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    Central Nervous System

    E-Poster Available

    (56) Efficacy and Safety of AXS-05 in Alzheimer's Disease Agitation: Results From ACCORD-2, a Phase 3 Randomized Withdrawal Double-Blind Placebo-Controlled Study

    Wednesday, October 29, 2025

      Co-Author(s)

    • Jeffrey Cummings, MD, ScD

      Joy Chambers-Grundy Professor of Brain Science
      University of Nevada, Las Vegas, Las Vegas, NV, USA
      Las Vegas, Nevada, United States

      • Primary Author(s)

    • Jeffrey Cummings, MD, ScD

      Joy Chambers-Grundy Professor of Brain Science
      University of Nevada, Las Vegas, Las Vegas, NV, USA
      Las Vegas, Nevada, United States

      • Co-Author(s)

    • George Grossberg, MD

      Samuel W. Fordyce Professor and Director of Geriatric Psychiatry
      Saint Louis University School of Medicine, St Louis, MO, USA
      St. Louis, Missouri, United States

    • Caroline Streicher, n/a

      SVP, Clinical Research
      Axsome Therapeutics Inc. New York, NY, USA
      New York, New York, United States

    • Ronnie DePue, PharmD

      Axsome Therapeutics Inc. New York, NY, USA
      New York, New York, United States

      • Presenter(s)

    • Ronnie DePue, PharmD

      Axsome Therapeutics Inc. New York, NY, USA
      New York, New York, United States

      • Co-Author(s)

    • Herriot Tabuteau, MD

      CEO
      Axsome Therapeutics Inc. New York, NY, USA
      New York, New York, United States


    Background:     : Alzheimer’s disease (AD) agitation is present in approximately 70% of individuals with AD. Current pharmacologic therapies are limited, leaving a need for additional rationally-designed treatments.

    Objective: : To report results from the ACCORD-2 Phase-3, multicenter, double-blind, placebo-controlled, randomized withdrawal study of AXS-05 (dextromethorphan-bupropion), an oral NMDA receptor antagonist/sigma-1 receptor agonist, in AD agitation.

    Methods: : ACCORD-2 was a randomized withdrawal study comprised of an AXS-05 open-label period (OLP; ≤12 months, n=295) followed by a 26-week, double-blind, randomized withdrawal period (DBP). Participants had a diagnosis of probable AD (National Institute on Aging-Alzheimer’s Association, 2011) and clinically-significant associated agitation. Of participants treated for at least 8 weeks, 167 achieving sustained clinical response in the OLP were randomized 1:1 into the DBP (AXS-05: n=83, placebo: n=84). Mean CMAI total scores at randomization were 44.3 and 45.4 for AXS-05 and placebo, respectively.

    Results: : AXS-05 statistically significantly delayed time to AD agitation relapse (hazard ratio=0.276, P=0.001, 3.6-fold lower risk), meeting the primary endpoint of ACCORD-2. AXS-05 statistically significantly prevented AD agitation relapse (key secondary endpoint; relapse rates: AXS-05=8.4%, placebo=28.6%, P=0.001). AXS-05 statistically significantly prevented worsening of severity of AD agitation (CGI-S agitation; proportion with worsening: AXS-05=20.5%, placebo=41.7%, P=0.004). Adverse event (AE) rates in the DBP: AXS-05=29.3%, placebo=32.1%; none occurred in >3.7% of participants. Two (2.4%) AXS-05 participants reported falls; one treatment-related. DBP discontinuations from AEs were low (AXS-05=0%, placebo=1.2%). AXS-05 was not associated with sedation or cognitive decline. No deaths were reported.

    Conclusions: : AXS-05 achieved primary and key secondary endpoints by statistically significantly delaying and preventing AD agitation relapse versus placebo, respectively. AXS-05 prevented worsening of severity of AD agitation and AD overall compared to placebo. AXS-05 was well tolerated, with no new safety signals.

    Sponsorship:: Axsome Therapeutics Inc.