Oral Blarcamesine Phase IIb/III Trial Confirms Identified Precision Medicine Patient Population – Significant Broad Clinical and Quality of Life Improvements for Early Alzheimer’s Disease Patients

IMPORTANCE There are no approved oral disease-modifying treatments for Alzheimer’s disease (AD) with the ability to prolong time in a stable disease state and with clinically meaningful outcomes clear to patients and caregivers. DESIGN The Phase IIb/III ANAVEX2-73-AD-004 study was a randomized, double-blind, placebo-controlled, 48-week trial with prespecified gene or GWAS identified genetic variant populations related to the mechanism of the pharmacological intervention.

Providing evidence of improved Precision Medicine neurology clinical treatment responses with optimal blarcamesine dose for up to ∼70% of AD patients within prespecified SIGMAR1 (ABCLEAR1) and GWAS identified COL24A1 (ABCLEAR2) and SIGMAR1/COL24A1 (ABCLEAR3) non-missense gene populations. Describing once-daily, oral therapeutic intervention of blarcamesine in early AD, with a differentiated upstream and constitutional mechanism of action by enhancing autophagy through SIGMAR1 activation and restoration of cellular homeostasis. SETTING Multicenter - 52 medical research centers/hospitals in 5 countries. INTERVENTION 508 participants with Early AD (Stage 3) were randomized to receive blarcamesine (n = 338) oral capsules once daily either in medium dose group (30 mg) or in high dose group (50 mg) or placebo (n = 170) for 48 weeks. An open-label-extension study ATTENTION-AD, continued for up to 192 weeks. MAIN OUTCOME AND MEASURES Further improved clinical and biomarker outcomes of the ABCLEAR2 and ABCLEAR3 populations were accretive to the previously reported intent-to-treat (ITT) and prespecified ABCLEAR1 populations. The co-primary cognitive and functional outcomes were assessed as changes in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB as well as patient assessed clinical outcomes CGI-I, NPI-Q and QoL-AD (Quality of Life AD Patient) as well as biomarkers global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), and volumetric MRI scans were analyzed by general linear model.

The ITT population (mean age, 73.7 years; 225 [48.7%] women), consisted of 462 randomized participants, with ABCLEAR1 population comprising of 300 participants, ABCLEAR2 population of 336 participants and ABCLEAR3 of 222 participants. In both the ABCLEAR2 and ABCLEAR3 populations, the co-primary outcomes as well as all other clinical outcomes were statistically significant. ABCLEAR3 blarcamesine group vs. placebo at Week 48 (ADAS-Cog13 difference of −4.179 [95% CI −6.512, −1.845]; P=0.0005; ADCS-ADL difference of +3.131 [95%CI 0.720, 5.542]; P=0.0111; CDR-SB difference of −1.076 [95% CI −1.645, −0.508]; P=0.0002; QoL-AD Patient improvement from baseline of 0.334 [95% CI −1.164, 1.833] and difference of 1.848 [95% CI 0.455, 3.241]; P=0.0095). The clinical outcomes were strongest in the blarcamesine 30 mg cohort (ADAS-Cog13 difference of −4.739 [95% CI −7.370, −2.108]; P=0.0004; ADCS-ADL difference of +4.245 [95%CI 1.518, 6.972]; P=0.0024; CDR-SB difference of −1.414 [95% CI −2.054, −0.775]; P<0.0001; QoL-AD Patient improvement from baseline of 0.182 [95% CI −1.472, 1.835]; and difference of 1.651 [95% CI 0.455, 3.241]; P=0.0392). Whole brain volume loss in blarcamesine group vs. placebo was significantly further decreased from ITT population (37.6%, P=0.0019) to ABCLEAR3 population (44.5%, P=0.0019). Participants in the 30 mg group ABCLEAR3 full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 10 participants (12.7%) in the blarcamesine and 6 (9.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. There were no deaths in the blarcamesine group and 1 in the placebo group.

