plaintiff(s) . MOTION to Appoint Counsel . MOTION to Consolidate Cases 1:24-cv-01910 .. Document filed by Kenneth Downing. (Attachments: # 1 Exhibit A - May 10 Press Release, # 2 Exhibit B - Humanigen Initial Complaint, # 3 Exhibit C - Humanigen Additional Complaint, # 4 Exhibit D - Humanigen Press Release, # 5 Exhibit E - Paycom Initial Complaint, # 6 Exhibit F - Paycom Additional Complaint, # 7 Exhibit G - BMPC May 8 Press Release, # 8 Exhibit H - Faruqi May 9 Press Release, # 9 Exhibit I - Robbins May 9 Press Release, # 10 Exhibit J - Gross May 10 Press Release).(Nagamani Raghavan, Radha) (Entered: 06/03/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/391750449/","id":391750449,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/400759520/","id":400759520,"tags":[],"absolute_url":"/docket/68511120/16/downing-v-anavex-life-sciences-corporation/","date_created":"2024-05-28T10:09:03.561652-07:00","date_modified":"2025-12-22T08:34:03.094343-08:00","sha1":"","page_count":null,"file_size":null,"filepath_local":null,"filepath_ia":"","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"","ocr_status":null,"date_upload":null,"document_number":"16","attachment_number":null,"pacer_doc_id":"127035534964","is_available":false,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Order for Initial Pretrial Conference","acms_document_guid":""}],"date_created":"2024-05-28T10:09:03.542554-07:00","date_modified":"2025-12-22T08:34:03.061467-08:00","date_filed":"2024-05-28","time_filed":"11:38:21","entry_number":16,"recap_sequence_number":"2024-05-28.001","pacer_sequence_number":76,"description":"CALENDAR NOTICE: Initial Conference set for 6/13/2024 at 10:00 AM in Courtroom 24A, 500 Pearl Street, New York, NY 10007 before Judge Colleen McMahon. Any scheduling difficulties must be brought to the attention of the Court in writing and filed on ECF. So Ordered. (Signed by Judge Colleen McMahon on 5/28/2024) (jca) (Entered: 05/28/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/390011028/","id":390011028,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/398945581/","id":398945581,"tags":[],"absolute_url":"/docket/68511120/13/downing-v-anavex-life-sciences-corporation/","date_created":"2024-05-13T22:07:47.012309-07:00","date_modified":"2025-12-22T08:34:02.934254-08:00","sha1":"","page_count":null,"file_size":null,"filepath_local":null,"filepath_ia":"","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":"","ocr_status":null,"date_upload":null,"document_number":"13","attachment_number":null,"pacer_doc_id":"127035461318","is_available":false,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Appoint Counsel AND Appoint Lead Plaintiff(s) AND Consolidate Cases","acms_document_guid":""}],"date_created":"2024-05-13T22:07:46.999168-07:00","date_modified":"2025-12-22T08:34:02.909309-08:00","date_filed":"2024-05-13","time_filed":"23:11:44","entry_number":13,"recap_sequence_number":"2024-05-13.003","pacer_sequence_number":62,"description":"MOTION to Appoint Kenneth Downing to serve as lead plaintiff(s) ., MOTION to Appoint Counsel ., MOTION to Consolidate Cases 1:24-cv-01910 . Document filed by Kenneth Downing. (Attachments: # 1 Proposed Order Text of Proposed Order).(Nagamani Raghavan, Radha) (Entered: 05/13/2024)","tags":[]},{"resource_uri":"https://www.courtlistener.com/api/rest/v4/docket-entries/390011027/","id":390011027,"docket":"https://www.courtlistener.com/api/rest/v4/dockets/68511120/","recap_documents":[{"resource_uri":"https://www.courtlistener.com/api/rest/v4/recap-documents/398945580/","id":398945580,"tags":[],"absolute_url":"/docket/68511120/14/downing-v-anavex-life-sciences-corporation/","date_created":"2024-05-13T22:07:46.939561-07:00","date_modified":"2025-12-22T08:34:02.982035-08:00","sha1":"021c5ee1add18789aaeca4ca9a3ccddddb317310","page_count":18,"file_size":300318,"filepath_local":"recap/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.14.0.pdf","filepath_ia":"https://archive.org/download/gov.uscourts.nysd.621044/gov.uscourts.nysd.621044.14.0.pdf","ia_upload_failure_count":null,"thumbnail":null,"thumbnail_status":0,"plain_text":" Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 1 of 18\n\n\n\n\n UNITED STATES DISTRICT COURT\n SOUTHERN DISTRICT OF NEW YORK\n\nJONATHAN BLUM, Individually and on behalf\nof All Others Similarly Situated, Case No.: 1:24-cv-01910\n\n Plaintiff, CLASS ACTION\n\n v.\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n\nKENNETH DOWNING, Individually and on\nbehalf of All Others Similarly Situated, Case No.: 1:24-cv-03529\n Plaintiff,\n CLASS ACTION\n v.\n\nANAVEX LIFE SCIENCES CORPORATION\nand CHRISTOPHER U. MISSLING,\n\n Defendants.\n\n\n\n MEMORANDUM OF LAW IN SUPPORT OF MOTION OF KENNETH\nDOWNING FOR CONSOLIDATION OF RELATED ACTIONS, APPOINTMENT AS\n LEAD PLAINTIFF, AND APPROVAL OF SELECTION OF LEAD COUNSEL\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 2 of 18\n\n\n\n\n TABLE OF CONTENTS\n\n Page\n\nTABLE OF AUTHORITIES .......................................................................................................... ii\n\nPRELIMINARY STATEMENT .................................................................................................... 