AXS-05 Significantly Reduces Agitation Relapse in Alzheimer Disease, Phase 3 ACCORD-2 Finds
Agitation affects approximately 70% of individuals living with Alzheimer disease (AD), contributing to patient distress, caregiver burden, and increased institutionalization rates. Despite its prevalence, effective pharmacologic options remain limited. Findings from the phase 3 ACCORD-2 trial now demonstrate that AXS-05 (dextromethorphan-bupropion) may offer a well-tolerated and effective therapeutic option to address this significant unmet need.
The ACCORD-2 study was a multicenter, randomized withdrawal, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of AXS-05 for AD agitation. The study enrolled 295 participants with probable AD and clinically significant agitation, defined using the 2011 National Institute on Aging–Alzheimer’s Association criteria.
Participants first entered an open-label period (OLP) lasting up to 12 months, during which all received AXS-05. Of those treated for at least 8 weeks, 167 individuals who achieved sustained clinical response were randomized 1:1 into the double-blind period (DBP) to either continue AXS-05 (n = 83) or switch to placebo (n = 84) for 26 weeks. At randomization, mean Cohen-Mansfield Agitation Inventory (CMAI) scores were 44.3 and 45.4 for AXS-05 and placebo groups, respectively.
AXS-05 met the study’s primary endpoint by significantly delaying time to agitation relapse compared with placebo (hazard ratio = 0.276; P = .001), translating to a 3.6-fold lower risk of relapse. The key secondary endpoint was also achieved, with relapse rates of 8.4% for AXS-05 versus 28.6% for placebo (P = .001).
Further, AXS-05 prevented worsening in overall AD clinical severity and agitation severity. On the Clinical Global Impression–Severity (CGI-S) scale, 13.3% of AXS-05 patients showed worsening of overall AD status compared with 39.3% on placebo (P < .001). Similarly, worsening of agitation severity occurred in 20.5% of AXS-05 patients vs 41.7% of those on placebo (P = .004).
According to the investigators, “AXS-05 achieved the primary and key secondary endpoints by statistically significantly delaying and preventing AD agitation relapse versus placebo…”
The treatment was well tolerated, with adverse event (AE) rates comparable between groups (AXS-05: 29.3%; placebo: 32.1%). No AE occurred in more than 3.7% of patients. Falls were reported in two (2.4%) AXS-05 patients, with one considered treatment-related. There were no discontinuations due to AEs in the AXS-05 group, compared with 1.2% in the placebo arm. Importantly, AXS-05 was not associated with sedation or cognitive decline, and no deaths were reported during the study.
For clinicians in long-term care and memory care settings, the ACCORD-2 results highlight AXS-05’s potential as a novel, rationally designed treatment for AD agitation. The significant delay and prevention of relapse, coupled with favorable tolerability and absence of sedation, suggest clinical utility in managing chronic agitation while maintaining patient function.
Reference
Grossberg G, et al. 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. Presented at: American Academy of Neurology Annual Meeting; April 5-9, 2025; San Diego.