AND RELEVANCE Blarcamesine group demonstrated a balanced safety profile with no associated neuroimaging adverse events. The respective once-daily oral 30 mg blarcamesine cohort in the respective ABCLEAR1, ABCLEAR2, and ABCLEAR3 populations demonstrates further improvement of the already adequate safety profile of the ITT population and hence representing the dose with the most balanced benefit-to-risk ratio. In both ABCLEAR2 and ABCLEAR3 populations significant slowing in decline and even stabilization of clinical worsening was demonstrated. Blarcamesine group vs. placebo was 75.9% reduction in decline at 48 weeks in the total blarcamesine group and was 84.7% in the 30 mg dose group, respectively on the prespecified co-primary cognitive endpoint ADAS-Cog13 in the ABCLEAR3 population. Blarcamesine demonstrated consistently significantly improved clinical effect for all clinical endpoints, which was in accordance with significant and further reduced brain atrophy. Furthermore, a significant absolute improvement in Quality of Life (QoL-AD) scores indicating a reversal of negative trajectory for Alzheimer’s disease patients from baseline to end of trial was observed. The Phase IIb/III ANAVEX2-73-AD-004 clinical study confirmed blarcamesine’s consistent efficacy leading to improved cognitive stabilization with continued benefit in the open-label-extension study ATTENTION-AD up to 192 weeks. Evidenced by the Precision Medicine paradigm, including in a prespecified ABCLEAR1 population, a consistent significant improvement for all clinical endpoints in the ABCLEAR2 and ABCLEAR3 populations, respectively, was demonstrated. Coupled with a convenient once daily, oral pill administration, blarcamesine could represent a novel treatment option for up to ∼70% of early AD patients benefiting from further improved outcomes using directed Precision Medicine to alleviate significant medical and economic burden. TRIAL REGISTRATION Clinicaltrials.gov: NCT03790709; Open-label extension NCT04314934 FUNDING This work was funded by Anavex Life Sciences. Key Message Within a heterogeneous Alzheimer’s disease (AD) population, clinical utility of disease-modifying drug candidates could be enhanced via a Precision Medicine approach of treating those with target-relevant genetic profiles, excluding missense gene populations. This effective targeting could alleviate significant medical and economic burden. Competing Interest Statement MNS has received consulting fees from Anavex Life Sciences, Eisai, Signant, Neurotherapia, AbbVie, FujiRebio, Cognito, Novo Nordisk and Johnson & Johnson; honoraria from Lilly; stock options from Alzheon, uMETHOD and Lighthouse Pharmaceuticals; participated in a monitoring or advisory board for Bristol Myers Squibb; has a leadership role in CervoMed; SM has received medical monitoring fees for Anavex's Rett syndrome studies; medical monitoring fees from Lilly, Johnson & Johnson and Eisai; TG received institutional support from Biogen, Eisai and Lilly; consulting fees from Acumen, Advantage Therapeutics, Alector, Anavex Life Sciences, Biogen, Bristol Myers Squibb, Cogthera, Eisai, Functional Neuromodulation, Grifols, Johnson & Johnson, Lilly, Neurimmune, Noselab, Novo Nordisk, Roche Diagnostics and Roche Pharma; honoraria from Anavex Life Sciences, Cogthera, Eisai, FEO, Grifols, Lilly, Pfizer, Roche Pharma, Schwabe and Synlab; TJO's institution has received consulting fees and honoraria from Eisai, UCB Pharma, ES Therapeutics, Kinoxis Pharmaceuticals, Supernus, Autobahn, Epidarex, Jazz Therapeutics, Kinoxis Therapeutics and NaviFUS; travel support from Longboard Pharmaceuticals and Bright Minds Pharmaceuticals; participated in a monitoring or advisory board for Kinoxis Pharmaceuticals and Bright Minds Biopharmaceuticals; MW has received consulting fees from Cerecin; honoraria from Eisai, Roche and