1\n\nFACTUAL BACKGROUND ......................................................................................................... 3\n\nARGUMENT .................................................................................................................................. 6\n\nI. THE RELATED ACTIONS SHOULD BE CONSOLIDATED ........................................ 6\n\nII. MOVANT SHOULD BE APPOINTED LEAD PLAINTIFF ............................................ 6\n\n A. The PSLRA Standard For Appointing Lead Plaintiff ............................................. 7\n\n B. Movant Is The \u201cMost Adequate Plaintiff\u201d .............................................................. 8\n\n 1. Movant\u2019s Motion Is Timely ........................................................................ 8\n\n 2. Movant Has A Substantial Financial Interest .............................................. 8\n\n 3. Movant Satisfies Rule 23\u2019s Typicality And Adequacy Requirements........ 9\n\n a. Movant\u2019s Claims Are Typical Of Those Of The Class ................. 10\n\n b. Movant Satisfies The Adequacy Requirement Of Rule 23 ........... 10\n\nIII. MOVANT\u2019S SELECTION OF LEAD COUNSEL MERITS APPROVAL .................... 12\n\nCONCLUSION ............................................................................................................................. 13\n\n\n\n\n i\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 3 of 18\n\n\n\n\n TABLE OF AUTHORITIES\n\nCases Page(s)\n\nBishins v. CleanSpark, Inc.,\n No. 21-cv-511 (LAP), 2021 WL 5741574 n.2 (S.D.N.Y. Dec. 2, 2021) .................................... 9\n\nCity of Monroe Employees\u2019 Ret. Sys. v. Hartford Fin. Servs. Grp., Inc.,\n 269 F.R.D. 291 (S.D.N.Y. 2010) .............................................................................................. 12\n\nDenny v. Canaan, Inc.,\n Case No. 21-cv-3299 (JPC), 2021 WL 5847647 (S.D.N.Y. Dec. 9, 2021) ................................ 8\n\nFaig v. Bioscrip, Inc.,\n Case No. 13-cv-06922-AJN, 2013 WL 6705045 (S.D.N.Y. Dec. 19, 2013) ............................ 10\n\nGilbert v. Azure Power Glob. Ltd.,\n No. 1:22-cv-7432 (GHW), 2022 WL 17539172 (S.D.N.Y. Dec. 8, 2022) ................................. 9\n\nIn re eSpeed, Inc. Sec. Litig.,\n 232 F.R.D. 95 (S.D.N.Y. 2005)................................................................................................. 11\n\nIn re Fuwei Films Sec. Litig.,\n 247 F.R.D. 432 (S.D.N.Y. 2008) ................................................................................................ 9\n\nIn re Initial Public Offering Sec. Litig.,\n 214 F.R.D. 117 (S.D.N.Y. 2002) .............................................................................................. 11\n\nIn re Olsten Corp. Sec. Litig.,\n 3 F. Supp. 2d 286 (E.D.N.Y. 1998)............................................................................................. 9\n\nIn re Third Ave. Mgmt. LLC Sec. Litig.,\n Case No. 16-CV-02758-PKC, 2016 WL 2986235 (S.D.N.Y. May 13, 2016) ............................ 9\n\nJohnson v. Celotex Corp.,\n 899 F.2d 1281 (2d Cir. 1990) ...................................................................................................... 6\n\nKemp v. Universal Am. Fin. Corp.,\n Case No. 05-CV-9883-JFK, 2006 WL 1190691 (S.D.N.Y. May 1, 2006) ................................. 8\n\nKux-Kardos v. VimpelCom, Ltd.,\n 151 F. Supp. 3d 471 (S.D.N.Y. 2016) ......................................................................................... 9\n\nLax v. First Merchs. Acceptance Corp., Case,\n No. 97-cv-2715, 1997 WL 461036 (N.D. Ill. Aug. 11, 1997) .................................................... 9\n\nLucas v. United States Oil Fund, LP,\n No. 20-cv-4740 (PGG), 2020 WL 5549719 (S.D.N.Y. Sept. 16, 2020) ..................................... 4\n\n\n\n ii\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 4 of 18\n\n\n\n\nMicholle v. Ophthotech Corp.,\n Case No. 17-cv-210 (VSB), 2018 WL 1307285 (S.D.N.Y. Mar. 13, 2018) ......................... 8, 10\n\nPipefitters Local No. 636 Defined Ben. Plan v. Bank of America Corp.,\n 275 F.R.D. 187 (S.D.N.Y. 2011) ................................................................................................ 6\n\nRagan v. AppHarvest, Inc.,\n No. 21-cv-7985 (LJL), 2021 WL 5909116 (S.D.N.Y. Dec. 13, 2021) ....................................... 3\n\nRandall v. Fifth St. Fin. Corp.,\n Case No. 15-CV-7759-LAK, 2016 WL 462479 (S.D.N.Y. Feb. 1, 2016).................................. 9\n\nRichman v. Goldman Sachs Grp.,\n 274 F.R.D. 473 (S.D.N.Y. 2011) ................................................................................................ 9\n\nSilverberg v. Dryships Inc.,\n Case No. 17-cv-4547, 2018 WL 10669653 (E.D.N.Y. Aug. 21, 2018) ...................................... 9\n\nStatutes\n\n15 U.S.C. \u00a7 78u-4(a)(1) .................................................................................................................. 