Alzheimers Dement. 2024 Dec;20 Suppl 6:e086940. doi: 10.1002/alz.086940.
ABSTRACT
BACKGROUND: Patients with Alzheimer’s disease (AD) often experience burdensome neuropsychiatric symptoms, including agitation which occurs in both home and long-term care (LTC) facilities, and is associated with substantial increases in caregiver burden and LTC placements. AXS-05 (45-mg dextromethorphan/105-mg bupropion), a novel, oral NMDA receptor antagonist and sigma-1 receptor agonist, approved by the FDA for major depressive disorder, is being investigated for treatment of AD agitation (ADA). AXS-05 has been evaluated in 2 randomized, double-blind studies: Phase 2 ADVANCE-1 (NCT03226522); Phase 3 ACCORD (NCT04797715).
METHOD: ADVANCE-1/ACCORD enrolled patients (65-90 y) with a diagnosis of probable AD using 2011 NIA-AA diagnostic criteria. ADVANCE-1 evaluated the acute effects of AXS-05 on improving ADA. Patients were randomized 1:1:1 for 5 weeks (AXS-05 or bupropion [105-mg] or matching placebo).
PRIMARY ENDPOINT: change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score. ACCORD evaluated the effects of AXS-05 in preventing ADA relapse using a randomized discontinuation design; it comprised an open-label period (OLP; ≤9 weeks) until response was sustained (≥4 consecutive weeks). In the double-blind period (DBP), patients were randomized 1:1 (AXS-05/placebo) for up to 26 weeks in the DBP or until relapse.
PRIMARY ENDPOINT: time-to-relapse.
RESULT: ADVANCE-1 comprised 357 patients in the modified intent-to-treat population: AXS-05 (n = 152) bupropion (n = 49), placebo (n = 156) (mean baseline CMAI total scores = 60.7, 66.1, 59.4, respectively). At Week 5, AXS-05 significantly reduced CMAI total score by 15.4 points vs bupropion (10.0 points; P<.001) and placebo (11.5 points; P = .010). In ADVANCE-1, common adverse events (AEs; ≥3%) included somnolence (8.2%), dizziness (6.3%), and diarrhea (4.4%). ACCORD comprised 178 patients in the OLP (mean CMAI = 70.9) and 108 patients in the DBP (AXS-05, n = 53; placebo, n = 55) (mean CMAI = 43.7). AXS-05 increased time-to-relapse vs placebo (hazard ratio = 0.275; P = .014). AXS-05 was associated with lower relapse rates vs placebo (7.5% vs 25.9%; P<.05). In ACCORD, common AEs (≥3%) included dizziness (9.6%), diarrhea (4.5%), and fall (5.1%). AXS-05 was not associated with cognitive impairment or sedation in either study.
CONCLUSION: AXS-05 demonstrated a substantial, rapid reduction in ADA vs controls after 5 weeks of treatment, increased time-to-relapse vs placebo, and was well-tolerated, supporting its development as a promising treatment option for ADA.
PMID:39782565 | DOI:10.1002/alz.086940