FDA Grants Priority Review to Investigational Therapy for Major Depressive Disorder


The FDA has granted priority review to Axsome Therapeutics’ dextromethorphan-bupropion (AXS-05) for the treatment of major depressive disorder.


The FDA has granted priority review to Axsome Therapeutics’ dextromethorphan-bupropion (AXS-05) for the treatment of major depressive disorder (MDD).1

Dextromethorphan-bupropion modulated delivery tablet is a novel, oral investigational NDMA receptor antagonist with multimodal activity under development for the treatment of MDD and other central nervous system disorders. The FDA previously granted breakthrough therapy designation for dextromethorphan-bupropion for the treatment of MDD in March 2019. Dextromethorphan-bupropion was also granted breakthrough designation for Alzheimer disease agitation in June 2020.1

The new drug application for the MDD indication is supported by results from 2 randomized, double-blind, controlled studies of dextromethorphan-bupropion: the GEMINI and ASCEND trials. In the studies, patients with confirmed diagnosis of moderate to severe MDD who were treated with dextromethorphan-bupropion demonstrated statistically significant improvements in depressive symptoms compared with placebo and active controls.1

The GEMINI study included 327 adult patients with confirmed moderate to severe MDD. Participants were randomized to treatment with either dextromethorphan-bupropion modulated delivery tablet or placebo once daily for the first 3 days and twice daily thereafter for a total of 6 weeks. At week 6, patients treated with dextromethorphan-bupropion demonstrated a highly statistically significant reduction in self-reported depressive symptoms compared with placebo, representing 48% and 34% reductions from baseline, respectively, in the Montgomery-Asberg Depression Rating Scale (MADRS) total score.2

In the active-controlled ASCEND trial, which enrolled 80 patients, those treated with dextromethorphan-bupropion demonstrated a statistically significant average mean reduction from baseline in the MADRS total score over the 6-week period of 13.7 points for dextromethorphan-bupropion compared with 8.8 for bupropion (P<0.001). At week 6, dextromethorphan-bupropion showed a 17.2 point reduction in the MADRS total score compared with a 12.1 point reduction for bupropion (P=0.013).3

Dextromethorphan-bupropion was well tolerated in both studies. The most commonly reported adverse events (AEs) were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. Treatment was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.3

The dextromethorphan component of dextromethorphan-bupropion is also a sigma-1 receptor agonist, and the bupropion component is a norepinephrine and dopamine reuptake inhibitor and serves to increase the bioavailability of dextromethorphan.1

According to the National Institutes of Health, an estimated 7% of US adults experience MDD each year. Nearly 2-thirds of diagnosed and treated patients with MDD do not experience adequate treatment response with currently available first-line therapy. If approved, dextromethorphan-bupropion would be a new treatment options for many Americans with MDD.1 

“We are pleased with the FDA’s acceptance and priority review designation of our NDA for AXS-05 in major depressive disorder and we look forward to continuing to work closely with the FDA throughout the review process,” said Harriet Tabuteau, MD, chief executive officer of Axsome.1


  1. Axsome Therapeutics Announces FDA Acceptance and Priority Review of New Drug Application for AXS-05 for Treatment of Major Depressive Disorder. News release. Axsome; April 26, 2021. Accessed April 28, 2021. https://www.globenewswire.com/news-release/2021/04/26/2216607/33090/en/Axsome-Therapeutics-Announces-FDA-Acceptance-and-Priority-Review-of-New-Drug-Application-for-AXS-05-for-Treatment-of-Major-Depressive-Disorder.html
  2. Axsome Therapeutics Presents New Data from GEMINI Phase 3 Trial with AXS-05 Demonstrating Rapid and Significant Improvements in Patient-Reported Outcomes in Major Depressive Disorder. News release. Axsome; September 14, 2021. Accessed April 28, 2021. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-presents-new-data-gemini-phase-3-trial-axs
  3. Axsome Therapeutics Completes Successful FDA Pre-NDA Meeting for AXS-05 for the Treatment of Major Depressive Disorder. News release. Axsome; July 13, 2020. Accessed April 28, 2021. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-completes-successful-fda-pre-nda-meeting-axs
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