The Food and Drug Administration (FDA) has granted Priority Review to AXS-05 (dextromethorphan-bupropion; Axsome Therapeutics) for the treatment of major depressive disorder (MDD).

AXS-05 consists of dextromethorphan, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, and bupropion, a norepinephrine and dopamine reuptake inhibitor that serves to increase the bioavailability of dextromethorphan. The NDA is supported by data from the randomized, double-blind, controlled phase 3 GEMINI ( NCT04019704) and phase 2 ASCEND ( NCT03595579) trials that evaluated AXS-05 in patients with MDD.

The GEMINI trial included 327 adults who met the DSM-5 criteria with confirmed moderate to severe MDD. Patients were randomly assigned 1:1 to receive either AXS-05 tablet or placebo once daily for the first 3 days, then twice daily thereafter for a total of 6 weeks. 

Findings from the GEMINI trial showed that treatment with AXS-05 led to a statistically significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with placebo at week 6 (16.6 points for AXS-05 vs 11.9 points for placebo; P =.002). Moreover, AXS-05 was associated with a significant improvement on the Clinical Global Impression of Improvement (CGI-I) scale at week 6 compared with placebo (P =.016). Patients treated with AXS-05 also reported rapid improvement in depressive symptoms starting at week 1 and at every time point thereafter.

In the ASCEND trial, 80 patients with confirmed moderate to severe MDD were randomly assigned to receive either AXS-05 or bupropion twice daily for 6 weeks. Results showed that AXS-05 met the primary endpoint demonstrating a statistically significant average mean reduction from baseline in the MADRS total of 13.7 points vs 8.8 points with bupropion (P <.001). 

As for safety, the most commonly reported adverse events included dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. Additionally, treatment with AXS-05 was not found to be associated with psychotomimetic effects or weight gain.

A Prescription Drug User Fee Act (PDUFA) target date of August 22, 2021 has been set for this application.

“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 Herriot Tabuteau, MD, CEO of Axsome. “If approved, AXS-05 would be an important new treatment option for the many Americans living with depression.”

The Company is also investigating AXS-05 in the phase 3 STRIDE-1 trial ( NCT02741791) as a potential therapy for treatment-resistant depression, as well as the ADVANCE-1 study ( NCT03226522) in patients with Alzheimer disease agitation.


  1. Axsome Therapeutics announces FDA acceptance and Priority Review of New Drug Application for AXS-05 for treatment of major depressive disorder. [press release]. New York, NY: Axsome Therapeutics, Inc; April 26, 2021. 
  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. [press release]. New York, NY: Axsome Therapeutics, Inc; September 14, 2020.
  3. Axsome Therapeutics completes successful FDA pre-NDA meeting for AXS-05 for the treatment of major depressive disorder. [press release]. New York, NY: Axsome Therapeutics, Inc; July 13, 2020.