FDA Approves Rapid-Acting Auvelity for Major Depression

The FDA has approved Axsome Therapeutics’ Auvelity (dextromethorphan-bupropion) extended-release tablets to treat major depressive disorder (MDD) in adults. Axsome anticipates Auvelity (formerly called AXS-05) to be commercially available in the United States in the fourth quarter of 2022.

Maurizio Fava, M.D.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral N-methyl D-aspartate (NMDA) antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, M.D., psychiatrist-in-chief, department of Psychiatry, Massachusetts General Hospital, said in a press release. He is also executive director, Clinical Trials Network & Institute, associate dean for Clinical & Translational Research, and Slater Family Professor of Psychiatry at Harvard Medical School.

Nearly two thirds of patients treated with currently available antidepressants do not adequately respond, Fava said. “Auvelity represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over sixty years.”

Auvelity is the first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared with placebo starting at one week. The rapid antidepressant effects were sustained at all subsequent timepoints.

The approval was based on two trials, including the GEMINI placebo-controlled study, and confirmatory evidence and the ASCEND study comparing Auvelity to bupropion sustained-release tablets. Data from the GEMINI study were published in May 2022 in The Journal of Clinical Psychiatry and data from the ASCEND study were published in May 2022 in The American Journal of Psychiatry.

In the GEMENI study, Auvelity was statistically significantly superior to placebo in improvement of depressive symptoms as measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week six, the study’s primary endpoint. To evaluate speed of onset of action, the change in MADRS total score from baseline to week one and from baseline to week two were pre-specified secondary efficacy endpoints.

In the ASCEND study, Auvelity was statistically significantly superior to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure. The most common adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.

The FDA granted breakthrough therapy designation for Auvelity for the treatment of MDD in March 2019, and the new drug application (NDA) was evaluated by the FDA under priority review.

Auvelity 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 of Auevelity is an aminoketone, which increases blood levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan.

Major depressive disorder is a debilitating, chronic, biologically-based disorder. An estimated 21 million U.S. adults experienced MDD each year, according to the Department of Health and Human Services.

Axome is also studying Auvelity in Alzheimer’s disease agitation and smoking cessation. The company is initiating a new placebo-controlled parallel group trial (ADVANCE-2) this quarter for the Alzheimer’s indication. Axome has amended the relapse criteria for its trials in this indication and is conducting a new trial to generate additional data. Topline results from ACCORD are now anticipated in the fourth quarter of 2022.

In smoking cessation, Axsome plans to proceed to a pivotal phase 2/3 trial, and will provide information on the timing of this study later this year.