Axsome Completes Phase 3 Clinical Program with AXS-05 in Alzheimer Disease Agitation

Jeffrey L Cummings, MD, ScD

Courtesy UNLV

Axsome Therapeutics announced the completion of the company’s phase 3 clinical trial program of AXS-05, the investigational oral dextromethorphan-bupropion combination being evaluated to treat agitation in Alzheimer disease.

Based on the sum of successful data on the efficacy and safety of AXS-05, Axsome plans to submit a New Drug Application to the FDA in the second half of 2025, according to a news release. The agency granted AXS-05 Breakthrough Therapy status in June 2020.

The clinical development program of AXS-05 in Alzheimer agitation includes 4 completed pivotal phase 3, placebo controlled clinical trials (ACCORD-1, ACCORD-2 and ADVANCE-1 and ADVANCE-2) and long-term safety trials in the indication. Findings from the ACCORD-2 and ADVANCE-2 trials, announced in the news release, concluded program.

In the ACCORD-2 trial, AXS-05 was associated with a 3.6-fold lower risk of relapse of agitation in adults with Alzheimer disease vs placebo, a statistically significant delay (HR, 0.276, P =.001) assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score, satisfying the trial’s primary endpoint, according Axsome. AXS-05 also met the key secondary endpoint (relapse prevention, P =.001) and reduced worsening of overall Alzheimer severity vs placebo, the latter as assessed by the Clinical Global Impression of Severity (CGI-S) for Alzheimer disease (P <.001)

The reduction in in CMAI total score from baseline to week 5 (primary endpoint) did not reach statistical significance in the ADVANCE-2 trial (13.8 points for AXS-05, 12.6 points for placebo), the company said. Results for the primary and nearly all secondary endpoints in the study, however, numerically favored AXS-05 over placebo. AXS-05 safety and tolerability profiles were favorable in both studies.

The medication’s long-term safety and tolerability were evaluated in more than 300 adults with Alzheimer agitation treated with AXS-05 for at least 6 months and 100 adults for at least 12 months, according to the Axsome statement. Across the completed phase 3 controlled and long-term studies, investigators reported no increased risk of falls, cognitive decline, or sedation among participants receiving AXS-05 nor have there been any deaths among any participants treated with the investigational drug.

ADVANCE-1 – achieved primary endpoint (P =.010)

ADVANCE-2 – primary endpoint not statistically significant

ACCORD-1 – achieved primary endpoint (P =.014)

ACCORD-2 – achieved primary endpoint (P =.001)

"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,” Jeffrey Cummings, MD, ScD, Vice chair of research, University of Nevada Las Vegas Department of Brain Health, said in the news release. The collective evidence from the program “strongly support the potential for AXS-05 to become an important treatment for patients living with Alzheimer’s disease agitation."

Acknowledging the shortfall in the ADVANCE-2 pivotal trial, Axsome CEO Herriot Tabuteau, MD, added that overall “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.”

Source: Axsome Therapeutics announces successful completion and results of phase 3 clinical program of AXS-05 in Alzheimer's disease agitation. News release. Axsome Therapeutics. December 30, 2024. Accessed January 2, 2025. https://axsometherapeuticsinc.gcs-web.com/node/11741/pdf