'Impressive' Results for Novel Antidepressant, So Why the FDA Delay?

Liam Davenport

October 12, 2021

A novel antidepressant (AXS-05, Axsome Therapeutics) appears to have a rapid and durable effect in patients with major depressive disorder (MDD), results of an open label, phase 3 trial, show. Yet, its new drug application (NDA) remains in limbo with the US Food and Drug Administration (FDA) for reasons that are unclear.

In the study, which included 876 patients with MDD, results showed the drug, a combination of dextromethorphan and bupropion, had a clinical response rate of 80% and a remission rate of almost 70%. In addition, functional improvements were "substantial" and AXS-05 was determined to be "generally safe and well-tolerated."

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.

The Study

The COMET trial was a phase 3, multicenter, US trial, in which patients with MDD were treated with AXS-05 twice daily for up to 12 months. Patients had to have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 25. They could have completed a prior AXS-05 study or be newly enrolled.

Of 876 patients included in the study, 611 were newly enrolled. The mean age was 42.4 years, and 62.4% were women. Just over half (58.1%) were white, with 35.6% black, and 2.0% Asian. The mean body mass index was 31.4 kg/m2.

The mean MADRS total score at baseline was 32.7 and the Sheehan Disability Scale (SDS) score was 20.0.

Presenting efficacy data in 609 newly enrolled patients, the team showed that MADRS total scores fell sharply on starting AXS-05, by 9.1 points at week 1, 14.0 points at week 2, and 21.2 points at week 6.

By 6 months, the reduction over baseline was 23.9 points, which was maintained out to 12 months, at a mean reduction of 23.0 points.

The proportion of patients achieving a clinical response, defined as a ≥ 50% improvement in MADRS scores, was 18.8% at week 1, 39.7% at week 2, and 73.2% at week 6. There was a clinical response in 84.6% of patients at 6 months and in 82.8% at 12 months.

Clinical remission, defined as a MADRS score ≤ 10, was achieved in 8.3% of patients at week 1, rising to 21.5% at week 2, and 52.5% at week 6. At 6 months, 68.7% of patients were in clinical remission, reaching 69.0% at 12 months.

These benefits were accompanied by substantial improvements in depressive symptoms on the Clinical Global Impression of Improvement scale, with a marked or moderate improvement seen in 86.7% of patients at 6 months and 93.1% at 12 months.

Moreover, a clinical response in functioning on the SDS was achieved by 80.6% of patients at 6 months and 75.9% at 12 months.

The safety analysis of AXS-05 in the entire cohort suggested it was well-tolerated, with dizziness seen in 12.7% of patients, along with nausea in 11.9%, headache in 8.8%, dry mouth in 7.1%, and decreased appetite in 6.1%.

The rate of discontinuation due to adverse events was 8.4%, and there were no signs of psychotomimetic effects, cognitive impairment, weight gain, or increased sexual dysfunction.

Other research presented at the meeting also showed that the drug was associated with a reduction in suicidal ideation and increased rates of suicidal ideation resolution, and was also effective for treatment-resistant depression.

Results from an analysis of the ASCEND phase 2 and GEMINI phase 3 trials also suggested that AXS-05 was superior to both bupropion and placebo in achieving rapid and sustained improvements in depression symptoms.

FDA Delay

Yet despite these seemingly positive findings, the FDA appears to have issues with the agent's new drug application.  

As reported by Medscape Medical News in August, the agency reviewed the NDA for AXS-05 for the treatment of MDD, but at that time the drug's manufacturer revealed that the agency had identified "deficiencies that preclude labeling discussions at this time."

With the latest results presented at ECNP 2021, Medscape Medical News asked Axsome about the status of the NDA and whether there had been any further discussions and/or movement with the FDA.

Instead of a direct reply from the drug company, Medscape Medical News was directed to a statement released by Axsome in August announcing that the FDA had informed the company that its NDA review "would not be completed by the Prescription Drug User Fee Act target action date of August 22, 2021."

"The FDA did not request additional information from the Company, and the review of the application is ongoing," the statement said. Axsome did not respond to further questions.

"Impressive" Remission Rate

Commenting on the research for Medscape Medical News, Marin Jukic, PhD, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden, who was not involved in the research, said AXS-05 "looks promising in relation to the efficacy and tolerability results" with a remission rate that is "truly impressive."

However, Jukic cautioned that it was an open-label trial and therefore had no placebo or active comparator arms.

He noted that it would be "interesting to compare the efficacy with placebo and escitalopram, for example, to evaluate the potential for the benefits and efficacy better."

34th European College of Neuropsychopharmacology (ECNP) Congress. Abstracts P.0384, P.0385, P.0386, P.0388. Presented October 2, 2021.

The research was funded by Axsome Therapeutics, and, except for one, the researchers for the four studies are employees of Axsome Therapeutics.

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