7\n15 U.S.C. \u00a7 78u-4(a)(3)(A)(i) ..................................................................................................... 7, 8\n15 U.S.C. \u00a7 78u-4(a)(3)(B) ......................................................................................................... 1, 7\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(i) ..................................................................................................... 2, 7\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii) ................................................................................................... 8, 9\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(I) ................................................................................................... 7\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II) ............................................................................................ 8, 11\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(v) .................................................................................................. 3, 12\n15 U.S.C. \u00a7 78u- 4(a)(3)(B)(iii)(I) .................................................................................................. 2\n15 U.S.C. \u00a7\u00a7 78u-4(a)(3)(A)(i)(II) & (B)(v)................................................................................. 11\n\nOther Authorities\n\nH.R. Conf. Rep. No. 104-369 )1995), as reprinted in 1995 U.S.C.C.A.N. 734 ........................... 12\n\n\n\n\n iii\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 5 of 18\n\n\n\n\n Proposed Lead Plaintiff Kenneth Downing (\u201cMovant\u201d) respectfully submits this\n\n Memorandum of Law pursuant to Federal Rule of Civil Procedure 42(a) and Section\n\n 21D(a)(3)(B) of the Securities Exchange Act of 1934 (the \u201cExchange Act\u201d), 15 U.S.C. \u00a7 78u-\n\n 4(a)(3)(B), as amended by the Private Securities Litigation Reform Act of 1995 (the \u201cPSLRA\u201d),\n\n for an Order: (1) consolidating the above-captioned actions (the \u201cRelated Actions\u201d);\n\n (2) appointing Movant as Lead Plaintiff on behalf of a class consisting of all persons other than\n\n Defendants who purchased or otherwise acquired Anavex Life Sciences Corporation (\u201cAnavex\u201d\n\n or the \u201cCompany\u201d) stock between June 21, 2021 and January 1, 2024, inclusive (the \u201cClass\n\n Period\u201d); (3) approving Movant\u2019s selection of the law firm of Berger Montague PC (\u201cBerger\n\n Montague\u201d) as Lead Counsel; and (4) granting such other and further relief as the Court may\n\n deem just and proper.\n\n PRELIMINARY STATEMENT\n\n The complaints filed in the Related Actions allege violations of Sections 10(b) and 20(a)\n\n of the Exchange Act on behalf of investors of Anavex securities during the Class Period against\n\n Anavex and Christopher U. Missling, the Company\u2019s Chief Executive Officer (collectively, the\n\n \u201cDefendants\u201d). Movant respectfully submits that he should be appointed Lead Plaintiff on behalf\n\n of all investors who purchased or acquired Anavex securities during the Class Period, and who\n\n were damaged thereby (the \u201cClass\u201d). 1\n\n As an initial matter, Movant respectfully requests that the Court consolidate the Related\n\nActions, as prescribed by Fed. R. Civ. P. 42. As the complaints in both cases allege substantially\n\nsimilar claims against identical defendants, with substantially overlapping facts and circumstances,\n\n\n1\n A copy of Movant\u2019s Certification pursuant to the PSLRA is attached as Exhibit (\u201cEx.\u201d) A to the\nDeclaration of Radha Nagamani Raghavan (\u201cRaghavan Decl.\u201d), submitted concurrently herewith.\nAll exhibit references are to the Raghavan Decl.\n\n\n 1\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 6 of 18\n\n\n\n\nconsolidation of the Related Actions under Rule 42 is appropriate.\n\n Following consolidation, the PSLRA requires that the Court appoint the \u201cmost adequate\n\nplaintiff\u201d to serve as Lead Plaintiff. See 15 U.S.C. \u00a7 78u-4(a)(3)(B)(i). In that regard, the Court\n\nmust determine which movant has the \u201clargest financial interest\u201d in the relief sought by the Class\n\nand whether such movant has made a prima facie showing that the movant is a typical and adequate\n\nClass representative under Federal Rule of Civil Procedure 23 (\u201cRule 23\u201d). See 15 U.S.C. \u00a7 78u-\n\n4(a)(3)(B)(iii)(I).\n\n For the reasons stated herein, Movant respectfully submits that he is the \u201cmost adequate\n\nplaintiff\u201d under the PSLRA and should be appointed Lead Plaintiff. Movant purchased 24,000\n\nshares of Avanex stock during the Class Period, with a total Class Period expenditure of\n\napproximately $399,623.22, and suffered a Class Period investment loss of approximately\n\n$216,243.88 on a last-in-first-out (\u201cLIFO\u201d) basis, or $255,806.08 on a first-in-first-out basis, for\n\nclaims arising under the Exchange Act. See Ex. B. Movant thus not only has a substantial financial\n\ninterest in this litigation, but he also has the largest known loss of any other movant and a\n\nsubstantial financial interest in recovering losses attributable to Defendants\u2019 violations of federal\n\nsecurities laws. Movant is, therefore, the \u201cmost adequate plaintiff\u201d under the PSLRA. See Section\n\nII.B.2, infra.