Rapid Antidepressant Effects and MADRS Item Improvements With AXS-05 (Dextromethorphan-Bupropion), an Oral NMDA Receptor Antagonist, in Major Depressive Disorder: Results from Two Randomized, Double-Blind, Controlled Trials

Abstract: Background: AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity being developed for MDD. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan. Methods: AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials. The GEMINI trial was placebo-controlled and the ASCEND trial used bupropion as the control. Here we focus on efficacy in the first 2 weeks of treatment and present a pooled analysis of the individual items of the MADRS for AXS-05 as compared to control. Results: In GEMINI, starting at Week 1, AXS 05 was superior (p 0.05) to placebo on: mean MADRS improvement (7.3 vs. 4.9), MADRS response (15% vs. 7%), CGI-I (22% vs. 13%), CGI-S (0.7 vs. 0.4) and Q-LES-Q-SF (9.0% vs. 5.8%). At Week 2, AXS-05 was also statistically superior to placebo on MADRS remission (17% vs. 8%) and on the SDS (6.8 vs. 4.5). In ASCEND, from Week 2, AXS-05 was superior (p 0.05) to bupropion on: mean MADRS improvement (12.5 vs. 7.8), MADRS remission (26% vs. 3%), and CGI-S (1.41 vs. 0.9). At Week 1, treatment with AXS-05 resulted in greater improvements (p 0.05) in reported sadness, inner tension, inability to feel, pessimistic thoughts, and suicidal thoughts, as compared to control. At Week 6, AXS-05 demonstrated significant improvements over control on seven of the 10 MADRS items. Conclusions: Treatment with AXS-05 resulted in rapid and broad antidepressant efficacy.Short Description: This abstract reviews the rapid efficacy of AXS-05 (dextromethorphan-bupropion) across a range of clinician and patient reported outcomes relevant to depression from two randomized controlled trials including: MADRS, Clinician Global Impression of Improvement, the Sheehan Disability Scale, and quality of life measures. In a pooled analysis of the individual MADRS items, AXS-05 compared to control resulted in statistically significant improvements in seven of the 10 MADRS items at Week 6.Name of Sponsoring Organization(s): Axsome Therapeutics