AXS-05 Shows Efficacy and Safety in Agitation in Alzheimer Disease
Key Clinical Summary
- AXS-05 significantly reduced agitation symptoms in Alzheimer disease (AD) versus placebo and bupropion in the ADVANCE-1 Phase 2/3 trial.
- Rapid therapeutic onset observed, with improvement in Cohen-Mansfield Agitation Inventory (CMAI) scores as early as week 1 in ACCORD-1.
- Long-term treatment reduced relapse risk 3.6-fold and was generally well tolerated.
Alzheimer disease–related agitation (ADA) remains a challenging neuropsychiatric symptom with limited treatment options. New data presented in a poster at the 2026 Psych Congress NP Institute in Nashville, TN, highlight the efficacy and safety of AXS-05 (dextromethorphan-bupropion) based on results from the Phase 2/3 ADVANCE-1 and Phase 3 ACCORD-1 randomized controlled trials.
Study Findings
ADVANCE-1 and ACCORD-1 evaluated AXS-05 in patients with probable Alzheimer disease (AD) experiencing agitation. AXS-05 is an oral NMDA receptor antagonist and sigma-1 receptor agonist previously approved for major depressive disorder (MDD).
In ADVANCE-1, 357 patients were randomized to AXS-05 (n=152), bupropion (n=49), or placebo (n=156) twice daily for 5 weeks. The primary endpoint was change in Cohen-Mansfield Agitation Inventory (CMAI) total score. AXS-05 demonstrated significantly greater reductions in CMAI scores compared with both bupropion and placebo at week 5.
ACCORD-1 employed a randomized discontinuation design. Patients initially received open-label AXS-05 until achieving sustained response, followed by a double-blind open-label period with randomization to AXS-05 (n=53) or placebo (n=55) for up to 26 weeks. Improvements in CMAI scores were observed as early as week 1 during the open-label phase. During the double-blind phase, AXS-05 significantly prolonged time to relapse and reduced relapse risk 3.6-fold versus placebo.
Safety findings were consistent across studies. In ADVANCE-1, common treatment-emergent adverse events (TEAEs) included somnolence (8.2%), dizziness (6.3%), and diarrhea (4.4%). In ACCORD-1, TEAEs included diarrhea (7.5%), falls (7.5%), and back pain (5.7%). Notably, AXS-05 was not associated with cognitive impairment or sedation.
Clinical Implications
These findings suggest AXS-05 may address a significant unmet need in managing agitation in Alzheimer disease. Current treatment strategies often rely on off-label antipsychotics, which carry safety concerns, including increased mortality risk in older adults.
The rapid onset of symptom improvement is clinically meaningful, particularly in acute care or caregiver distress scenarios. Additionally, the demonstrated reduction in relapse risk supports the potential role of AXS-05 as a maintenance therapy for sustained symptom control.
The absence of cognitive worsening is particularly relevant in this population, where preserving baseline function is critical. The tolerability profile further supports its potential use in elderly patients, though clinicians should monitor for gastrointestinal and fall-related adverse events.
Reference
Roybal D. Clinical profile of axs-05 in treating Alzheimer’s disease agitation: results from the ADVANCE-1 and ACCORD-1 randomized, placebo-controlled studies. Poster presented at Psych Congress NP Institute; March 19-22, 2026; Nashville, Tennessee.