\n\n Further, Movant satisfies the typicality and adequacy requirements of Rule 23 in that:\n\n(1) Movant\u2019s claims arise from the same course of events as those of the other Class members,\n\n(2) Movant relies on similar legal theories to prove Defendants\u2019 liability, and (3) Movant has\n\nretained experienced counsel and is committed to vigorously prosecuting the claims. See Section\n\nII.B.3, infra.\n\n Finally, pursuant to the PSLRA, Movant respectfully requests that the Court approve his\n\n\n\n\n 2\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 7 of 18\n\n\n\n\nselection of the law firm of Berger Montague as Lead Counsel for the Class. See 15 U.S.C. \u00a7 78u-\n\n4(a)(3)(B)(v) (\u201c[T]he most adequate plaintiff shall, subject to the approval of the court, select and\n\nretain counsel to represent the class\u201d). Proposed Lead Counsel has decades worth of experience\n\nrepresenting investors in shareholder litigation and securities class actions, including extensively\n\nin this District, and has the expertise and resources necessary to handle this complex litigation. See\n\nSection III, infra.\n\n Accordingly, Movant respectfully requests that the Court appoint him as Lead Plaintiff for\n\nthe Class and approve his selection of Lead Counsel.\n\n FACTUAL BACKGROUND 2\n\n Anavex is a clinical stage biopharmaceutical company that engages in the development\n\nof therapeutics for the treatment of central nervous system (\u201cCNS\u201d) disorders. The Company\u2019s\n\nlead product candidate is blarcamesine, known as ANAVEX 2-73, which is intended to modify\n\nspecific genetic pathways associated with some CNS disorders. Anavex has sponsored several\n\nresearch studies concerning blarcamesine\u2019s suitability to treat various CNS disorders, and the\n\ndrug is undergoing clinical trials for the treatment of Alzheimer\u2019s disease and Parkinson\u2019s\n\ndisease, as well as rare diseases, such as Rett syndrome, a rare severe neurological monogenic\n\ndisorder primarily affecting females.\n\n Prior to the start of the Class Period, 3 Anavex sponsored the AVATAR Phase II and III\n\n(\u201cAVATAR\u201d) clinical trials which tested ANAVEX 2-73 as a treatment for adults with Rett\n\n\n2\n The factual allegations are derived from the complaint filed in Downing v. Anavex Life Sciences\nCorporation, et al., No. 24-cv- 03529 (S.D.N.Y.) (\u201cDowning\u201d), which alleges the broadest and\nmost inclusive class period.\n3\n The Blum action alleges a class period of February 1, 2022 through January 1, 2024, while the\nDowning action alleges a class period of June 21, 2021 through January 1, 2024. For purposes of\nthis Motion, the broadest and most inclusive alleged class period \u2013 here, the class period alleged\nin Downing \u2013 is used. See Ragan v. AppHarvest, Inc., No. 21-cv-7985 (LJL), 2021 WL 5909116,\n\n\n 3\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 8 of 18\n\n\n\n\nsyndrome. According to the study protocol Defendants posted on \u201cclinicaltrials.gov\u201d\n\n(\u201cClinicalTrials\u201d), an FDA-sponsored online resource for pertinent information about\n\npharmaceutical trial research protocols \u2013 a website where trial information is updated routinely\n\n\u2013 Anavex intended to use several \u201cPrimary Outcome Measures\u201d and \u201cSecondary Outcome\n\nMeasures\u201d to evaluate AVATAR\u2019s efficacy and overall clinical benefit.\n\n The Class Period commences on June 21, 2021, when Anavex announced \u201cconvincing\n\nbiomarker correlating efficacy data\u201d for the AVATAR study. In a press release entitled \u201cAnavex\n\nLife Sciences Announces ANAVEX\u00ae2-73 (Blarcamesine) Biomarker Correlated with Efficacy\n\nEndpoints in Placebo-Controlled U.S. Phase 2 Clinical Trial for the Treatment of Adult Patients\n\nwith Rett Syndrome,\u201d the Company reported \u201cstrong and consistent data demonstrating\n\nbiomarker-correlated rapid and clinically meaningful improvement in key measures of Rett\n\nsyndrome symptoms in the Anavex 2-73 treatment group compared to placebo.\u201d\n\n Throughout the AVATAR study, Defendants represented that Anavex would use certain\n\nprimary and secondary research outcomes for its testing of ANAVEX 2-73 as a treatment for\n\nRett syndrome in adults. These research outcomes, or endpoints, were listed on the ClinicalTrials\n\nwebsite, where Anavex routinely updated the status of the study.\n\n The complaint alleges that investors began to learn the truth about Defendants\u2019\n\nmanipulation of the endpoints for the AVATAR trial on February 1, 2022, when the Company\n\nissued a press release announcing, \u201cAVATAR Phase 3 Trial met Primary and Secondary Efficacy\n\nEndpoints.\u201d The Company also filed a Form 8-K presentation on February 1, 2022 that described\n\nthe AVATAR results and revealed the RSBQ scores were \u201canchor-based,\u201d using CGI-I scores as\n\n\n\nat *7 (S.D.N.Y. Dec. 13, 2021) (\u201cWhere there are two potential class periods, courts addressing\nlead plaintiff motions generally apply the longer class period.