FDA Approves First, Only NMDA Receptor Antagonist for Major Depressive Disorder

Officials with the FDA have approved Auvelity (dextromethorphan Hbr -bupropion HCI; Axsome Therapeutics) extended-release tablets for the treatment of adults with major depressive disorder. Auvelity is the first and only rapid-acting oral medication approved for major depressive disorder with labeling of statistically significant antidepressant efficacy compared to placebo starting at 1 week.

Auvelity uses the first new oral mechanism of action for major depressive disorder developed in more than 60 years, according to an Axsome press release. It works on the NMDA receptor, an ionotropic glutamate receptor, and on the sigma-1 receptor in the brain via its dextromethorphan component. The bupropion component is an aminoketone, which increases blood levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6 (CYP2D6). This action catalyzes a major biotransformation pathway for dextromethorphan.

The FDA granted Breakthrough Therapy designation to Auvelity for the treatment of major depressive disorder in March 2019 and the New Drug Application was evaluated under priority review.

“Auvelity, which was granted Breakthrough Therapy designation by the FDA, represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over 60 years,” said Maurizio Fava, MD, psychiatrist-in-chief in the Department of Psychiatry at Massachusetts General Hospital, in the press release. “Nearly two-thirds of patients treated with currently available antidepressants do not adequately respond, and those that do may not achieve clinically meaningful responses for up to 6 to 8 weeks. Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition.”

It was investigated in a comprehensive clinical program including more than 1100 patients with depression. The efficacy of Auvelity for major depressive disorder was demonstrated in the GEMINI placebo-controlled study and confirmatory evidence was established in the ASCEND study comparing Auvelity to bupropion sustained-release tablets.

According to the GEMINI study findings, Auvelity showed statistically significantly superiority to placebo in improvement of depressive symptoms as measured by the trial’s primary endpoint, change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6. To evaluate the speed of onset of action, the change in MADRS total score from baseline to week 1 and from baseline to week 2 were pre-specified secondary efficacy endpoints. The difference between Auvelity and placebo in change from baseline in MADRS total score was statistically significant at week 1 and week 2.

In the ASCEND trial, Auvelity showed statistically significant superiority to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure. In the placebo-controlled clinical study, the most common adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.

“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,” Fava said in the press release.

REFERENCE

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; August 19, 2022. Accessed August 19, 2022. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-fda-approval-auvelitytm-first-and