Axsome’s AXS-05 Advances Alzheimer’s Agitation Treatment With Positive Phase 3 Results

Axsome Therapeutics, Inc., a biopharmaceutical company focused on developing innovative treatments for central nervous system (CNS) disorders, announced the successful completion of its Phase 3 clinical program for AXS-05 (dextromethorphan-bupropion). This investigational oral therapy combines NMDA receptor antagonism, sigma-1 receptor agonism, and CYP2D6 inhibition to address agitation in Alzheimer’s disease. The program included the ACCORD-2, ADVANCE-2, and long-term safety studies.

In the ACCORD-2 Phase 3 trial, AXS-05 met its primary goal by significantly delaying the relapse of agitation in Alzheimer’s patients compared to placebo. The results, assessed via the Cohen-Mansfield Agitation Inventory (CMAI) total score, showed a hazard ratio of 0.276 (p=0.001), indicating a 3.6-fold lower risk of relapse. AXS-05 also met its key secondary endpoint for relapse prevention (p=0.001). It demonstrated reduced worsening of overall Alzheimer’s disease severity, as measured by the Clinical Global Impression of Severity (CGI-S) scale (p<0.001).

Jeffrey Cummings, MD, ScD, Vice Chair of Research, UNLV Department of Brain Health, said in a statement, "Agitation is one of the most troubling and consequential aspects of Alzheimer’s disease, poses significant challenges to both the patient and their family, and represents a high unmet need. The robust, clinically meaningful efficacy results of the ACCORD-2 trial are consistent with the statistically significant results of the previously completed ADVANCE-1 and ACCORD-1 Phase 3 trials of AXS-05.”

He also commented, “The improvement in overall Alzheimer's disease severity with AXS-05 in the ACCORD-2 trial is noteworthy. Importantly, short and long-term treatment with AXS-05 was well tolerated and not associated with increased mortality, risk of falls, sedation, or cognitive decline. Taken together, results from this comprehensive Phase 3 program encompassing distinct clinical trial designs strongly support the potential for AXS-05 to become an important treatment for patients living with Alzheimer’s disease agitation."

The ADVANCE-2 Phase 3 trial, while not achieving statistical significance for the primary endpoint of CMAI score change from baseline to Week 5, showed numerical improvements favouring AXS-05 across primary and most secondary endpoints compared to placebo. AXS-05 was well tolerated in all studies, including long-term evaluations involving over 300 patients treated for six months or more and over 100 patients treated for at least 12 months. Importantly, the therapy was not linked to increased risks of falls, cognitive decline, or sedation. No deaths were reported among patients receiving AXS-05 across all trials.

To date, AXS-05 has demonstrated statistically significant efficacy in three pivotal Phase 3 trials (ADVANCE-1, ACCORD-1, and ACCORD-2), with supportive efficacy and safety results from a fourth trial (ADVANCE-2). Axsome plans to submit a New Drug Application (NDA) for AXS-05 for Alzheimer’s disease agitation to the FDA in the second half of 2025, supported by this robust dataset. The treatment has already received Breakthrough Therapy designation for this indication, underscoring its potential to address an urgent unmet medical need.

Herriot Tabuteau, MD, CEO of Axsome Therapeutics, said, “We are very pleased with the successful completion of the planned Phase 3 clinical trial program of AXS-05 in the treatment of Alzheimer’s disease agitation. With the strong results of the ACCORD-2 trial, AXS-05 has now demonstrated substantial and statistically significant improvements in Alzheimer’s disease agitation across three pivotal, Phase 3, placebo-controlled trials, underscoring its potential to provide meaningful benefit to patients living with this condition and their families. 

Mr Herriot Tabuteau also continued, saying, “The improvements in the AXS-05 arm relative to placebo in ADVANCE-2 did not reach statistical significance. However, we are pleased with the very positive controlled safety data from this trial, which will be an essential part of our planned NDA submission of AXS-05 in Alzheimer’s disease agitation, which is targeted for the second half of 2025.”