\u201d) (citing Lucas v. United States Oil\nFund, LP, No. 20-cv-4740 (PGG), 2020 WL 5549719, at *4 (S.D.N.Y. Sept. 16, 2020)).\n\n\n 4\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 9 of 18\n\n\n\n\nan anchor. In the presentation, the Company failed to note it previously described the RSBQ as\n\nthe \u201cmore rigorous endpoint\u201d and that it did not want to \u201cover-emphasize\u201d the CGI-I.\n\n Despite the Company announcing its \u201cpositive\u201d news about AVATAR, shares lost\n\nground, falling from a closing price of $13.08 per share on January 31, 2022 to a closing price\n\nof $10.55 per share on February 2, 2022 over two trading days \u2013 a decline of $2.53 per share, or\n\nmore than 19% \u2013 on abnormally high volume.\n\n Nevertheless, Defendants continued to mislead investors regarding the outcome measures\n\nfor its testing of ANAVEX 2-73 on patients suffering from Rett syndrome, including in the\n\nCompany\u2019s EXCELLENCE trial, which tested ANAVEX 2-73 on pediatric Rett syndrome\n\npatients.\n\n Then, on January 2, 2024, the Company issued a press release announcing, \u201cTopline\n\nResults from Phase 2/3 EXCELLENCE Clinical Study in Pediatric Rett Syndrome.\u201d The\n\nCompany used a \u201cmixed-effect model for repeated measure (MMRM)\u201d method for analyzing\n\nimprovement on the RSBQ for ANAVEX 2-73-treated patients versus those on placebo. Of the\n\nvarious MMRM statistics reported result, one reached statistical significance \u2013 \u201cANAVEX 2-73-\n\ntreated patients demonstrated a rapid onset of action with improvements at 4 weeks after\n\ntreatment with a RSBQ total score LS Mean (SE) -10.32 (2.086) points in the drug-treated group\n\ncompared to a LS Mean (SE) -5.67 (2.413) points in placebo-treated patients.\u201d\n\n The MMRM method was not used in the AVATAR study nor was an LS Mean score\n\nreported in AVATAR. The RSBQ AUC was not reported in EXCELLENCE though it had been\n\nreported in AVATAR. Further, an anchor-based RSBQ using the CGI-I was not reported in\n\nEXCELLENCE though it had been reported in AVATAR. Nonetheless, the Company blamed\n\nany perceived deficiencies in the EXCELLENCE study on \u201clarge placebo effect which may have\n\n\n\n\n 5\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 10 of 18\n\n\n\n\nmasked the compound\u2019s therapeutic effect,\u201d according to the press release. The Company offered\n\nno evidence to support that claim.\n\n Following the Company\u2019s release of the EXCELLENCE results, Anavex shares tumbled,\n\nfalling from $9.31 per share on December 29, 2023 to $6.05 on January 2, 2024.\n\n ARGUMENT\n\nI. THE RELATED ACTIONS SHOULD BE CONSOLIDATED\n\n Consolidation pursuant to Rule 42 is proper when actions involve common questions of\n\nlaw and fact. Johnson v. Celotex Corp., 899 F.2d 1281, 1284 (2d Cir. 1990). Each of the Related\n\nActions presents substantially similar factual and legal issues, as they both allege violations of\n\nthe Exchange Act, present the same or similar theories for recovery, and are based on the same\n\nallegedly wrongful course of conduct. Specifically, each action asserts that Defendants made\n\nmaterially false and misleading statements or omissions regarding the primary and secondary\n\nendpoints by which the Company evaluated blarcamesine as a treatment for Rett syndrome, both\n\nin adults and children, in Anavex\u2019s clinical trials. As such, the Related Actions present virtually\n\nidentical factual and legal issues during substantially overlapping class periods, and name\n\nidentical defendants.\n\n Because these Related Actions arise from the same facts and circumstances and involve\n\nthe same subject matter, consolidation of these cases under Rule 42 is appropriate. See Pipefitters\n\nLocal No. 636 Defined Ben. Plan v. Bank of America Corp., 275 F.R.D. 187, 192 (S.D.N.Y.\n\n2011) (consolidation is appropriate \u201cif the cases present sufficiently common questions of fact\n\nand law, and the differences do not outweigh the interests of judicial economy served by\n\nconsolidation.\u201d).\n\nII. MOVANT SHOULD BE APPOINTED LEAD PLAINTIFF\n\n Movant respectfully submits that he should be appointed Lead Plaintiff because he filed\n\n\n 6\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 11 of 18\n\n\n\n\nthe instant Motion in a timely manner, has a substantial\u2014if not the largest\u2014financial interest in\n\nthis litigation under the Exchange Act claims, and satisfies the typicality and adequacy\n\nrequirements of Rule 23. Moreover, he is the Plaintiff in one of the two Related Actions.\n\n A. The PSLRA Standard For Appointing Lead Plaintiff\n\n The PSLRA provides a straightforward, sequential procedure for selecting a Lead Plaintiff\n\nfor \u201ceach private action arising under [the Exchange Act] that is brought as a plaintiff class action\n\npursuant to the Federal Rules of Civil Procedure.