SIGMAR1 Activating Agent Blarcamesine Meets Pre-Specified Efficacy in Phase 2/3 Trial of Alzheimer Disease

Marwan Sabbagh, MD

A subgroup analysis of a phase 2/3 trial assessing Anavex’s blarcamesine further confirmed the therapy’s mechanism of action as an orally bioavailable small molecule activator of the sigma-1 receptor (SIGMAR1). Overall, treatment with blarcamesine resulted in slowed clinical progression over a 48-week period in patients with Alzheimer disease (AD) without the SIGMAR1 rs1800866 gene variant, suggesting greater benefit in these individuals and further supporting SIGMAR1 activation as a key mechanism of action.¹

Also known as AD-004, the randomized, double-blind, parallel-group trial comprised of 508 individuals with a confirmed diagnosis of early-stage AD who were randomly assigned to prespecified blarcamesine (n = 338) in medium (30 mg) or high (50 mg) dose groups or placebo (n = 170) once daily for 48 weeks. The analysis, which aimed to confirm blarcamesine-specific mechanism of action, had clinical efficacy end points analyzed based on prespecified genetic SIGMAR1 variants (wild-type [WT] genotype and rs1800866 genotype [RS variant]) for all participants.

The findings were presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain, by Marwan Sabbagh, MD, a professor of neurology at Barrow Neurological Institute. In the study, Sabbagh and colleagues performed a pre-specified genetic variant analysis for the primary end point of change in Alzheimer’s Disease Assessment Scale-cognitive subscale 13 (ADAS-Cog13) and key secondary end point of Clinical Dementia Rating-sum of boxes (CDR-SB).

Results showed that participants with the SIGMAR1 WT gene demonstrated greater clinical benefit for both ADAS-Cog13 (slowed clinical progression by 49.3% vs 36.3%) and CDR-SB (slowed clinical progression by 33.7% vs 27.6%) compared with the full intent-to-treat population. This group, which includes those without mutated SIGMAR1 rs1800866 variant, demonstrated the consistency of SIGMAR1 activation with blarcamesine.

In SIGMAR1 WT participants, blarcamesine slowed clinical decline significantly compared with placebo. On the ADAS-Cog13, WT participants in the blarcamesine group showed a difference of –2.317 points (95% CI, –4.182 to –0.453) compared with placebo, reflecting a 49.8% reduction in decline at 48 weeks (P = .015). For those with the rs1800866 variant, the difference from placebo was –1.593 (95% CI, –4.174 to 0.989), which was not statistically significant (P = .2254). On the CDR-SB scale, WT participants in the blarcamesine group had 33.7% less decline than placebo (difference of -0.601, 95% CI: -1.070 to -0.133, P = 0.012), whereas those with the variant showed a smaller, non-significant difference of -0.230 (95% CI: -0.826 to 0.367, P = 0.4485).

"These data are very exciting, particularly featuring blarcamesine’s novel upstream mechanism of action, enhancing autophagy through SIGMAR1 activation, a key clearance mechanism that removes protein aggregates and misfolded proteins across the Alzheimer disease continuum,” Juan Carlos Lopez-Talavera, MD, PhD, head of research and development at Anavex, said in a statement.¹ "The advantage of blarcamesine is that it is a small oral molecule that exerts clinical benefits on cognition and neurodegeneration and could be appealing because of its route of administration and good comparative safety profile. We are on track for regulatory submission of blarcamesine in Europe (EMA) in the current quarter 2024."

Earlier this year, at the 2024 Alzheimer’s Association International Conference, Anavex shared additional data from the phase 2b/3 study, demonstrating the safety and efficacy of blarcamesine. In terms of safety, treatment-emergent adverse events (TEAEs) tended to occur within the first 24 weeks after starting treatment and were primarily related to titration schedule. Across both dosed groups, the most common treatment titration AEs were dizziness, confusional state, balance disorder, and fatigue, among others.³

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After 48 weeks, participants on blarcamesine showed significantly reduced brain atrophy compared with those on placebo (P <.001). Specifically, the treatment slowed brain 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), while no significant difference was observed in total while matter (P = .8318).

In plasma biomarkers, pooled blarcamesine groups exhibited significant increases in amyloid-ß (Aß)42/40 ratio compared to placebo, with a difference of +0.013 (P = .048). Additionally, while placebo patients showed increases in neurofilament light (NfL) and plasma phosphorylated tau (p-tau181 and p-tau213), blarcamesine-treated patients demonstrated significantly less change over 48 weeks, with P values of 0.28 for NfL, 0.39 for p-tau181, and 0.44 for p-tau213.

"Alzheimer disease is such a devastating disease that affects tens of millions worldwide. We believe, the clinically meaningful study results provide the potential for patients and their families to have a better and longer quality of life," Christopher U. Missling, PhD, president and chief executive officer at Anavex, said in a statement.¹ "We believe the scalable and convenient features of blarcamesine could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer disease and provide broader access to a diverse population with early Alzheimer disease."

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REFERENCES
1. Anavex’s Blarcamesine Achieves Pre-specified Efficacy in Phase IIb/III Alzheimer’s Trial: Data Presented at CTAD Conference 2024. News release. Anavex Life Sciences. October 31, 2024. Accessed November 1, 2024. https://finance.yahoo.com/news/anavex-blarcamesine-achieves-pre-specified-080000308.html
2. Sabbagh M, Lopez-Talavera JC, Jin K, Chezem W, Christopher M. Phase 2b/3 trial of blarcamesine in early Alzheimer disease demonstrates pre-specified clinical efficacy through upstream SIGMAR1 activation. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) conference; October 29-November 1, 2024; ABSTRACT LB09.
3. Sabbagh MN. Blarcamesine in early Alzheimer’s disease: phase 2b/3 randomized clinical trial. Anavex Life Sciences. July 28, 2024. Accessed November 1, 2024. https://www.anavex.com/_files/ugd/79bcf7_79c4b8754b9f4eaca6da3e912e11689b.pdf