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
Anton Porsteinsson1, Jeffrey Cummings2, George Grossberg3, Candace Andersson4, Caroline Streicher5, Herriot Tabuteau5
1University of Rochester School of Medicine and Dentistry, 2UNLV, 3St Louis School of Medicine, 4Axsome Therapeutic, 5Axsome Therapeutics
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 3, 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.