\u201d See 15 U.S.C. \u00a7 78u-4(a)(1); see also\n\n15 U.S.C. \u00a7 78u-4(a)(3)(B) (setting forth procedure for selecting lead plaintiff). First, the\n\nExchange Act, as amended by the PSLRA, specifies that:\n\n Not later than 20 days after the date on which the complaint is filed, the plaintiff or\n plaintiffs shall cause to be published, in a widely circulated national business-\n oriented publication or wire service, a notice advising members of the purported\n plaintiff class \u2013\n\n (I) of the pendency of the action, the claims asserted therein,\n and the purported class period; and\n\n (II) that, not later than 60 days after the date on which the notice\n is published, any member of the purported class may move the court\n to serve as lead plaintiff of the purported class.\n\n15 U.S.C. \u00a7 78u-4(a)(3)(A)(i).\n\n Next, a court is to consider any motion made by class members to serve as Lead Plaintiff\n\nand appoint the \u201cmost adequate plaintiff.\u201d 15 U.S.C. \u00a7 78u-4(a)(3)(B)(i). In adjudicating a lead\n\nplaintiff motion, a court should adopt a presumption that the \u201cmost adequate plaintiff\u201d is the person\n\nor group of persons who: (i) filed a complaint or timely filed a motion to serve as lead plaintiff;\n\n(ii) has the largest financial interest in the relief sought by the class; and (iii) otherwise satisfies\n\nthe requirements of Rule 23. See 15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(I). Here, Movant both filed a\n\ncomplaint and timely filed a lead plaintiff motion. This presumption may be rebutted only by\n\n\u201cproof\u201d that the presumptively most adequate plaintiff \u201cwill not fairly and adequately protect the\n\n\n 7\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 12 of 18\n\n\n\n\ninterests of the class\u201d or \u201cis subject to unique defenses that render such plaintiff incapable of\n\nadequately representing the class.\u201d 15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II); see also Micholle v.\n\nOphthotech Corp., Case No. 17-cv-210 (VSB), 2018 WL 1307285, at *4 (S.D.N.Y. Mar. 13,\n\n2018).\n\n Under the criteria established by the PSLRA, Movant is the most adequate plaintiff and\n\nshould be appointed Lead Plaintiff.\n\n B. Movant Is The \u201cMost Adequate Plaintiff\u201d\n\n 1. Movant\u2019s Motion Is Timely\n\n Movant has timely filed this Motion to serve as Lead Plaintiff. Pursuant to 15 U.S.C.\n\n\u00a7 78u-4(a)(3)(A)(i), the plaintiff in the first-filed action, Blum v. Anavex Life Sciences\n\nCorporation, et al., No. 1:24-cv-01910 (S.D.N.Y.), properly caused notice regarding the pending\n\nnature of the case to be published on Globe Newswire, a widely circulated, business-oriented news\n\nwire service, on March 13, 2024. See Ex. C. The PSLRA provides that any person who is a member\n\nof the proposed Class may apply to be appointed Lead Plaintiff within sixty days after publication\n\nof the notice, i.e., on or before May 13, 2024. Movant filed this Motion seeking appointment as\n\nLead Plaintiff within this prescribed period of time and thus has satisfied the procedural\n\nrequirements of the PSLRA.\n\n 2. Movant Has A Substantial Financial Interest\n\n The PSLRA requires a court to adopt the rebuttable presumption that \u201cthe most adequate\n\nplaintiff . . . has the largest financial interest in the relief sought by the class.\u201d 15 U.S.C. \u00a7 78u-\n\n4(a)(3)(B)(iii); see also Kemp v. Universal Am. Fin. Corp., Case No. 05-CV-9883-JFK, 2006 WL\n\n1190691, at *2 (S.D.N.Y. May 1, 2006). 4\n\n\n4\n \u201c[T]he PSLRA does not delineate how to calculate which plaintiff has the \u2018largest financial\ninterest.\u2019\u201d Denny v. Canaan, Inc., Case No. 21-cv-3299 (JPC), 2021 WL 5847647, at *2 (S.D.N.Y.\n\n\n 8\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 13 of 18\n\n\n\n\n Movant has suffered a loss of approximately $216,243.88 on a LIFO basis for claims\n\n arising under the Exchange Act. See Ex. B; see also Bishins v. CleanSpark, Inc., No. 21-cv-511\n\n (LAP), 2021 WL 5741574, at *3 n.2 (S.D.N.Y. Dec. 2, 2021) (finding movant with largest total\n\n loss under the LIFO methodology was \u201cthe largest stakeholder in this litigation\u201d). Movant is not\n\n aware of any other Class member with a larger interest in this litigation. Accordingly, having a\n\n substantial financial interest in the outcome of the litigation, Movant is presumptively the \u201cmost\n\n adequate plaintiff.\u201d See 15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii); Randall v. Fifth St. Fin. Corp., Case No.\n\n 15-CV-7759-LAK, 2016 WL 462479, at *1 (S.D.N.Y. Feb. 1, 2016) (same).\n\n 3. Movant Satisfies Rule 23\u2019s Typicality And Adequacy Requirements\n\n The PSLRA further provides that in addition to possessing the largest financial interest in\n\n the outcome of the litigation, a lead plaintiff must \u201cotherwise satisf[y] the requirements of Federal\n\n Rule of Civil Procedure 23.\u201d See In re Third Ave. Mgmt. LLC Sec. Litig., Case No. 16-CV-02758-\n\n PKC, 2016 WL 2986235, at *1 (S.D.N.Y. May 13, 2016). At the lead plaintiff selection stage, all\n\n that is required to satisfy Rule 23 is a preliminary showing that the lead plaintiff\u2019s claims are\n\n typical and adequate. See Kux-Kardos v. VimpelCom, Ltd., 151 F. Supp. 3d 471, 477 (S.D.N.Y.