Oral Blarcamesine Shows Marked Reduction in Cognitive Decline in Early Alzheimer Disease: Phase 2b/3 Data

Oral blarcamesine, a small-molecule SIGMAR1 activator, significantly reduced cognitive decline in adults with early Alzheimer disease (AD) over 48 weeks of treatment, according to new phase IIb/III trial results reported by Anavex Life Sciences.¹

_{Image courtesy of Anavex Life Sciences}

In a genetically defined “Precision Medicine” population, ie, individuals with SIGMAR1 WT/COL24A1 WT gene variants, a group representing approximately 70% of the early AD population, once-daily 30 mg oral blarcamesine led to cognitive outcomes closely resembling normal aging, with an 84.7% reduction in decline on the primary endpoint, the ADAS-Cog13 score, compared to placebo.¹

The findings suggest the potential for a shift in the AD treatment paradigm, emphasizing individualized, mechanism-based therapy that moves beyond amyloid-centric "fit-for-all" approaches, the company said in a statement.¹

Key Clinical & Mechanistic Findings

After 48 weeks of treatment, the Precision Medicine cohort exhibited a mean ADAS-Cog13 change from baseline of 0.853, comparable to the minimal annual decline typical in prodromal aging adults. Functional decline assessed by Clinical Dementia Rating—Sum of Boxes (CDR-SB) likewise showed a change from baseline of 0.465, aligning with the 0–0.5 point annual range observed in prodromal older adults. The similarity to referenced barely detectable prodromal decline is notable, Anavex noted in its statement, given "the more advanced stage of AD impairment at baseline of the blarcamesine population."¹

In contrast, the respective placebo group experienced an ADAS-Cog13 least squares mean decline of 5.592 points, yielding a mean difference of –4.739 (95% CI –7.37 to –2.11; P =.0004), representing the 84.7% relative reduction favoring blarcamesine.¹

Earlier mechanistic studies confirmed that blarcamesine restores impaired autophagy through SIGMAR1 activation, acting upstream of amyloid and tau pathology, with both in vitro and in vivo models demonstrating enhanced autophagic activity and improved proteostasis.^2,3 The prespecified SIGMAR1 non-mutated population (ABCLEAR1) in these studies achieved deeper clinical responses to blarcamesine than the intent-to-treat population.^2,3 This supports the rationale for future GWAS analyses to identify additional genetic profiles responsive to targeted therapy, Anavex stated.

Original AD-004 Trial

Findings from the original trial of AD-004 highlighted functional endpoints and neuroanatomic outcomes with blarcamesine. Treatment with the study drug in the double-blind portion led to significant slowing of clinical decline by 34.6% in the 30-mg group and by 38.5% in the 50-mg group, compared to placebo, as measured by ADAS-Cog13. On the functional coprimary endpoint, changes in Alzheimer's Disease Assessment Scale-Cognitive Subscale-Activities of Daily Living (ADAS-ADL), results trended positive but did not reach statistical significance at week 48.^4,5

Brain MRI revealed that blarcamesine slowed whole brain atrophy by 37.6% (P = .002), gray matter atrophy by 63.5% (P =.004), and ventricular enlargement by 25.1% (P =.002), with no significant change seen in white matter volume.^4,5

Precision Medicine is the Future

"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" treatment that aims to alleviate the "significant medical and economic burden” of the disease, Juan Carlos Lopez-Talavera, MD, PhD, head of research and development at Anavex, said in a statement.¹

“We believe these data reinforce the opportunity to potentially transform the treatment paradigm for individuals living with Alzheimer’s disease, Anavex CEO Christopher U Missling, PhD, added. "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."¹

Anavex will continue to evaluate the phase IIb/III early AD data and as well as data from the ATTENTION-AD open label extension study of blarcamesine; findings will be published in peer-reviewed journals and presented at future international AD conferences, the company said.

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.

2. Christ MG, Huesmann H, Nagel H, Kern A, Behl C. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3):211. doi:3390/cells8030211

3. Baeken MW, Christ M, Schmitt D, et al. Conserved LIR-specific interaction of sigma-1 receptor and GABARAP. iScience. 2025;28(9):113287. doi.org/10.1016/j.isci.2025.113287

4. 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 11, 2025. https://www.anavex.com/post/results-from-anavex-life-sciences-landmark-phase-iib-iii-trial-of-blarcamesine-presented-at-alzheime

5. MacFarlane S, Grimmer T, Teo K, et al. Blarcamesine for the treatment of early Alzheimer's disease: Results from the ANAVEX2-73-AD-004 phase IIB/III trial. J Prev Alzheimers Dis. 2025;12(1):100016. doi:10.1016/j.tjpad.2024.100016