Oral Blarcamesine Reduces Cognitive Decline in Phase 2b/3 Trial for Early Alzheimer Disease

Marwan Sabbagh, MD

(Credit: NeuroReserve)

Anavex Life Sciences has announced new 48-week results for its placebo-controlled, phase 2b/3 trial (NCT04314934) of blarcamesine, an investigational oral small molecule, reporting that treatment with the agent was associated with reduced cognitive decline in patients with early Alzheimer disease (AD). The company noted that it will continue to analyze the phase 2b/3 AD-004 study in early AD and the open-label extension data, which are planned for publication and presentation at future international AD conferences.¹

At 48 weeks, patients with defined SIGMAR1 wild type (WT)/COL24A1 WT with early AD who received 30-mg of blarcamesine once-daily showed minimal decline on standard cognitive measures, with changes comparable to those typically observed in prodromal aging.² Overall, investigators reported a mean change from baseline of 0.853 points on Alzheimer’s Disease Assessment Scale-Cognitive Subcale-13 (ADAS-Cog13) and of 0.465 points on the Clinical Dementia Rating – Sum of Boxes (CDR-SB), despite more advanced impairment at baseline.

"Given the strong interest in living a longer life without Alzheimer’s dementia, novel therapeutic directions are required. Blarcamesine’s mechanism of autophagy restoration via SIGMAR1 activation addresses a non-amyloid, upstream target, representing such a highly transformative clinical innovation,” Marwan Sabbagh, MD, behavioral neurologist at Barrow Neurological Institute and chairman of the scientific advisory board at Anavex, said in a statement.¹ “We are thrilled that today's findings show the superior effect of blarcamesine Precision Medicine population shifting the previous cognitive decline of Alzheimer’s disease to barely detectable decline resembling prodromal older cognitive decline.”

The Alzheimer’s Blarcamesine Cognition Efficacy and Resilience gene variants non-carrier population (SIGMAR1 WT/COL24A1 WT), defined as the Precision Medicine population, may represent up to approximately 70% of the global population, according to Anavex. In the latest data update, those in the placebo group had an ADAS-Cog13 least squares mean decline of 5.592 points, resulting in a mean difference of –4.739 (95% CI, –7.370 to –2.108; P = .0004) and representing an 84.7% relative reduction in decline favoring blarcamesine.

Mechanistic studies previously demonstrated that blarcamesine restores impaired autophagy through SIGMAR1 activation, acting upstream of amyloid and tau pathology. In vitro and in vivo experiments have shown enhanced autophagic flux in human cells and in C. elegans, increased proteostasis capacity, and mitigation of paralysis associated with protein aggregation in C. elegans. In the prespecified SIGMAR1 WT nonmutated subgroup, known as the ABCLEAR1, deeper clinical responses to blarcamesine were observed compared with the intent-to-treat population, potentially supporting clinical SIGMAR1 activation. The company noted that additional nonmutated subgroups with potentially enhanced responses may be identified through Genome-Wide Association Study analyses.

“Today’s data exemplify how precision medicine is transforming Alzheimer’s care – oral blarcamesine enables a shift from fit-for-all approaches to individualized, tailored therapy. We are finally moving toward measurable individualized benefit with a high confidence of the meaningful clinical effectiveness of blarcamesine at 30 mg dose level and a favorable safety profile,” Audrey Gabelle, MD, PhD, professor of neurology at Montpellier University and member of the scientific advisory board at Anavex, said in a statement.¹ “Ensuring equitable access to effective Alzheimer’s treatments is not just a scientific goal, but a societal responsibility. Blarcamesine combines scientific precision with a bold commitment to equity by offering easy-to-implement, safe, scalable and equitable access of care for people living with Alzheimer’s.”

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In the original trial of AD-004, published in the Journal of Prevention of Alzheimer's Disease, patients were randomly assigned 1:1:1 to either blarcamesine at 30-mg (n = 170) or 50-mg (n = 168) doses, or placebo (n = 170), for a 48-week period. Results showed that treatment with the investigational agent led to significant slowing of clinical decline by 38.5% in the 50-mg group and by 34.6% in the 30-mg group, relative to placebo, on ADAS-Cog13, the coprimary end point. The functional coprimary end point, change in Alzheimer's Disease Assessment Scale-Cognitive Subscale-Activities of Daily Living (ADAS-ADL) was trending positive but did not reach statistical significance at week 48.^3,4

Additional data from the double-blind portion showed that after 48 weeks, blarcamesine significantly reduced brain atrophy compared with placebo (P <.001), slowing atrophy by 37.6% in whole brain volume (P = .0019), 63.5% in total gray matter (P = .0035), and 25.1% in lateral ventricles (P = .0015), with no significant difference observed in total white matter (P = .8318). After 48 weeks of treatment, the CDR-SB, a key secondary end point, showed significant improvement with Mixed effect Model Repeat Measure (MMRM)-estimated deltas of –0.502 (P = .020) and –0.465 (P = .045) for the blarcamesine 30-mg and 50-mg groups, respectively.

“Our company’s goal is to provide potential high-quality options for patients with Alzheimer’s disease. Today’s new clinical efficacy data update from our Phase IIb/III trial is critical, as it adds contemporary context to Precision Medicine data showing strong protection from Alzheimer’s disease with an oral once daily potential solution with the aim to alleviate significant medical and economic burden,” Juan Carlos Lopez-Talavera, MD, PhD, head of research and development at Anavex, said in a statement.¹ “We’re excited by the meaningful improvements seen with blarcamesine, confirmed by results of patients identified and confirmed through Precision Medicine.”

“We believe these data reinforce the opportunity to potentially transform the treatment paradigm for individuals living with Alzheimer’s disease. In this Precision Medicine population blarcamesine’s once-daily oral administration may support broader implementation across diverse care settings, offering a patient-friendly and scalable option for early-stage Alzheimer’s disease,” Christopher U Missling, PhD, president and chief executive officer at Anavex, said in a statement.¹ “Blarcamesine’s combination of efficacy and safety may streamline treatment pathways in the complex Alzheimer’s ecosystem, paving the way for broader adoption and equitable access among patients.”

REFERENCES
1. Anavex Life Sciences Announces Oral Blarcamesine Cognitive Resilience Results Approximating Normal Aging in New Precision Medicine Clinical Data from Phase IIb/III Alzheimer’s Disease Trial. News Release. Anavex Life Sciences. Published September 9, 2025. Accessed September 9, 2025. https://www.anavex.com/post/anavex-life-sciences-announces-oral-blarcamesine-cognitive-resilience-results-approximating-normal-a
2. McDougall F, Edgar C, Mertes M, et al. Psychometric Properties of the Clinical Dementia Rating - Sum of Boxes and Other Cognitive and Functional Outcomes in a Prodromal Alzheimer's Disease Population. J Prev Alzheimers Dis. 2021;8(2):151-160. doi:10.14283/jpad.2020.73
3. Results from Anavex Life Sciences landmark phase 2b/3 trial of blarcamesine presented at Alzheimer’s Association Conference. News Release. Anavex Life Sciences. Published July 28, 2024. Accessed September 9, 2025. https://www.anavex.com/post/results-from-anavex-life-sciences-landmark-phase-iib-iii-trial-of-blarcamesine-presented-at-alzheime
4. Sabbagh MN, Chezem WR, Jin K, Missling CU. Blarcamesine in Early Alzheimer Disease Phase 2b/3 Randomized Clinical Trial. Alzheimers Dement. 2025;9(20):e090729. doi:10.1002/alz.090729