Efficacy and safety of AXS 05 in agitation associated with Alzheimer’s disease: results from ACCORD, a phase III, relapse prevention trial ; Axsome Therapeutics

15 April 2025.Abstract;  . Efficacy and Safety Of AXS 05 in Agitation Associated with Alzheimer’s Disease: Results from ACCORD, a Phase III, Double-blind, Placebo-controlled, Relapse Prevention Trial ; Objective: To evaluate AXS 05 (dextromethorphan-bupropion), an oral NMDA receptor antagonist/sigma-1 receptor agonist FDA approved for major depressive disorder, for the treatment of Alzheimer’s disease (AD) associated agitation (A). Background: Up to 70% of individuals with AD experience ADA. Associated negative outcomes associated ADA include increased caregiver burden and mortality. Design/Methods: ACCORD (NCT04797715), a Phase III, double-blind, multi-center, randomized-controlled trial, evaluated the efficacy and safety of AXS 05 in ADA. In the 9-week, open-label period (OLP) participants were treated with AXS 05 and responders (≥30% improvement from baseline in the Cohen Mansfield Agitation Inventory [CMAI] total score and Patient Global Impression of Change [PGI-C] score improvements ≤3 lasting ≥4 consecutive weeks) were randomized. Participants were discontinued if relapse of agitation occurred. Primary and key secondary endpoints were time from randomization to relapse of agitation symptoms and rates of agitation relapse. Results: Participants (N=178; mean CMAI baseline total score, 70.9) were enrolled into the OLP. OL AXS 05 treatment resulted in statistically significant improvement from baseline in CMAI scores at all timepoints from Week 1 (6.7 points; P<.001) to Week 5 (20.6 points; P<.001). Responders (n=108) were randomized receive AXS 05 (n=53) or placebo (n=55) for a 26-week double-blind period (DBP). AXS  05 met the primary endpoint by substantially delaying the time to relapse of agitation symptoms as compared to placebo (hazard ratio=0.276; P=.014), representing a 3.6-fold lower risk. AXS  05 also met the key secondary endpoint of improved relapse prevention (7.5%) compared to placebo (25.9%, P=.018). Overall adverse event rates in the DBP were 28.3% AXS 05, 22.2% placebo. Discontinuations due to adverse events were 0% AXS-05, 1.9% placebo. There was no evidence of cognitive decline or associated sedation with AXS-05 treatment. Conclusions: AXS -05 substantially reduced the risk of agitation symptom relapse in participants with AD and was generally well-tolerated in those who achieved sustained clinical response in the OL period.

 Citation:  Efficacy and Safety Of AXS 05 in Agitation Associated with Alzheimer’s Disease: Results from ACCORD, a Phase III, Double-blind, Placebo-controlled, Relapse PreventionTrial (PL5.004) Jeffrey Cummings, George Grossberg, Candace Andersson, Caroline Streicher, and Herriot Tabuteau. April 9, 2024 issue102 (7_supplement_1)https://doi.org/10.1212/WNL-.0000000000205634. Neurology.