Axsome Therapeutics Reports Successful Phase III Clinical Trial Program Treating Alzheimer Disease Agitation

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Axsome Therapeutics announced the successful completion of a Phase III clinical program for its treatment AXS-05 (dextromethorphan-bupropion) in the treatment of Alzheimer disease (AD) agitation. According to the company, the ACCORD-2, ADVANCE-2, and ACCORD-1 studies demonstrated statistically significant efficacy with AXS-05, with plans to submit a New Drug Application (NDA) in the second half of the year after previously receiving Breakthrough Therapy designation.¹

"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. 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,” said Jeffrey Cummings, MD, ScD, vice chair, research, UNLV Department of Brain Health, in a press release.

The double-blind, placebo-controlled, randomized withdrawal ACCORD-2 trial of AXS-05 in AD patients with agitation consisted of an open-label treatment period with AXS-05, and a randomized, double-blind treatment period. The trial consisted of 295 patients who were treated with open-label AXS-05 for up to 12 months and assessed for efficacy. The primary endpoint of the study was to delay the time to relapse of agitation, assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score compared to placebo.

The double-blind, placebo-controlled, parallel group ADVANCE-2 trial of AXS-05 consisted of 408 patients, who were randomly assigned in a 1:1 ratio to treatment for five weeks.

Results from ACCORD-2 found that AXS-05 was associated with a mean reduction from baseline in the CMAI total score of 20.4 points at week six, representing a 46% decrease from the mean baseline score. Additionally, clinical response by week six was achieved by 69% of patients after treatment with AXS-05. Further, improvement in agitation was achieved by 78% of patients based on the clinician rated modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Lastly, the same improvements were achieved by 71% of patients at week four and 78% by week eight based on the caregiver rated Patient Global Impression of Change.

Results from the ADVANCE-2 trial did not demonstrate statistical significance for a change in CMAI total score from baseline to week five, with total reductions of 13.8 and 12.6 points for AXS-05 and placebo, respectively. However, results of the primary endpoint and almost all secondary endpoints numerically favored AXS-05 over the placebo group.

The rate of adverse events (AEs) of the ADVANCE-2 trial were 26.0% in the AXS-05 group and 21.6% in the placebo group. The most common AEs included dizziness and headache. In ACCORD-2, overall rates of AEs were 29.3% in the AXS-05 group and 32.1% in the placebo group, with no individual AEs occurring in more than 3.7% of subjects.¹

“We are very pleased with the successful completion of the planned Phase III 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 III, placebo-controlled trials, underscoring its potential to provide meaningful benefit to patients living with this condition and their families. 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,” said Herriot Tabuteau, MD, CEO, Axsome Therapeutics, in the press release.

Reference

Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS-05 in Alzheimer’s Disease Agitation. Axsome. December 30, 2024. Accessed January 6, 2025. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-successful-completion-and-results