Lilly; travel support from Merck and Roche; BJB has received consulting fees from Eisai; CS has received honoraria from Lilly and Roche; participated in advisory boards for Eisai and Lilly; SK received an honorarium from Roche; RL has received consulting fees from Eisai; CK received research funding, consulting fees and honoraria from Roche Diagnostics; NP has received consulting fees from Novartis, Aribio and Lilly; honoraria from Lilly; LF has received institutional research support from Roche; consulting fees from Anavex Life Sciences, Biogen, BioVie, Bristol Myers Squibb, Charles River Associates, Lilly, Eisai, GE Healthcare, Grifols, Johnson & Johnson, Neurimmune, Noselab, Novo Nordisk, Roche, TauRx and Schwabe; honoraria from Lilly, Eisai, DerCampus, Medscape, Medfora, FOMF, Novo Nordisk, Roche and Schwabe; participated in a monitoring or advisory board for Neuroscios, ReMynd, Otsuka/Avanir and Vivoryon; PT received honoraria from Ipsen Pharma and Merz Therapeutics; travel support from Boston Scientific, Medtronic, Ipsen and Merz; OP has received consulting fees from Biogen, Eisai, Grifols, Noselab, Novo Nordisk, Prinnovation and Roche; honoraria from Eisai, Lilly and Roche; AHB received institutional research support from Novo Nordisk, AriBio, Alnylam, Cerevel, IGC Pharma; consulting and advisory board fees from Eisai and Lilly; honoraria from Eisai and Lilly; SHP received institutional research support from and has patent authorship with Zywie Bio; honoraria from Lilly; HC has received research site support or fees from Roche, TauRx, Lilly, Anavex Life Sciences, Alector, Biogen, Eisai and Immunocal; participated in advisory boards for Lilly, Eisai and Biogen; GRH has received institutional research support from Biogen, Roche, Cassava and Eisai; has received consulting fees from Biogen, Roche, Novo Nordisk, Eisai and Lilly; CT has received institutional research support from Johnson & Johnson, UCB, Novo Nordisk, Bristol Myers Squibb, Passage Bio, Aribio and Anavex Life Sciences; received consulting fees from Eisai, Lilly and Novo Nordisk; SC has received institutional research support from Acumen, AgeneBio, Alector, Alnylam, Alzheon, Anavex Life Sciences, Biogen, Bristol Myers Squibb, Cassava, Eisai, Eli Lilly, GAP, GSK, INmune Bio, Johnson & Johnson, Merck, Novartis, Novo Nordisk, RetiSpec, Roche, UCB, Vielight and Voyager; consulting fees from AbbVie, Biogen, Biohaven, Bristol Myers Squibb, Eisai, Kisbee Therapeutics, Lilly, Novo Nordisk, Parexel and Retispec; travel support from Biogen, Eisai, Lilly and Novo Nordisk; participated in monitoring or advisory boards for Altoida, Biogen, Cassava, Cognivue, CogState, Eisai, GSK, Lilly, Johnson & Johnson, Medscape, Novo Nordisk, Novartis, Roche and Sci Neuro. OC and EG are QYNAPSE employees with ownership interest. LV and NG are QYNAPSE employees. JE, TK, JCL, KJ and WC are employees of Anavex Life Sciences with ownership interest. DG is a consultant of Anavex Life Sciences. WL is a consultant of Anavex Life Sciences; receives intermittent consulting fees from Novartis, Google Ventures, Structure Therapeutics and Enveda; is a member of the scientific advisory boards of Axonis Therapeutics, MuriPhys and AfaSci. CM is an employee of Anavex Life Sciences with ownership interest and patent authorship. AG is a member of the scientific advisory board of Anavex Life Sciences. Clinical Trial NCT03790709 Funding Statement This study was funded by Anavex Life Sciences Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: St. Vincent's Hospital Melbourne Human Research Ethics Committee gave ethical approval for this work Ethikkommission an der Technischen Universität München gave ethical approval for this work London Bridge Research Ethics Committee gave ethical approval for this work WCG IRB Canada gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors