Positive Phase 2b/3 Open-Label Extension Trial Results: Blarcamesine for Treatment of Early Alzheimer Disease

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CONFERENCE REPORTER

Anavex Life Sciences shared promising results from a phase 2b/3 open-label extension trial of extended oral blarcamesine for the treatment of early Alzheimer disease (AD) at the 2025 Alzheimer's Association International Conference (AAIC) in Toronto.Blarcamesine demonstrated significant cognitive (ADAS-Cog13: -5.43, P=0.0035) and functional (ADCS-ADL: +9.50, P<0.0001) improvements in patients with early AD.¹

The ATTENTION-AD open-label extension phase 2b/3 treatment trial followed the 48-week ANAVEX®2-73-AD-004 double-blind clinical trial, for a total of up to 192 weeks. Investigators designed the trial to evaluate the safety and tolerability of blarcamesine as well as its long-term effects on cognition (ADAS-Cog13) and function (ADCS-ADL) in participants with early AD.

Participants treated with blarcamesine accrue benefits through up to 4 years, as measured by the prespecified clinical endpoints ADAS-Cog13 and ADCS-ADL, respectively. In the intent-to-treat (ITT) population, delayed-start analysis of treatment with oral blarcamesine was significant for both cognition and function. For ADAS-Cog13, investigators observed a significant difference between the early-start and late-start treatment groups at week 192 (LS mean difference −3.83, P = 0.0165). For ADCS-ADL, statistical significance (LS mean difference +4.30, P = 0.0206) was reached at week 192, also favoring the early-start group.

The data were presented by Marwan Noel Sabbagh, MD, professor of Neurology and Chairman of the Anavex Scientific Advisory Board.

“This Precision Medicine data provide potentially continued persuasive evidence that earlier initiation of treatment with blarcamesine may have a significant positive impact on disease progression and may provide sustained clinically meaningful benefits to patients with early Alzheimer disease over the long-term,” said Sabbagh. “Prespecified delayed-start analysis indicate disease-modifying effect of oral blarcamesine and highlight the importance of early and continued long-term treatment of chronic Alzheimer disease. These enhanced clinically meaningful improvements are accompanied by blarcamesine’s favorable safety profile. This could help reduce crucial barriers within the currently complex health care ecosystem for Alzheimer disease and potentially provide broader access to a diverse population with early Alzheimer disease.”

‘Time saved’ is an important marker of patient quality of life, referring to the estimated amount of time the treatment delays the progression of the disease and patients can maintain their independence longer.^2,3 The trial demonstrated up to 84.6 weeks (19.5 months) of 'time saved' in disease progression for patients who started treatment early.

Blarcamesine’s mechanism of action restores impaired autophagy through SIGMAR1 activation, which acts upstream of amyloid-beta and tau pathologies at the molecular level. This mechanism was confirmed both in vitro and in vivo,⁴ showing increased proteostasis capacity and improved cognitive outcomes.

A clinical Precision Medicine approach confirmed that the prespecified SIGMAR1 nonmutated population, termed ABCLEAR1, which represents approximately 70% of the global population, achieved deeper clinical responses to blarcamesine than the respective ITT population. Specifically, blarcamesine demonstrated greater cognition improvements, ADAS-Cog13 (LS mean difference −5.43, P = 0.0035), and function improvements, ADCS-ADL (LS mean difference +9.50, P < 0.0001). This also confirms clinical activation of SIGMAR1 through blarcamesine. Additional nonmutated populations with potentially enhanced responses could also be identified through GWAS analyses. Data confirmed that within a heterogeneous AD population by targeting a prevalent genetic profile through Precision Medicine approach, the efficacy of blarcamesine may be further improved.

“We remain excited about these enhanced clinically meaningful improvements which were further confirmed by the observed efficacy treatment effects from the two blarcamesine clinical trials with identified Precision Medicine patient populations,” said Juan Carlos Lopez-Talavera, MD, PhD, head of research and development of Anavex. “Convenient once-daily oral dosing of blarcamesine may allow us to offer a scalable and patient friendly oral pill administration option to patients with early Alzheimer’s.”

A further significant improvement was also observed in the prespecified analysis of SIGMAR1 wild type carriers, ABCLEAR1 population. Compared with the ITT population, the ABCLEAR1 population demonstrated additional and consistent improvement vs placebo. ADAS-Cog13 and CDR-SB for the total blarcamesine group improved by 49.8% and 33.6%, respectively and for the 30 mg blarcamesine group by 49.1% and 35.5%, respectively.

The trial also reported a favorable safety profile for blarcamesine with no treatment-related deaths. Serious treatment emergent adverse events occurred in 10 participants (12.7%) receiving blarcamesine and in 6 participants (9.1%) receiving placebo. Common adverse effects included dizziness, which was typically mild to moderate and transient. These results underscore the potential of blarcamesine to offer a long-term therapeutic benefit for early AD through a convenient once-daily oral dosing regimen.

“We are motivated by the Anavex team’s continued contributions to advancing science across this devastating chronic disease at the Alzheimer’s Association International Conference 2025. Alzheimer disease, like other chronic progressive diseases, requires a long-term therapeutic strategy. Blarcamesine’s Precision Medicine mechanism of action with its convenient once daily oral dosing may lead to greater clinical benefit,” said Christopher U. Missling, PhD, president and chief executive officer of Anavex. “Additionally, the comprehensive data from the blarcamesine Alzheimer disease program represents a solid foundation for continuous engagement with the Alzheimer disease community.”

Further research through GWAS could improve the drug’s efficacy by identifying populations with enhanced clinical responses.

References

1. Anavex Life Sciences announces positive Precision Medicine results from up to 4-years of oral blarcamesine treatment in phase IIb/III open-label extension trial in early Alzheimer’s disease. News release. July 31, 2025. Accessed July 31, 2025. https://www.anavex.com/post/anavex-life-sciences-announces-positive-precision-medicine-results-from-up-to-4-years-of-oral-blarca

2. Petersen RC, Aisen PS, Andrews JS, et al. Expectations and clinical meaningfulness of randomized controlled trials. Alzheimers Dement. 2023;19(6):2730-2736.

3. Dickson SP, Haaland B, Mallinckrodt CH, et al. "Time saved" calculations to improve decision-making in progressive disease studies. J Prev Alzheimers Dis. 2024;11(3):529-536.

4. Christ MG, Huesmann H, Nagel H, et al. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3):211.