Poster
184
(#184) 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
Psych Congress 2025
Abstract: Introduction: Alzheimer's disease (AD) agitation occurs in ~70% of individuals with AD. ACCORD-2 was a Phase-3, double-blind, placebo-controlled, randomized withdrawal study of AXS-05 (dextromethorphan-bupropion), an oral NMDA receptor antagonist and 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 patients treated for ≥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 (AXS-05) and 45.4 (placebo).
Result: AXS-05 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 significantly prevented AD agitation relapse (key secondary endpoint; relapse rates: AXS-05=8.4%, placebo=28.6%, P=0.001). AXS-05 significantly prevented worsening of severity of AD agitation as measured by 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 treated with AXS-05. 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.
Conclusions: AXS-05 achieved primary and key secondary endpoints by significantly delaying and preventing AD agitation relapse versus placebo, respectively. AXS-05 also prevented worsening of severity of AD agitation versus placebo. AXS-05 was well-tolerated.
Short Description: Pharmacotherapies for Alzheimer's Disease (AD) agitation are often used off-label, exhibit limited efficacy, and carry considerable safety concerns. AXS-05 (dextromethorphan-bupropion) is a novel, oral N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 receptor agonist, and aminoketone CYP2D6 inhibitor. In the ACCORD-2 Phase 3 trial, AXS-05 significantly delayed the time to relapse of AD agitation versus placebo, meeting the primary endpoint. ACCORD-2 also significantly prevented relapse of AD agitation versus placebo. AXS-05 was well-tolerated, with no new safety signals.
Name of Sponsoring Organization(s): Axsome Therapeutics
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 patients treated for ≥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 (AXS-05) and 45.4 (placebo).
Result: AXS-05 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 significantly prevented AD agitation relapse (key secondary endpoint; relapse rates: AXS-05=8.4%, placebo=28.6%, P=0.001). AXS-05 significantly prevented worsening of severity of AD agitation as measured by 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 treated with AXS-05. 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.
Conclusions: AXS-05 achieved primary and key secondary endpoints by significantly delaying and preventing AD agitation relapse versus placebo, respectively. AXS-05 also prevented worsening of severity of AD agitation versus placebo. AXS-05 was well-tolerated.
Short Description: Pharmacotherapies for Alzheimer's Disease (AD) agitation are often used off-label, exhibit limited efficacy, and carry considerable safety concerns. AXS-05 (dextromethorphan-bupropion) is a novel, oral N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 receptor agonist, and aminoketone CYP2D6 inhibitor. In the ACCORD-2 Phase 3 trial, AXS-05 significantly delayed the time to relapse of AD agitation versus placebo, meeting the primary endpoint. ACCORD-2 also significantly prevented relapse of AD agitation versus placebo. AXS-05 was well-tolerated, with no new safety signals.
Name of Sponsoring Organization(s): Axsome Therapeutics
