Promising Results for Novel Sigma-1 Receptor Therapy as Alzheimer Treatment

Treatment with Anavex2-73 (blarcamesine; Anavex Life Sciences, New York, NY) for people with early Alzheimer disease (AD) was associated with slowed clinical progression in cognitive and functional outcomes. Anavex2-73 is a small-molecule activator of the sigma-1 receptor (SIGMAR1) that is orally available, designed to restore cellular homeostasis including autophagy enhancement to thereby provide neuroprotection. Results of the phase 2b/3 ANAVEX2-73-AD-004 (NCT04314934) clinical trial were presented at the 2024 meeting of the Alzheimer’s Association International Conference (AAIC).

The multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled 508 people with early AD from 52 medical research centers or hospitals across 5 countries from 2018 to 2021. Participants were randomized to receive either once-daily oral capsules of placebo (n=170) or Anavex2-73 (n=338) for a period of 48 weeks. Co-primary outcomes included change in Alzheimer Disease Assessment Scale cognitive subscale (ADAS-Cog) and Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL), with secondary outcomes including Clinical Dementia Rating sum of boxes (CDR-SB) and Clinical Global Impressions Scale of Improvement (CGI-I).

At 48 weeks, compared to those receiving placebo, participants receiving Anavex2-73 demonstrated improvements in all clinical endpoints as demonstrated by differences in least-squares mean (LSM) change:

• A LSM change difference in ADAS-Cog13 of -1.783 (95% CI, -3.314 to -.251; P=.0226)
• ADCS-ADL: 1.019 (95% CI, -.66 to 2.70; P=.234)
• CDR-SB: -.456 (95% CI, -.831 to -.080; P=.0175)
• CGI-I: -.285 (95% CI, -.474 to -.095; P=.0033)

A total of 56 participants (16.7%) who received Anavex2-73 and 17 participants (10.1%) who received placebo demonstrated ≥1 serious treatment-emergent adverse events (TEAEs). Mild-to-moderate dizziness was a common reported TEAE.