FDA Staff Voice Concerns Over MDMA Trial Design and Side Effects Ahead of Landmark Judgment

As Lykos Therapeutics' midomafetamine (MDMA) approaches potential FDA approval as the first psychedelic treatment, concerns highlighted by the agency's staff scientists may hinder its progress. Lykos is seeking approval for MDMA to treat post-traumatic stress disorder (PTSD) based on promising Phase III trials, MAPP1 and MAPP2, which showed significant symptom reduction without serious adverse events. The FDA's decision is anticipated by August 9, following a priority review.

However, FDA briefing documents released before MDMA's advisory committee meeting on June 4 underline several issues with the trial design and results, such as the functional unblinding of participants, increased cardiovascular side effects, and insufficient data on potential abuse.

This isn't the first critique of Lykos' trials; the Institute for Clinical and Economic Review (ICER) recently questioned the validity of the MAPP studies due to biases and preconceived notions from therapists and patients about the efficacy of psychedelics in treating mental health conditions.

Key Concerns Highlighted by FDA

The FDA's briefing documents emphasize the problem of functional unblinding. In the trials, 94% of participants who received MDMA identified or suspected they had taken the drug, leading to "expectation bias." This bias could make interpreting the efficacy results challenging. However, the placebo group also showed improvement, suggesting that disappointment from not receiving the active drug did not exacerbate PTSD symptoms.

Another significant concern is the combination of MDMA with psychotherapy in the trials. Since psychotherapy is not regulated by the FDA, it complicates how the agency might reflect such co-treatment on the drug's label. The FDA expressed uncertainty about which component—MDMA or psychotherapy—was responsible for the treatment effect. The lack of data separating the effects of MDMA from psychotherapy raises questions about how to describe the role of psychotherapy in the product label.

Safety and Abuse Potential

A notable gap in the data pertains to the potential abuse of MDMA. The FDA had requested in 2017 that Lykos document all adverse events (AEs) related to potential abuse or overdose. However, Lykos did not systematically collect AEs deemed neutral, positive, or favorable, such as euphoria or stimulation, which could indicate "drug-liking." Without these data points, assessing the abuse potential of MDMA is more challenging.

Furthermore, the FDA's briefing documents reported significant increases in mean blood pressure and heart rate in patients who received MDMA compared to the placebo group. This concern is not merely theoretical; illicit use of MDMA has been linked to severe cardiovascular events like myocardial infarction and aortic dissection, although no such major events were reported in the clinical trials.

The psychedelic nature of MDMA, which can reduce inhibition and increase susceptibility to suggestion, also raises safety concerns. The documents suggest that patients could be at risk for serious harm due to impairment.

Proposed Safety Measures and Conclusion

If MDMA is approved, the FDA is likely to implement a Risk Evaluation and Mitigation Strategy (REMS). This strategy would include Elements to Assure Safe Use (ETASU), such as dispensing the drug only in specific healthcare settings and under medical supervision during and after administration. A patient registry might also be established to better understand patient risks.

The FDA concluded that, due to the small size of the safety database, limited clinical data, and no recording of positive effects perceived by patients, a post-marketing trial should be required if MDMA is approved.

In summary, while MDMA shows promise as a treatment for PTSD, the FDA's concerns about trial design, functional unblinding, cardiovascular side effects, and potential abuse could impact its approval prospects. If approved, stringent safety measures and additional post-marketing studies will likely be necessary to ensure its safe use.

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