Axsome's Phase III Results Show Significant Improvement in Depression

New York-based Axsome Therapeutics published results from the pivotal Phase III Gemini trial of AXS-05 (dextromethorphan-bupropion) in major depressive disorder (MDD). The study demonstrated rapid, substantial and statistically significant improvement in depressive symptoms and induction of remission. The drug is an NMDA receptor antagonist, using a proprietary formulation and dose of dextromethorphan and bupropion.

The study was published in The Journal of Clinical Psychiatry.

About two weeks ago, the company published promising data from its Phase II Ascend trial of the drug in The American Journal of Psychiatry. That study also demonstrated rapid, substantial and statistically significant improvement in depressive symptoms as well as inducing remission in comparison to the treatment of only bupropion in patients with moderate to severe MDD. Remission rates were also significantly higher with AXS-05 at week two of treatment and every period afterward.

AXS-05 has received Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of MDD. A new drug application (NDA) is currently under review. It is also being evaluated for treatment for Alzheimer’s disease, with an ongoing Phase III study launched in December 2020.

“The results published in The Journal of Clinical Psychiatry are consistent with strong and rapid antidepressant effects, and with a favorable safety profile with AXS-05,” said Dr. Maurizio Fava, M.D., psychiatrist-in-chief, Department of Psychiatry, Massachusetts General Hospital, executive director, Clinical Trials Network & Institute, associate dean for Clinical & Translational Research, Slater Family Professor of Psychiatry, Harvard Medical School, and co-author of the study.

Fava added, “Depression is a difficult-to-treat condition with potentially devastating consequences for patients and their families. Based on these results and its novel oral NMDA antagonist mechanism, AXS-05 may represent an important new treatment option for patients with depression.”

The study evaluated a total of 327 patients with confirmed diagnoses of moderate to severe MDD. They received either AXS-05 or a placebo once a day for the first three days and twice daily after, for a total of six weeks. The primary endpoint was a change in the Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to week six. The key secondary endpoints were changed from baseline in the MADRS total score at week two, remission on the MADRS at week 2, and clinical response on the MADRS at week six.

The change from baseline in MADRS score to week 6 was significantly greater with the drug versus placebo, -15.9 points versus -12.0 points, and hit the secondary endpoints. The drug was well tolerated. The most common side effects were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. It was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.

“We are very pleased with the publication of the pivotal Gemini trial results in The Journal of Clinical Psychiatry, a leading scientific journal, less than two weeks after the publication of the pivotal ASCEND trial results in The American Journal of Psychiatry,” said Dr. Herriot Tabuteau, M.D., chief executive officer of Axsome. “These studies demonstrate a consistent efficacy profile for AXS-05 and form the basis of our NDA for the treatment of depression. If approved, we look forward to making AXS-05 available to Americans suffering from depression as soon as possible.”

In early May, the company received a complete response letter from the FDA for a different drug, AXS-07, for migraine. At issue were chemistry, manufacturing and controls (CMC) data-related concerns and the company indicates it is using FDA communication channels to expedite the resolution of the concerns. AXS-07 is an oral drug for fast relief of migraines, utilizing rizatriptan in combination with meloxicam in a formulation of the company’s molecular solubility enhanced inclusion complex (MoSEIC) technology.