Anavex Life Sciences has released the findings from its recent Phase IIb/III clinical trial (ANAVEX2-73-AD-004), which evaluated the efficacy and safety of its oral Alzheimer’s disease medication, blarcamesine (ANAVEX 2-73). This study focused on patients in the early stages of Alzheimer’s disease (AD) and assessed the drug’s potential as a disease-modifying treatment. Blarcamesine is an orally available small molecule designed to activate the SIGMAR1 receptor, enhancing autophagy and restoring cellular homeostasis, which could address underlying mechanisms of Alzheimer’s disease.
Study Design and Participants
The trial was a randomized, double-blind, placebo-controlled study, involving 508 participants with early-stage Alzheimer’s disease (Stage 3). The trial was conducted across 52 medical centers in five countries over a 48-week period. Participants were randomized into three groups: a medium-dose blarcamesine group (30 mg), a high-dose group (50 mg), and a placebo group. Patients took one oral capsule daily. At the end of the trial, participants were invited to enroll in an open-label extension study (ATTENTION-AD), which is slated to conclude in June 2024 (ClinicalTrials.gov Identifier NCT04314934).
Primary and Secondary Outcomes
The primary outcomes of the study were changes in cognitive and functional performance, assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scales, measured from baseline to week 48. Secondary outcomes included the Clinical Dementia Rating-Sum of Boxes (CDR-SB), plasma Aβ42/40 ratio, and global brain volume changes evaluated via MRI.
Results from the trial revealed that blarcamesine significantly improved cognitive function and slowed the progression of Alzheimer’s disease in patients. For the ADAS-Cog13 score, blarcamesine showed a statistically significant difference in comparison to placebo, with a difference in the least-squares mean (LSM) change of -2.027 (95% CI -3.522 to -0.533; P=0.008). The CDR-SB score, a commonly used metric in Alzheimer’s drug submissions, also demonstrated statistically significant improvement, with an LSM difference of -0.483 (95% CI -0.853 to -0.114; P=0.010).
However, the ADCS-ADL score did not reach statistical significance by week 48, showing a difference of 0.775 (95% CI -0.874 to 2.423; P=0.357). Despite this, biomarkers, including the plasma Aβ42/40 ratio, increased significantly in the blarcamesine group compared to placebo (P=0.048), and global brain volume loss decreased (P=0.002), supporting the drug’s potential disease-modifying effects.
Safety and Adverse Events
In terms of safety, blarcamesine demonstrated a favorable profile. Among the participants, 16.7% of those treated with blarcamesine experienced serious treatment-emergent adverse events (TEAEs), compared to 10.1% in the placebo group.
Common side effects included dizziness, which was mostly mild to moderate and transient in nature. Importantly, no neuroimaging abnormalities were linked to the treatment.
Clinical Impact
Blarcamesine slowed clinical progression by 36.3% over 48 weeks when compared to placebo. This was seen in both the medium-dose (34.6%) and high-dose (38.5%) groups on the primary cognitive endpoint (ADAS-Cog13). Improvements in the CDR-SB score were also consistent with the primary endpoint findings, further validating the drug’s potential role in early Alzheimer’s disease management. These findings suggest that blarcamesine could offer an important new option in treating early Alzheimer’s disease, with potential benefits over or complementary to existing anti-beta amyloid therapies.
The study also performed a subgroup analysis focused on participants with a specific SIGMAR1 gene variant. This analysis confirmed that the beneficial effects of blarcamesine were closely linked to SIGMAR1 activation, underscoring the importance of targeting this receptor in early Alzheimer’s treatment.
Future Outlook
Anavex Life Sciences is actively continuing research to further understand the potential of blarcamesine as an oral Alzheimer’s disease medication. With the results from the ANAVEX2-73-AD-004 trial and the ongoing ATTENTION-AD open-label extension study, the company is committed to developing treatments that could offer novel mechanisms of action for addressing the cognitive decline associated with Alzheimer’s disease.
The results of this trial position Anavex Life Sciences at the forefront of the development of oral therapies for Alzheimer’s disease. Given the lack of approved oral, disease-modifying treatments for Alzheimer’s, blarcamesine represents a critical advancement in the search for effective therapies. As more data becomes available, this treatment could potentially play a pivotal role in slowing the progression of early-stage Alzheimer’s disease.
By targeting the SIGMAR1 receptor and influencing key biomarkers associated with disease progression, Anavex Life Sciences aims to bring an effective oral Alzheimer’s disease medication to the market that can significantly alter the course of the disease for patients in its early stages.