Supplemental New Drug Application Submitted for AXS-05 as Treatment for Alzheimer Disease Agitation

According to a recent announcement from Axsome Therapeutics, the company has submitted a supplemental new drug application for AXS-05, an investigational, orally administered combination of dextromethorphan and bupropion, as a treatment for patients with Alzheimer disease (AD) agitation.¹

AXS-05, an N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor, has a clinical program that consists of several phase 3 studies, including ACCORD-2 and ADVANCE-2. These trials, both double-blind and placebo-controlled in design, included 167 and 408 patients, respectively, testing the efficacy and safety of AXS-05 in AD agitation.

In ACCORD-2, participants completed an open-label treatment period followed by a 26-week, double-blind, placebo-controlled randomized withdrawal phase. All told, AXS-05 achieved its primary end point, showing a statistically significant delay in time to relapse of agitation compared with placebo, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score (hazard ratio, 0.276; P = .001). The therapy also met its key secondary end point, with only 8.4% of patients on AXS-05 experiencing relapse versus 28.6% of those receiving placebo (P = .001).²

The ADVANCE-2 study, another double-blind, placebo-controlled trial, randomly assigned 408 patients to receive either AXS-05 or placebo for five weeks. Although the trial did not reach statistical significance for its primary end point—change in CMAI total score (mean reduction: 13.8 points with AXS-05 vs 12.6 with placebo)—numerical improvements across primary and secondary measures favored AXS-05. Among the four pivotal trials conducted for AXS-05 (ADVANCE-1, ADVANCE-2, ACCORD-1, and ACCORD-2), ADVANCE-2 was the only study that did not achieve statistical significance on its primary outcome.

Additional data from ACCORD-2 revealed that 20.5% of AXS-05–treated patients showed worsening on the Clinical Global Impression–Severity (CGI-S) for agitation versus 41.7% of those switched to placebo (P = .004). Similarly, only 13.3% of patients on AXS-05 experienced worsening in the CGI-S AD overall clinical status domain compared with 39.3% of placebo-treated patients (P < .001).

During the open-label phase preceding randomization, 295 patients received AXS-05 for up to 12 months. By Week 6, the mean CMAI total score declined by 20.4 points, representing a 46% reduction from baseline, with 69% achieving a clinical response (≥30% reduction). Improvements in agitation were reported by 78% of participants on the mADCS-CGIC and 71–78% on the PGI-C between Weeks 4 and 8. Among those treated for at least eight weeks, 70% achieved sustained clinical responses and advanced to the double-blind phase.

READ MORE: FDA Feedback Provides Clarity for Phase 3 Trial of Neflamapimod in Dementia With Lewy Bodies

In its announcement, Axsome noted that it plans to initiate a pivotal phase 2/3 trial of AXS-05 in smoking cessation in the fourth quarter of 2025.¹ In addition to AD agitation, the therapy has shown some promise in patients with major depressive disorder (MDD), through the phase 3 GEMINI trial (NCT04019704).

Published in the Journal of Clinical Psychiatry, GEMINI was a double-blind trial that comprised 327 patients with MDD who were randomized to either AXS-05 (45 mg-105 mg tablet) or placebo for a 6-week period. Overall, results showed that treatment with the agent led to a –15.9-point least square mean change in Montgomery-Asberg Depression Rating Scale (MADRS), the primary end point, over the double-blind period. For context, those on placebo demonstrated changes of –12.0, leading to a least-square mean difference of –3.87 (95% CI, –1.39 to –6.36; P = .002).

In GEMINI, AXS-05 demonstrated superiority over placebo in improving MADRS scores at all time points, including week 1 (P = .007) and week 2 (P < .001). By week 6, 39.5% of patients receiving dextromethorphan-bupropion achieved remission compared with 17.3% on placebo (treatment difference, 22.2%; 95% CI, 11.7–32.7; P < .001), and 54.0% achieved a clinical response versus 34.0% for placebo (difference, 20.0%; 95% CI, 8.4–31.6; P < .001). Most secondary endpoints similarly favored the active treatment, including the CGI-S least-squares mean difference at week 6 (–0.48; 95% CI, –0.79 to –0.48; P = .002).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://www.manilatimes.net/2025/11/03/tmt-newswire/globenewswire/axsome-therapeutics-reports-third-quarter-2025-financial-results-and-provides-business-update/2214234
2. 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 November 7, 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
3. Losifescu DV, Jones A, O’Gorman C, et al. Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345. doi:10.4088/JCP.21m14345.