FDA Accepts, Grants Priority Review to AXS-05 sNDA for Alzheimer’s Disease Agitation

Announced by Axsome Therapeutics, Inc., on December 31, 2025, the US Food and Drug Administration (FDA) has accepted – and granted Priority Review to – the supplemental New Drug Application (sNDA) for AXS-05 for the treatment of agitation in Alzheimer’s disease.1

“Up to 76% of people with Alzheimer’s disease experience agitation, representing a significant unmet medical need for patients and their caregivers, and currently there is a dearth of approved treatments,” Herriot Tabuteau, MD, chief executive officer of Axsome Therapeutics, said in a statement. “We look forward to continuing to work with the FDA for the remainder of the review.”1

AXS-05 is a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor under development for Alzheimer’s disease and smoking cessation. The medication utilizes a proprietary dextromethorphan and bupropion formulation and dose, along with Axsome’s metabolic inhibition technology, to modulate component delivery. It has already received FDA approval for major depressive disorder in adults.1

The sNDA was submitted following positive results from a series of phase 3 clinical trials, including ACCORD/ACCORD-2 and ADVANCE-2. ACCORD was a double-blind, multi-center, randomized-controlled trial consisting of a 9-week open-label period followed by a 26-week double-blind period. A total of 178 participants with a mean Cohen Mansfield Agitation Inventory (CMAI) baseline total score of 70.9 were enrolled in the open-label phase and were treated with AXS-05. During this phase, AXS-05 treatment was associated with improvements from baseline in CMAI scores at all timepoints from Week 1 (6.7 points; P <.001) to Week 5 (20.6 points; P <.001).2

A total of 108 responders, defined as those with ≥30% improvement from baseline in CMAI total score and with Patient Global Impression of Change (PGI-C) score improvements ≤3 lasting ≥4 consecutive weeks, were then randomly assigned in a 1:1 ratio to either AXS-05 (n = 53) or placebo (n = 55). During the second phase, AXS-05 delayed time to relapse of agitation symptoms compared to placebo (HR, 0.276; P = .014), representing a 3.6-fold lower risk. It also displayed improved relapse prevention (7.5%) compared to placebo (25.9%; P = .018).2

ADVANCE-2 was a multi-center, double-blind, placebo-controlled, randomized study investigating AXS-05's safety and efficacy compared to placebo. Investigators enrolled patients with a diagnosis of probable Alzheimer’s disease based on the 2011 National Institute on Aging-Alzheimer Association (NIA-AA) criteria and a diagnosis of clinically significant agitation resulting from probable Alzheimer’s disease according to the International Psychogeriatric Association (IPA) provisional definition of agitation. Patients who had dementia of a non-Alzheimer’s type were excluded.3

Ultimately, a total of 408 patients were enrolled and randomly assigned in a 1:1 ratio to either AXS-05 or placebo for ≤5 weeks, both in the form of tablets taken twice daily. During the trial, AXS-05 failed to demonstrate statistical significance in changing the CMAI total score from baseline to Week 5 (AXS-05, 13.8 points; placebo, 12.6 points). However, the results from this endpoint did numerically favor AXS-05.4

AXS-05 was safe and well-tolerated in both studies, and it was not associated with an increased risk of falls, cognitive decline, or sedation. Additionally, AXS-05 led to no deaths in the clinical program.4

According to the press release, the FDA has established a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2026.1

References

1. Axsome Therapeutics. Axsome Therapeutics Announces FDA Acceptance and Priority Review of Supplemental New Drug Application for AXS-05 for the Treatment of Alzheimer’s Disease Agitation. December 31, 2025. Accessed December 31, 2025. https://www.globenewswire.com/news-release/2025/12/31/3211743/33090/en/Axsome-Therapeutics-Announces-FDA-Acceptance-and-Priority-Review-of-Supplemental-New-Drug-Application-for-AXS-05-for-the-Treatment-of-Alzheimer-s-Disease-Agitation.html?_gl=1*10bx1vl*_up*MQ..*_ga*MTMwMTY4NzU1OC4xNzY3MTk1NDM2*_ga_ERWPGTJ5X8*czE3NjcxOTU0MzUkbzEkZzAkdDE3NjcxOTU0OTgkajYwJGwwJGgw

2. Cummings J, Grossberg G, Andersson C, et al. Efficacy and Safety of AXS-05 in Agitation Associated with Alzheimer’s Disease: Results from ACCORD, a Phase 3, Double-blind, Placebo-controlled, Relapse Prevention Trial (PL5.004). Neurology. April 9, 2024. Accessed December 31, 2025. https://www.neurology.org/doi/10.1212/WNL-.0000000000205634

3. Axsome Therapeutics, Inc. A Study to Assess the Efficacy and Safety of AXS-05 in Subjects With Alzheimer’s Disease Agitation (ADVANCE-2). ClinicalTrials.gov Identifier: NCT05557409. Updated November 26, 2025. Accessed December 31, 2025. https://clinicaltrials.gov/study/NCT05557409

4. Axsome Therapeutics. Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS-06 in Alzheimer’s Disease Agitation. BioSpace. December 30, 2024. Accessed December 31, 2025. https://www.biospace.com/press-releases/axsome-therapeutics-announces-successful-completion-and-results-of-phase-3-clinical-program-of-axs-05-in-alzheimers-disease-agitation