Over 19 million U.S. adults experience at least one episode of major depressive disorder (MDD) annually. Nearly two-thirds of patients do not experience adequate response to first-line therapy, and most of these patients also fail second-line treatment. Time to clinically meaningful response with existing antidepressants (up to 6-8 weeks) is also suboptimal. There is an urgent need for superior, mechanistically novel, and faster-acting treatments. AXS-05 (dextromethorphan-bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. AXS-05 utilizes a proprietary formulation and doses of dextromethorphan and bupropion, and metabolic inhibition technology, to modulate the delivery of the components. The dextromethorphan component is an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and the bupropion component increases the bioavailability of dextromethorphan. GEMINI was a Phase 3, randomized, double-blind, placebo-controlled, multi-center, U.S. trial, in which 327 adult subjects with a diagnosis of moderate to severe MDD were randomized to treatment with either AXS-05 (dextromethorphan 45 mg-bupropion 105 mg) (n=163), or placebo (n=164), twice daily for 6 weeks. The primary efficacy endpoint was the change in the MADRS total score from baseline to Week 6. On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the MADRS total score of 16.6 points versus 11.9 for placebo (p=0.002). AXS-05 demonstrated rapid, statistically significant improvement versus placebo on the key secondary endpoint of change from baseline in the MADRS total score at Week 1, the earliest time point measured (p=0.007), and all timepoints thereafter. Rates of response were statistically significantly greater for AXS-05 versus placebo at Week 1 (p=0.035) and at all timepoints thereafter, being achieved by 54% of AXS-05 patients versus 34% of placebo patients at Week 6 (p<0.001). Remission rates were statistically significantly greater for AXS-05 versus placebo at Week 2 (p=0.013) and at all timepoints thereafter, being achieved by 40% of AXS-05 patients versus 17% of placebo patients at Week 6 (p<0.001). Antidepressant effects translated into early and statistically significant improvements in daily functioning and quality of life. AXS-05 was safe and well tolerated with the most common adverse events being dizziness, nausea, headache, diarrhea, somnolence and dry mouth. AXS-05 was not associated with psychotomimetic effects, weight gain, cognitive impairment or increased sexual dysfunction.