FDA Rejects MDMA-Assisted Therapy to Treat PTSD in Setback for Psychedelic Medicine

The FDA has issued a complete response letter (CRL) to a new drug application (NDA) for midomafetamine (MDMA)-assisted therapy to treat post-traumatic stress disorder (PTSD) in adults, Lykos Therapeutics announced in a release.¹ The decision, which would have made MDMA-assisted therapy the first psychedelic-assisted therapy available in the United States if it was approved, marks a significant setback for the psychedelic medicine community.

FDA Rejects MDMA-Assisted Therapy to Treat PTSD in Setback for Psychedelic Medicine / Tada Images - stock.adobe.com

In the FDA’s response, the agency said it could not approve the NDA based on the submitted data and requested an additional Phase 3 trial to “further study the safety and efficacy” of MDMA. Lykos said that the issues expressed in the CRL were similar to ones raised at an advisory committee meeting held in June. During that meeting, members of the Psychopharmacologic Drugs Advisory Committee voiced concerns about the occurrence of functional unblinding in the studies, as well as adverse events that occurred, particularly around cardiovascular effects from the drug. Committee members also cited the lack of data on the potential for abuse as an issue and ultimately voted against the use of the therapy.

WATCH: As FDA Decision on MDMA for PTSD Looms, What Would Approval Mean for Mental Health Treatment?

"Developing the first-ever clinical trial design to assess the safety and efficacy of midomafetamine-assisted therapy with patients suffering from moderate to severe PTSD is an enormously complex undertaking," Jennifer Mitchell, PhD, professor of neurology and psychiatry and behavioral sciences at UCSF, said in a release.¹ "Over the course of many years, the researchers, with the support of our sponsor, Lykos, developed and executed Phase 3 studies that we believe demonstrated the approvability of this treatment. We did so in consultation with the FDA and with an agreed Special Protocol Assessment in place. The FDA's decision to request another Phase 3 study is a major setback for the field."

The NDA from Lykos was based on data from the phase 3 MAPP1 (NCT03537014) and MAPP2 (NCT04077437) trials, in which MDMA-assisted therapy met its primary endpoint of changes in PTSD symptom severity as measured by change from baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The therapy also met its key secondary endpoint of improvement in functional impairment associated with PTSD as measured by change from baseline in the Sheehan Disability Scale (SDS). Data from both studies were published separately in Nature Medicine.^2,3

MAPP1 was a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial evaluating the efficacy and safety of MDMA-assisted therapy in patients with severe PTSD. The study cohort included 90 patients who were randomly assigned to receive manualized therapy with MDMA or placebo, combined with 3 preparatory and 9 integrative therapy sessions. MAPP2 was a multi-site, randomized, double-blind, confirmatory phase 3 study evaluating the efficacy and safety of MDMA-assisted therapy in patients with moderate to severe PTSD. The study cohort included 104 participants who were randomly assigned to receive MDMA-assisted therapy or placebo with therapy.

In MAPP1, investigators found that MDMA-assisted therapy induced significant and robust attenuation in CAPS-5 score compared with placebo, and significantly decreased the SDS total score. The mean change in CAPS-5 scores was −24.4 in the MDMA group and −13.9 in the placebo group. In MAPP2, least squares (LS) mean change in CAPS-5 score was −23.7 in the MDMA-assisted therapy group, compared to −14.8 in the placebo group. In the MDMA-assisted therapy group, LS mean change in SDS score was −3.3, compared to −2.1 in the placebo group.

In both studies, MDMA-assisted therapy was seen to be generally well tolerated with no serious treatment related adverse events occurring. In MAPP1, the therapy did not induce adverse events of abuse potential, suicidality or QT prolongation. In MAPP2, there were severe treatment emergent adverse events in 7 patients, with 5 occurring in the therapy group and 2 in the placebo group. The mostly commonly reported adverse events, which were transient and mild to moderate in severity, included muscle tightness, nausea, decreased appetite and hyperhidrosis.

“The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over 2 decades," Amy Emerson, CEO of Lykos, said in a release.¹ "While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature."

Lykos said that it plans to “work diligently” in the coming months to try and address the issues raised by the FDA in the CRL. The company added that it intends to request a meeting with the FDA to discuss the decision and aims to provide an update following that meeting.

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References

1. Lykos Therapeutics Announces Complete Response Letter for Midomafetamine Capsules for PTSD. News Release. August 9, 2024. Accessed August 9, 2024. https://news.lykospbc.com/2024-08-09-Lykos-Therapeutics-Announces-Complete-Response-Letter-for-Midomafetamine-Capsules-for-PTSD

2. Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025–1033 (2021). https://doi.org/10.1038/s41591-021-01336-3

3. Mitchell, J.M., Ot’alora G., M., van der Kolk, B. et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med 29, 2473–2480 (2023). https://doi.org/10.1038/s41591-023-02565-4