Axsome Submits sNDA for AXS-05 to Treat Agitation in Alzheimer Disease

Axsome Therapeutics has submitteed a supplemental NDA (sNDA) to the US Food and Drug Administration (FDA) for its investigational combination of dextromethorphan-bupropion (AXS-05) for the treatment of Alzheimer disease agitation, according to a third quarter financial and business update.1

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“Our broad development pipeline continues to advance, and we recently submitted our supplemental NDA for AXS-05 for the treatment of Alzheimer disease agitation, a serious condition affecting millions of patients in the US, and a critical unmet medical need,” Herriot Tabuteau, MD, Axsome Therapeutics CEO said in the statement. “With robust commercial performance and pipeline execution, Axsome is well positioned to continue delivering...transformative new medicines for patients living with serious CNS disorders.”1

AXS-05 is a novel, oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor in development for Alzheimer agitation and for smoking cessation. AXS-05 was granted FDA Breakthrough Therapy designation for Alzheimer disease agitation in 2020,2 the second Breakthrough Therapy designation for the agent, with the first being for major depressive disorder.2

The desingation in 2020 for AXS-05 in Alzheimer disease agitation was based on the agency's review of posititve findings from the pivotal phase 2/3 ADVANCE-1 study, a randomized, double-blind, controlled, multicenter US trial. Investigators treated 366 participants with Alzheimer disease with AXS-05, bupropion, or placebo. Participapnts treated with the investigational combination experienced a rapid, substantial, and statistically significant improvement in agitation vs those treated with placebo.2

AXS-05 demonstrated a statistically significant mean reduction from baseline in the Cohen Mansfield Agitation Inventory (CMAI) total score, the primary study endpoint, compared to placebo at week 5, with mean reductions of 15.4 points for AXS-05 and 11.5 points for placebo (P =.010). AXS-05 was also superior to bupropion on the CMAI total score (P <.001), establishing component contribution.2

The tolerability profile was favorable with no instances of cognitive impairment or sedation reported. The most commonly reported adverse events in the AXS-05 arm were somnolence (8.2% for AXS-05 vs 4.1% for bupropion and 3.2% for placebo), dizziness (6.3%, 10.2%, 3.2%, respectively), and diarrhea (4.4%, 6.1%, 4.4%, respectively).2

Smoking Cessation Trials to Advance

In other developments reported in the update, Axsome said it intends to initiate a pivotal phase 2/3 trial of AXS-05 in smoking cessation in late 2025. In earlier studies, the novel medication significantly reduced daily smoking when compared with bupropion, with a 25% greater decrease in the average number of cigarettes smoked each day over a 3-week period.3 Patients receiving AXS-05 reduced smoking behavior by an average of 8.49 cigarettes per day, compared with a 6.79 reduction for participants receiving bupropion. Study drug recipients also showed a greater than 50% reduction in expired carbon monoxide levels, a biochemical marker of smoking intensity, compared with a 30.4% reduction for patients receiving bupropion.3

References

1. Axsome Therapeutics reports third quarter 2025 financial results and provides business update. News release. Axsome Therapeutics. November 3, 2025. Accessed November 7, 2025. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-reports-third-quarter-2025-financial-results
2. Axsome Therapeutics receives FDA breakthrough therapy designation for AXS-05 for the treatment of Alzheimer’s disease agitation. News release. Axsome Therapeutics. June 26, 2020. Accessed November 4, 2025. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-receives-fda-breakthrough-therapy-0
3. Axsome’s AXS-05 helps patients quit smoking significantly in phase II trial. News release. Axsome Therapeutics. April 16, 2019. Accessed November 7, 2025. https://www.biospace.com/axsome-s-smoking-cessation-drug-positive-in-phase-ii-clinical-trial