\n\n 2016); see also Gilbert v. Azure Power Glob. Ltd., No. 1:22-cv-7432 (GHW), 2022 WL\n\n\n\n\nDec. 9, 2021). Courts typically regard the factors that comprise the Olsten-Lax test: (1) the number\nof shares purchased during the class period; (2) the number of net shares purchased during the\nclass period; (3) total net funds expended during the class period; and (4) the approximate losses\nsuffered. See In re Olsten Corp. Sec. Litig., 3 F. Supp. 2d 286, 295 (E.D.N.Y. 1998); Lax v. First\nMerchs. Acceptance Corp., Case No. 97-cv-2715, 1997 WL 461036, at *5 (N.D. Ill. Aug. 11,\n1997). Many courts place \u201cthe most emphasis on the last of the four factors.\u201d In re Fuwei Films\nSec. Litig., 247 F.R.D. 432, 437 (S.D.N.Y. 2008) (citation omitted) (internal quotation marks\nomitted); see also Silverberg v. Dryships Inc., Case No. 17-cv-4547, 2018 WL 10669653, at *4\n(E.D.N.Y. Aug. 21, 2018) (\u201cCourts generally consider those factors to be \u2018properly ordered, so\nthat the number of shares purchased (Factor 1) is the least important and the loss suffered (Factor\n4) is the most important.\u2019\u201d) (quoting Richman v. Goldman Sachs Grp., 274 F.R.D. 473, 476\n(S.D.N.Y. 2011).\n\n\n 9\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 14 of 18\n\n\n\n\n 17539172, at *3 (S.D.N.Y. Dec. 8, 2022) (\u201cthe Court considers only whether the proposed\n\n plaintiff has made a preliminary showing that two of Rule 23\u2019s requirements\u2013typicality and\n\n adequacy\u2013are satisfied.\u201d). Here, Movant satisfies both requirements.\n\n a. Movant\u2019s Claims Are Typical Of Those Of The Class\n\n The Rule 23(a) typicality requirement is satisfied when a plaintiff\u2019s claims arise from the\n\nsame event, practice, or course of conduct that gives rise to other class members\u2019 claims, and\n\nplaintiff\u2019s claims are based on the same legal theory. See Faig v. Bioscrip, Inc., Case No. 13-cv-\n\n06922-AJN, 2013 WL 6705045, at *3 (S.D.N.Y. Dec. 19, 2013). Rule 23 does not require the lead\n\nplaintiff to be identically situated with all class members. See id.\n\n Movant\u2019s claims are typical of the claims asserted by the proposed Class. Like all members\n\nof the Class, Movant alleges that, in violation of the federal securities laws, Defendants, among\n\nother things, misled investors about the primary and secondary endpoints by which the Company\n\nevaluated blarcamesine as a treatment for Rett syndrome, both in adults and children, in Anavex\u2019s\n\nclinical trials. Because Movant\u2019s claims arise from the same course of events as the claims of all\n\nother Class members, the typicality requirement is satisfied. See Micholle, 2018 WL 1307285, at\n\n*6.\n\n b. Movant Satisfies The Adequacy Requirement Of Rule 23\n\n In addition, Movant satisfies the adequacy requirement of Rule 23. The adequacy of\n\nrepresentation requirement of Rule 23(a)(4) is satisfied when a representative party establishes that\n\nit \u201cwill fairly and adequately protect the interests of the class.\u201d\n\n Courts in this District have held that:\n\n [t]he adequacy requirement is satisfied where (1) class counsel is qualified,\n experienced, and generally able to conduct the litigation; (2) the class members\u2019\n interests are not antagonistic to one another; and (3) the class has a sufficient\n interest in the outcome of the case to ensure vigorous advocacy.\n\n\n\n 10\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 15 of 18\n\n\n\n\nIn re eSpeed, Inc. Sec. Litig., 232 F.R.D. 95, 102 (S.D.N.Y. 2005) (quoting In re Initial Public\n\nOffering Sec. Litig., 214 F.R.D. 117, 121 (S.D.N.Y. 2002).\n\n Here, Movant will fairly and adequately represent the interests of the proposed Class.\n\nMovant has the resources and motivation sufficient to pursue a class action to a successful\n\nconclusion and is committed to prosecuting the claims on behalf of Anavex investors. Moreover,\n\nMovant is committed to pursuing the best recovery possible for himself and all other Class\n\nmembers. Movant is sixty-five years old and resides in Santa Monica, California. He is employed\n\nas a real estate property manager and has been investing in equities for approximately twenty-five\n\nyears. Movant incurred substantial losses in his Anavex investment during the Class Period and\n\nthus is highly motivated to maximize any recovery. Movant also has selected and retained\n\nexperienced counsel, Berger Montague, as proposed Lead Counsel. Berger Montague has an\n\nextensive record of successfully prosecuting securities class actions vigorously and efficiently,\n\nboth within this District and beyond. See Section III, infra. Movant has timely submitted his choice\n\nto the Court for approval, in accordance with the PSLRA. See 15 U.S.C. \u00a7\u00a7 78u-4(a)(3)(A)(i)(II)\n\n& (B)(v).