Anavex Life Sciences continues to make strides in the development of innovative therapeutics for neurodegenerative diseases, with their lead candidate, ANAVEX®2-73 (blarcamesine), demonstrating significant potential for the treatment of early-stage Alzheimer’s disease (AD). Recent results from the Phase IIb/III ANAVEX2-73-AD-004 clinical trial highlight the efficacy and safety of blarcamesine, an orally administered small-molecule drug. This trial marks a key step in Anavex’s journey toward developing a novel therapeutic option for Alzheimer’s, a disease that still lacks any approved oral disease-modifying treatments.

ANAVEX2-73-AD-004 Trial

The ANAVEX2-73-AD-004 study was a 48-week, randomized, double-blind, placebo-controlled trial conducted across 52 medical research centers in five countries. It involved 508 participants, all diagnosed with early-stage Alzheimer’s disease (Stage 3). The trial aimed to assess the efficacy and safety of blarcamesine in comparison to a placebo. Participants were divided into three groups: those receiving 30 mg or 50 mg of blarcamesine and those receiving a placebo. At the conclusion of the trial, participants were offered enrollment in an open-label extension study, ATTENTION-AD, which is anticipated to provide additional long-term safety data​.

Key Findings: Cognitive and Functional Improvements

The co-primary endpoints of the trial were improvements in cognitive and functional outcomes, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB). At 48 weeks, the blarcamesine group demonstrated significant improvements in both cognitive and functional domains compared to the placebo group.

Specifically, the least-squares mean change in ADAS-Cog13 scores showed a statistically significant improvement of -2.027 (P=0.008) in participants receiving blarcamesine, representing a 36.3% reduction in the rate of cognitive decline compared to the placebo group. Similarly, the CDR-SB score, which assesses functional abilities, showed a significant improvement of -0.483 (P=0.010), with participants receiving blarcamesine demonstrating a slower functional decline by 34.6% to 38.5% depending on the dosage​.

However, the study’s other co-primary endpoint, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), did not reach statistical significance, although the blarcamesine group still outperformed the placebo group.

Biomarker Insights: Reduced Brain Atrophy and Improved Aβ42/40 Ratio

Beyond cognitive and functional improvements, the study also measured key Alzheimer’s biomarkers to further evaluate the drug’s potential. Participants who received blarcamesine showed a significant increase in the plasma Aβ42/40 ratio (P=0.048), an important biomarker in Alzheimer’s research, as well as a reduction in whole-brain atrophy (P=0.002), suggesting that the drug may have a disease-modifying effect by slowing the physical degeneration of the brain​​.

These findings underscore the potential of blarcamesine as a treatment that not only addresses the symptoms of Alzheimer’s but also targets the underlying biological mechanisms of the disease.

Safety Profile of Blarcamesine

The safety of blarcamesine was thoroughly evaluated throughout the trial. Serious treatment-emergent adverse events (TEAEs) occurred in 16.7% of participants in the blarcamesine group compared to 10.1% in the placebo group. The most commonly reported side effect was dizziness, which was generally transient and mild to moderate in severity. Importantly, no neuroimaging abnormalities were associated with the treatment, reinforcing the drug’s favorable safety profile​.

Mechanism of Action: Targeting SIGMAR1

ANAVEX®2-73 (blarcamesine) functions through the activation of SIGMAR1, a receptor known to play a crucial role in cellular homeostasis and neuroprotection. By restoring the balance of key cellular processes, including autophagy and mitochondrial function, blarcamesine holds the potential to not only slow down the progression of Alzheimer’s disease but also possibly reverse some of its effects. An additional analysis of patients with a specific SIGMAR1 gene variant confirmed a stronger clinical response, highlighting the receptor’s importance in the drug’s efficacy​.

A New Hope for Alzheimer’s Treatment?

With Alzheimer’s disease affecting millions of people worldwide and no approved oral disease-modifying treatments currently available, the results from Anavex Life Sciences’ ANAVEX2-73-AD-004 trial offer hope for the future. Blarcamesine’s demonstrated efficacy in slowing cognitive decline, improving functional outcomes, and reducing brain atrophy positions it as a candidate for addressing the unmet medical need in early-stage Alzheimer’s disease.

As Anavex Life Sciences continues its work, including further clinical trials and long-term studies like ATTENTION-AD, blarcamesine could soon become a pivotal part of Alzheimer’s treatment strategies, complementing or even offering an alternative to existing anti-beta amyloid therapies.