OBJECTIVES : With existing therapies for major depressive disorder (MDD), improvements in functioning and quality of life, often trail behind depressive symptom improvement. AXS-05 (dextromethorphan-bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity being developed for MDD. Herein, we report the effects of AXS-05 on humanistic outcomes during the first 2-weeks of treatment.

METHODS : GEMINI (N=327) was a Phase 3, double-blind, placebo-controlled, multi-center study, in which subjects with moderate-severe MDD were randomized (1:1) to receive AXS-05 (dextromethorphan HBr 45 mg-bupropion HCl 105 mg) or placebo, twice daily for 6 weeks. The primary efficacy outcome, change from baseline in MADRS total score, demonstrated a rapid and statistically significant improvement starting at Week 1, which was maintained through Week 6 (primary timepoint). Starting at Week 1, secondary endpoints including the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) and the Sheehan Disability Scale (SDS) were assessed. The Q-LES-Q-SF is a self-reported, 16-item scale. Scores are expressed as the percentage of maximum score, with higher percentages reflecting better quality of life. The SDS is a 3-item questionnaire evaluating impairments in work, social life/leisure, and family life/home responsibility.

RESULTS : Improvements from baseline were statistically significant for AXS-05 versus placebo on the Q-LES-Q-SF at Week 1 (9.04% and 5.79%, respectively, p=0.031), the first timepoint measured, Week 2 (13.2% and 8.88%, respectively, p= 0.017) and at every time point thereafter. On the SDS total score, improvements from baseline were statistically significant for AXS-05 versus placebo beginning at Week 2 (6.82 and. 4.47, respectively, p=0.003) and at every time point thereafter.

CONCLUSIONS : AXS-05 improved depression and humanistic outcomes compared to placebo within 1-2 weeks of treatment. These improvements were maintained throughout the course of the study. These findings suggest that AXS-05, as a mechanistically novel medicine, rapidly improves depressive symptoms, quality of life, and functioning.