\n\n Furthermore, no antagonism exists between Movant\u2019s interests and those of the absent\n\nClass members. Rather, they are aligned. Like all other Class members, Movant suffered\n\nsubstantial losses due to Defendants\u2019 alleged misconduct and, therefore, has a sufficient and\n\nidentical interest in the outcome of this case to ensure vigorous prosecution of the litigation for the\n\nbenefit of all Class members.\n\n Finally, there is no evidence to suggest that Movant is \u201csubject to unique defenses that\n\nrender such plaintiff incapable of representing the class,\u201d because no such evidence exists. See\n\n15 U.S.C. \u00a7 78u-4(a)(3)(B)(iii)(II). Accordingly, Movant satisfies the adequacy requirement.\n\n\n\n\n 11\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 16 of 18\n\n\n\n\n Thus, Movant clearly satisfies the requirements of the PSLRA for lead plaintiff\n\nappointment and should be appointed Lead Plaintiff on behalf of the putative Class of damaged\n\nAnavex investors here.\n\nIII. MOVANT\u2019S SELECTION OF LEAD COUNSEL MERITS APPROVAL\n\n The PSLRA vests authority in the lead plaintiff to select and retain lead counsel, subject to\n\nthe court\u2019s approval. See 15 U.S.C. \u00a7 78u-4(a)(3)(B)(v); City of Monroe Employees\u2019 Ret. Sys. v.\n\nHartford Fin. Servs. Grp., Inc., 269 F.R.D. 291, 297 (S.D.N.Y. 2010) (stating that \u201cthe [PSLRA]\n\nevidences a strong presumption in favor of approving a properly-selected lead plaintiff\u2019s decisions\n\nas to counsel selection and counsel retention\u201d). Consistent with Congressional intent, a court\n\nshould not disturb the Lead Plaintiff\u2019s choice of counsel unless it is \u201cnecessary to protect the\n\ninterests of the plaintiff class.\u201d H.R. Conf. Rep. No. 104-369, at 35 (1995), as reprinted in 1995\n\nU.S.C.C.A.N. 730, 734.\n\n Here, Movant has selected the law firm of Berger Montague to represent the Class. Berger\n\n Montague has a long record of success in securities litigation and has achieved many of the largest\n\n securities recoveries since Congress enacted the PSLRA. The firm advises clients on litigation\n\n and recovery options in securities proceedings throughout the United States and internationally.\n\n Berger Montague has served as lead or co-lead counsel in numerous other major securities class\n\n action cases, both within this District and beyond, where substantial settlements were achieved\n\n on behalf of investors. See Ex. D.\n\n In light of the foregoing, by approving Movant\u2019s selection of the law firm of Berger\n\nMontague as Lead Counsel for the Class, the Court can be assured that the Class will receive the\n\nhighest quality representation. Thus, the Court should approve this selection.\n\n\n\n\n 12\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 17 of 18\n\n\n\n\n CONCLUSION\n\n For the foregoing reasons, Movant respectfully request that the Court grant his Motion and\n\nenter an Order of the following: (1) consolidating the Related Actions; (2) appointing Movant as\n\nLead Plaintiff on behalf of a Class consisting of all persons other than Defendants who purchased\n\nor otherwise acquired Anavex stock during the Class Period; (3) approving Movant\u2019s selection of\n\nthe law firm of Berger Montague as Lead Counsel for the Class; and (4) granting such other and\n\nfurther relief as the Court may deem just and proper.\n\nDated: May 13, 2024 Respectfully submitted,\n\n BERGER MONTAGUE PC\n\n /s/ Radha Nagamani Raghavan\n Radha Nagamani Raghavan\n Michael Dell\u2019Angelo\n Andrew D. Abramowitz\n James A. Maro\n 1818 Market Street, Suite 3600\n Philadelphia, PA 19103\n Tel: (215) 875-3000\n Email: rraghavan@bm.net\n mdellangelo@bm.net\n aabramowitz@bm.net\n jmaro@bm.net\n\n Counsel for Lead Plaintiff Movant Kenneth\n Downing and Proposed Lead Counsel for the Class\n\n SCHALL LAW FIRM\n Brian Schall\n Rina Restaino\n Brian England\n 2049 Century Park East, Suite 2460\n Los Angeles, CA 90067\n Tel: (310) 301-3335\n Email: brian@schallfirm.com\n rina@schallfirm.com\n briane@schallfirm.com\n\n Additional Counsel for Lead Plaintiff Movant\n Kenneth Downing\n\n\n 13\n\f Case 1:24-cv-03529-CM Document 14 Filed 05/13/24 Page 18 of 18\n\n\n\n\n CERTIFICATE OF SERVICE\n\n I hereby certify that on May 13, 2024, a true and correct copy of the foregoing document\n\nwas served by CM/ECF to the parties registered to the Court\u2019s CM/ECF system.\n\n\n /s/ Radha Nagamani Raghavan\n Radha Nagamani Raghavan\n\n\n\n\n 14\n\f","ocr_status":2,"date_upload":"2024-08-19T11:02:53.637200-07:00","document_number":"14","attachment_number":null,"pacer_doc_id":"127035461322","is_available":true,"is_free_on_pacer":null,"is_sealed":null,"document_type":1,"description":"Memorandum of Law in Support of Motion","acms_document_guid":""}],"date_created":"2024-05-13T22:07:46.924464-07:00","date_modified":"2025-12-22T08:34:02.959204-08:00","date_filed":"2024-05-13","time_filed":"23:12:24","entry_number":14,"recap_sequence_number":"2024-05-13.004","pacer_sequence_number":66,"description":"MEMORANDUM OF LAW in Support re: 13 MOTION to Appoint Kenneth Downing to serve as lead plaintiff(s) . 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