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Abstract Details

Efficacy and Safety of AXS-05 in Alzheimer's Disease Agitation: A Phase 3 Randomized Withdrawal Double-Blind Placebo-Controlled Study
Aging, Dementia, and Behavioral Neurology
LS1 - Late-breaking Science 1 (11:27 AM-11:33 AM)
003

To report results from ACCORD-2, a 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 Alzheimer’s disease agitation.

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

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 patients treated for at least 8 weeks, 167 achieved sustained clinical response in the OLP and 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.

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. 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 overall (CGI-S AD overall clinical status; proportion with worsening: AXS-05=13.3%, placebo=39.3%, P<0.001), and 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 patients. Two (2.4%) AXS-05 patients 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.

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. 
Authors/Disclosures
George Grossberg, MD (St Louis University School of Medicine Department of Neurology & Psychiatry)
PRESENTER 		Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Axsome Therapeutics. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BioXcel. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Karuna. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Maplight Therapeutics. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Otsuka. Dr. Grossberg has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Takeda. The institution of Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Anavex. The institution of Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Newron. The institution of Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Oligomerix. The institution of Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Quince. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Dr. Grossberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka. The institution of Dr. Grossberg has received research support from NIA. The institution of Dr. Grossberg has received research support from Functional Neuromodulation .
Jeffrey L. Cummings, MD, FAAN Dr. Cummings has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. Dr. Cummings has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia, Biogen, Genentech, Grifols, Janssen, Karuna, Otsuka, reMYND, Roche, Signant Health. Dr. Cummings has stock in Artery, Vaxxinity, Behrens, Alzheon, MedAvante-Prophase, and Acumen. Dr. Cummings has received research support from NIH. Dr. Cummings has received research support from NIGMS. Dr. Cummings has received intellectual property interests from a discovery or technology relating to health care.
Caroline Streicher (Axsome Therapeutics) Caroline Streicher has received personal compensation for serving as an employee of Axsome Therapeutics. Caroline Streicher has stock in Axsome Therapeutics.
Herriot Tabuteau (Axsome Therapeutics) Herriot Tabuteau has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Axsome Therapeutics.