AXS-05 (Auvelity®) in Major Depressive Disorder: Pooled Data from Two Six-Week Controlled Trials (GEMINI and ASCEND)

Background: Many patients with major depressive disorder (MDD) experience enduring tolerability problems associated with antidepressant treatments (ADTs), leading to discontinuation and decreased functional and quality-of-life outcomes. AXS-05 (dextromethorphan-bupropion; AUVELITY®), a novel, oral, NMDA receptor antagonist, sigma-1 receptor agonist, and aminoketone CYP2D6 inhibitor, is approved for the treatment of MDD in adults.

Methods: GEMINI (Phase 3; NCT04019704) and ASCEND (Phase 2; NCT03595579) were two 6-week, randomized controlled studies assessing AXS-05 vs placebo or 105 mg bupropion, respectively, in participants with MDD. Pooled post-hoc analyses evaluated treatment-emergent adverse event (TEAE) incidence, prevalence, and duration. Efficacy, measured as change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) vs control, was further stratified by prior use of an ADT in the current major depressive episode, sex, and race.

Results: TEAEs in ≥5% of participants treated with AXS-05 were dizziness (17.1%), nausea (13.8%), headache (8.1%), diarrhea (6.7%), dry mouth (6.7%), anxiety (5.7%), somnolence (5.7%), sexual dysfunction (5.2%), and decreased appetite (5.2%). Most incidences were reported in Week 1, and absolute prevalence over time ranged from 1.8%-6.1%. Median durations were 2.5-16 days. AXS-05 demonstrated improvement vs control in MADRS at Weeks 1, 2, and 6, irrespective of prior ADT use, sex, or race.

Conclusions: Pooled data from two randomized AXS-05 studies support the early occurrence and resolution of the most common TEAEs within < 1-3 weeks of treatment. Participants treated with AXS-05 exhibited consistent improvement in depressive symptoms regardless of baseline demographics assessed. These results further distinguish the safety and efficacy of AXS-05 from traditional ADTs.