sNDA Submitted for AXS-05 for the Treatment of Alzheimer Disease Agitation

Axsome Therapeutics recently announced they have submitted a supplemental NDA (sNDA) to the US Food and Drug Administration (FDA) for dextromethorphan-bupropion (AXS-05) for the treatment of Alzheimer disease agitation.¹

“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,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome Therapeutics. “With robust commercial performance and pipeline execution, Axsome is well positioned to continue delivering substantial and sustained growth and transformative new medicines for patients living with serious CNS disorders.”

AXS-05 is Axsome’s novel, oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor being developed for the treatment of Alzheimer disease agitation and smoking cessation. AXS-05 was granted FDA Breakthrough Therapy designation for Alzheimer disease agitation back in 2020,the second Breakthrough Therapy designation granted to Axsome for AXS-05 (the first being for major depressive disorder).²

The Breakthrough Therapy designation for AXS-05 in Alzheimer disease agitation was supported by the positive results 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. In this trial, treatment with AXS-05 resulted in a rapid, substantial, and statistically significant improvement in agitation as compared with placebo. On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the Cohen Mansfield Agitation Inventory (CMAI) total score compared to placebo at week 5, with mean reductions of 15.4 points for AXS-05 and 11.5 points for placebo (P=0.010). AXS-05 was also superior to bupropion on the CMAI total score (P <0.001), establishing component contribution. AXS-05 was also well tolerated and not associated with cognitive impairment or sedation. 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

Axsome also intends to initiate a pivotal phase 2/3 trial of AXS-05 in smoking cessation in late 2025. According to research, AXS-05 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. Patients receiving AXS-05 had an average reduction of 8.49 cigarettes per day, compared with a 6.79 reduction for patients receiving bupropion. Additionally, patients receiving AXS-05 showed a more 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. November 3, 2025. Accessed November 4, 2025. https://ir.tevapharm.com/news-and-events/press-releases/press-release-details/2025/FDA-Approves-Expanded-Indication-for-UZEDY-risperidone-Extended-Release-Injectable-Suspension-as-a-Treatment-for-Adults-Living-with-Bipolar-I-Disorder/default.aspx

2. Axsome Therapeutics receives FDA breakthrough therapy designation for AXS-05 for the treatment of Alzheimer’s disease agitation. News release. June 26, 2020. Accessed November 4, 2025. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-receives-fda-breakthrough-therapy-0?field_nir_news_date_value%5Bmin%5D=

3. Axsome’s AXS-05 helps patients quit smoking significantly in phase II trial. News release. April 16, 2019. Accessed November 4, 2025. https://www.biospace.com/axsome-s-smoking-cessation-drug-positive-in-phase-ii-clinical-trial