Axsome Therapeutics, Inc. (NASDAQ:AXSM), a biopharmaceutical company developing and delivering novel therapies for the management of central nervous system (CNS) disorders, today announced the successful completion of its Phase 3 clinical program evaluating AXS-05 (dextromethorphan-bupropion), a novel, oral, investigational NMDA receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor, in Alzheimer's disease agitation, and results of the ACCORD-2, ADVANCE-2, and long-term safety trials in this indication.
The ACCORD-2 Phase 3 trial achieved the primary endpoint with AXS-05 statistically significantly delaying the time to relapse of agitation, assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score, in patients with Alzheimer's disease compared to placebo (hazard ratio for time to relapse of 0.276, p=0.001), demonstrating a 3.6-fold lower risk of relapse compared to placebo. AXS-05 also met the key secondary endpoint (relapse prevention, p=0.001). Further, AXS-05 reduced worsening for overall Alzheimer's disease severity compared to placebo, as assessed by the Clinical Global Impression of Severity (CGI-S) for Alzheimer's disease (p<0.001).
The ADVANCE-2 Phase 3 trial did not demonstrate statistical significance for the primary endpoint, change in the CMAI total score from baseline to Week 5 (CMAI reductions of 13.8 and 12.6 points for AXS-05 and placebo, respectively). However, results for the primary and nearly all secondary endpoints numerically favored AXS-05 over placebo.
AXS-05 was safe and well tolerated in both controlled studies. The long-term safety and tolerability of AXS-05 was also evaluated in more than 300 subjects treated for at least 6 months and more than 100 subjects treated for at least 12 months. In the controlled and long-term studies in subjects with Alzheimer's disease, AXS-05 was not associated with increased risk of falls, cognitive decline, or sedation. In the clinical program for AXS-05 in Alzheimer's disease agitation, there have been no deaths in subjects receiving AXS-05.
AXS-05 has now demonstrated statistically significant efficacy compared to placebo in three completed pivotal Phase 3 trials (ADVANCE-1, ACCORD-1 and ACCORD-2), with supportive efficacy and controlled safety results in a fourth trial (ADVANCE-2). Axsome plans to submit an NDA for AXS-05 in Alzheimer's disease agitation to the FDA in the second half of 2025, based on the efficacy and safety data from the above controlled and long-term studies. AXS-05 has been granted Breakthrough Therapy designation for the treatment of Alzheimer's disease agitation.
