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

Abstract: Introduction: AXS-05 (dextromethorphan-bupropion; Auvelity) is a novel, oral, N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist approved for treating major depressive disorder (MDD) in adults. Methods: GEMINI and ASCEND assessed AXS-05 versus placebo and 105 mg bupropion, respectively, in 6-week trials of patients with MDD. In both, patients took AXS-05 or comparator once-daily for 3 days, then twice-daily. GEMINI and ASCEND data were pooled, with placebo and bupropion arms combined into a Control arm in this post hoc analysis. Efficacy was measured as change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) among participants stratified by prior antidepressant treatment (ADT) in the current major depressive episode, gender, and race. Safety analyses quantified timing of treatment emergent adverse event (TEAE) onset and duration of TEAEs. Results: AXS-05 produced statistically significant reductions in MADRS total score from baseline compared to control every week from Week 1 onward irrespective of prior ADT (Week 1: P=0.032 without prior ADT and P=0.015 with ≥1 prior ADT). AXS-05 also produced greater improvement in MADRS total score versus control regardless of gender every week from Week 2 onward (Week 6: P=0.007 for females and P=0.009 for males) and irrespective of race every week from Week 4 onward (Week 6: P=0.005 for white patients and P=0.020 for non-white patients). Most incidences of TEAEs in ≥5% of AXS-05 patients were reported in Week 1 and resolved with a median duration of 2.5-16 days. Conclusions: AXS-05 exhibited consistent efficacy and tolerability characterized by early onset and brief duration TEAEs.Short Description: Differences in treatment response have been observed for patients with major depressive disorder by number of prior antidepressant therapies, gender, and race. Alongside these treatment response variations, many individuals experience enduring and burdensome tolerability problems associated with common antidepressant therapies. Here, we show that AXS-05 demonstrated both efficacy and tolerability.Name of Sponsoring Organization(s): Axsome Therapeutics