(#9) Efficacy and Safety of AXS-05 in Alzheimer's Disease Agitation: A Phase 3 Randomized-Withdrawal Double-Blind Placebo-Controlled Study

Abstract: Approximately 70% of individuals with Alzheimerís disease (AD) experience agitation. Current pharmacologic therapies are limited and additional treatments are needed. AXS-05 (dextromethorphan-bupropion), an oral NMDA receptor antagonist/sigma-1 receptor agonist, was assessed in AD agitation in the Phase-3, randomized-withdrawal, multicenter, placebo-controlled ACCORD-2 study. ACCORD-2 was comprised of an AXS-05 open-label period (OLP; ?12 months, n=295) and a 24-week, double-blind, randomized withdrawal period (DBP). Participants had a diagnosis of probable AD (National Institute on Aging-Alzheimerís Association, 2011) and clinically-significant associated agitation. Of patients treated for at least 8 weeks, 167 achieved 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 (AXS-05) and 45.4 (placebo). 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 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 AD agitation severity. AXS-05 was well tolerated, with no new safety signals.Short Description: Despite high rates of agitation among individuals with Alzheimerís disease (AD), pharmacological interventions remain limited. ACCORD-2 ña Phase-3, double-blind randomized-withdrawal study evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion) in AD agitation. ACCORD-2 achieved primary and key secondary endpoints by statistically significantly delaying and preventing relapse of AD agitation versus placebo, respectively. AXS-05 was well tolerated, with no new safety signals from prior studies, supporting its potential as a new treatment option for AD agitation.Name of Sponsoring Organization(s): Axsome Therapeutics, Inc.