The Food and Drug Administration (FDA) has approved Auvelity (dextromethorphan HBr-buproprion HCl) extended-release tablets for the treatment of adults with major depressive disorder (MDD).

Auvelity 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 by competitively inhibiting cytochrome P450 2D6. The exact mechanism of action of Auvelity in the treatment of MDD is unclear. 

The approval was based on efficacy and safety data from the randomized, double-blind, controlled phase 3 GEMINI (ClinicalTrials.gov: NCT04019704) and phase 2 ASCEND (ClinicalTrials.gov: NCT03595579) trials that evaluated Auvelity in patients with MDD.

The GEMINI trial included 318 adults who met the DSM-5 criteria for MDD. Patients were randomly assigned 1:1 to receive either Auvelity (dextromethorphan HBr 45mg and bupropion HCl 105mg) twice daily or placebo for a total of 6 weeks. 

Findings from the GEMINI trial showed that treatment with Auvelity met the primary endpoint, achieving a statistically significantly superior improvement of depressive symptoms as measured in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with placebo at week 6 (15.9 points for Auvelity vs 12.1 points for placebo). Moreover, there was a statistically significant difference in the change from baseline in MADRS total score at weeks 1 and 2 between Auvelity and placebo.

In the ASCEND trial, 80 patients with confirmed diagnosis of moderate to severe MDD were randomly assigned to receive either Auvelity (dextromethorphan HBr 45mg and bupropion HCl 105mg) or bupropion HCl sustained-release tablets 105mg twice daily for 6 weeks. Results showed that Auvelity 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). The trial showed that dextromethorphan contributes to the antidepressant properties of Auvelity.

As for safety, Auvelity carries a Boxed Warning associated with the risk of suicidal thoughts and behaviors. The most commonly adverse reactions (incidence of at leats 5% and more than twice as frequently as placebo) were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis. Additionally, treatment with AXS-05 was not found to be associated with psychotomimetic effects or weight gain.

Maurizio Fava, MD, Psychiatrist-In-Chief, Massachusetts General Hospital said, “The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile.” 

Auvelity is supplied as dextromethorphan HBr 45mg/bupropion HCl 105mg extended-release tablets in 30-count bottles. The product is expected to be available in the fourth quarter of 2022.

References

  1. Axsome Therapeutics announces FDA approval of Auvelity™, the first and only oral NMDA receptor antagonist for the treatment of major depressive disorder in adults. News release. Axsome Therapeutics, Inc. Accessed August 19, 2022. https://www.globenewswire.com/news-release/2022/08/19/2501453/33090/en/Axsome-Therapeutics-Announces-FDA-Approval-of-AUVELITY-the-First-and-Only-Oral-NMDA-Receptor-Antagonist-for-the-Treatment-of-Major-Depressive-Disorder-in-Adults.html
  2. Auvelity. Package insert. Axsome Therapeutics, Inc.; 2022. Accessed August 19, 2022. https://www.auvelity.com/prescribing-information.pdf
  3. Axsome Therapeutics announces publication of pivotal ascend phase 2 trial of axs-05 in major depressive disorder in The American Journal of Psychiatry. News release. Axsome Therapeutics, Inc. May 18, 2022. Accessed August 19, 2022. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-publication-pivotal-ascend-phase-2