Anavex Life Sciences' blarcamesine, an orally bioavailable small molecule activator of the sigma-1 receptor (SIGMAR1), has demonstrated significant efficacy in slowing clinical progression in Alzheimer's disease (AD) patients without the SIGMAR1 rs1800866 gene variant. The findings, from a subgroup analysis of a Phase 2/3 trial, were presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference.
The randomized, double-blind, parallel-group trial involved 508 individuals with early-stage AD, who were randomly assigned to blarcamesine (30 mg or 50 mg) or placebo once daily for 48 weeks. The analysis focused on clinical efficacy endpoints based on pre-specified genetic SIGMAR1 variants (wild-type [WT] genotype and rs1800866 genotype [RS variant]).
Clinical Benefits in SIGMAR1 Wild-Type Patients
Participants with the SIGMAR1 WT gene exhibited greater clinical benefit compared to the full intent-to-treat population. Specifically, they showed a 49.8% reduction in decline on the Alzheimer's Disease Assessment Scale-cognitive subscale 13 (ADAS-Cog13) (difference of –2.317 points, 95% CI, –4.182 to –0.453, P = .015) and 33.7% less decline on the Clinical Dementia Rating-sum of boxes (CDR-SB) scale (difference of -0.601, 95% CI: -1.070 to -0.133, P = 0.012) compared to placebo. In contrast, those with the rs1800866 variant did not show statistically significant differences.
Impact on Brain Atrophy and Biomarkers
After 48 weeks, blarcamesine-treated participants showed significantly reduced brain atrophy compared to those on placebo (P < .001). 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).
In plasma biomarkers, the blarcamesine group exhibited significant increases in the amyloid-β (Aβ)42/40 ratio compared to placebo (difference of +0.013, P = .048). Furthermore, blarcamesine-treated patients demonstrated significantly less change in neurofilament light (NfL) and plasma phosphorylated tau (p-tau181 and p-tau213) levels over 48 weeks compared to placebo.
Mechanism of Action and Regulatory Plans
"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," said Juan Carlos Lopez-Talavera, MD, PhD, head of research and development at Anavex. He added that the company is on track for regulatory submission of blarcamesine in Europe (EMA) in the current quarter of 2024.
The most common treatment-emergent adverse events (TEAEs) were dizziness, confusional state, balance disorder, and fatigue, primarily occurring within the first 24 weeks of treatment.
