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FDA staff raised concerns about the available safety data and limitations in the study design for midomafetamine (MDMA) to treat post-traumatic stress disorder (PTSD) in released ahead of an FDA Psychopharmacologic Drugs Advisory Committee (PDAC) .

If eventually approved by the agency, Lykos Therapeutics' MDMA could become a first-in-class treatment for PTSD, which affects an estimated 5% of the U.S. population in any given year, according to the Veterans' Administration National Center for PTSD. While PTSD can be treated with selective serotonin reuptake inhibitors (SSRIs), FDA staff noted that response rates with these drugs rarely exceed 60%, and achieve full remission.

"Thus, there remains an unmet need for additional options for safe and effective therapies to treat PTSD," the FDA reviewers wrote.

The agency will ask the PDAC to discuss several major points during the June 4 meeting. The committee will first focus on efficacy, including the potential effect of functional unblinding on the interpretability of efficacy results, the durability of effects, and the role of psychotherapy in the treatment paradigm. It will assess the adequacy of the safety characteristics of MDMA, and review the potential for patient impairment or serious harm from treatment. In addition, the PDAC will weigh in on a proposed risk mitigation strategy to prevent serious patient harms related to MDMA treatment.

Two phase III trials conducted have assessed the efficacy and safety of MDMA in PTSD. Both studies, MAPP1 and MAPP2, were randomized, double-blind, placebo-controlled trials that included 91 and 104 participants with PTSD, respectively. Participants received three dosing sessions of MDMA with additional psychological support sessions before and after dosing.

In both trials, the MDMA arm experienced statistically significantly greater improvement in PTSD symptoms based on the total severity score.

In MAPP1, the MDMA and psychotherapy group saw an average drop in CAPS-5 score of 24.4 points, while those receiving psychotherapy alone saw an average drop of 13.9 points. In MAPP2, patients in the MDMA arm had a least-squares mean change of -23.7 in CAPS-5 score compared with -14.8 for those in the placebo arm (P<0.001). Patients taking MDMA also achieved the prespecified secondary endpoints in both trials.

"Based on the clinical trial data submitted with this application, participants appear to experience rapid, clinically meaningful, durable improvement in their PTSD symptoms," FDA staff wrote. "However, several factors make these data challenging to interpret and complicate the benefit-risk assessment for this application. Chief among these factors is the nature of the treatment itself."

MDMA often causes profound alterations in mood, sensation, suggestibility, and cognition, they noted. These effects make it nearly impossible to blind participants in clinical trials. In fact, FDA staff pointed out that roughly 90% of patients in the treatment arm and 75% in the placebo arm of the MDMA trials were able to correctly guess their assignment during a post-study survey.

The safety assessment of MDMA also presents numerous challenges, the reviewers pointed out. "For example, the cardiac safety profile of midomafetamine is not well characterized and the QT-assessment is incomplete," they wrote. "Significant increases in both blood pressure and pulse were observed and were considered adverse events of special interest (AESI). This has the potential to trigger cardiovascular events, which have been described in literature reports of illicit MDMA use."

FDA staff noted that there were limited clinical laboratory data available, which meant some potential adverse events like hepatotoxicity would not be sufficiently identified in the safety data. "If this application were to be approved, the [FDA] would likely issue a postmarketing requirement to collect additional laboratory safety data, including liver function tests," they wrote.

The reviewers said the subjective effects of MDMA could present additional safety concerns for several reasons, including prolonged impairment and vulnerability or potential for abuse.

MDMA treatment has been a hotly debated subject in recent years, with advocates calling for full approval for a range of mental health conditions, and others expressing concerns about potential harms. While the FDA is not required to follow the recommendations of its advisory committees, it typically does.

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