Clinical Profile of AXS-05 in Treating Alzheimer’s Disease Agitation: Results From the Phase 2/3 Development Program

Background: Alzheimer’s disease agitation (ADA) is characterized by emotional distress, aggression, and disinhibition. AXS-05 (dextromethorphan-bupropion) is a novel, oral NMDA receptor antagonist and sigma-1 receptor agonist approved for treating major depressive disorder in adults. Here, we present two randomized, controlled studies evaluating AXS-05 use in ADA: ADVANCE-1 (Phase 2) and ACCORD-1 (Phase 3).

Methods: The studies enrolled patients with probable AD. In ADVANCE-1, patients took AXS-05 (n=152), bupropion (n=49), or placebo (n=156) twice-daily for 5 weeks. Primary endpoint was change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score. ACCORD-1 was a randomized discontinuation study with an open-label period where patients received AXS-05 until sustained CMAI response. In the double-blind period, patients took AXS-05 (n=53) or placebo (n=55) for ≤26 weeks or until relapse. Primary endpoint was time to agitation relapse.

Results: In ADVANCE-1, AXS-05 significantly reduced CMAI scores vs bupropion or placebo at Week 5. The most common treatment-emergent adverse events (TEAEs) for AXS-05 included somnolence (8.2%), dizziness (6.3%), and diarrhea (4.4%). In ACCORD-1, AXS-05 treatment was associated with improved CMAI scores as early as Week 1 of the open-label period. In the double-blind period, AXS-05 significantly improved time-to-relapse and relapse rates versus placebo; relapse risk was 3.6-fold lower. The most common TEAEs for AXS-05 included diarrhea (7.5%), fall (7.5%), and back pain (5.7%). AXS-05 was not associated with cognitive impairment or sedation.

Conclusions: AXS-05 led to a substantial, rapid reduction in ADA symptoms and was generally well tolerated. Long-term treatment significantly increased ADA time-to-relapse, supporting further investigation.