FDA Declines to Approve MDMA for PTSD

Updated at 9:31 am on August 12, 2024.

The FDA has issued a complete response letter (CRL) for Lykos Therapeutics' midomafetamine (MDMA) capsules for the treatment of posttraumatic stress disorder (PTSD).

The agency is requesting an additional phase 3 trial to determine the safety and efficacy of MDMA.¹ Lykos said it has requested a meeting with the FDA to ask it to reconsider the decision in addition to discussing recommendations for a resubmission.

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In the days leading up to the FDA's decision, there was growing attention on the therapy for PTSD. In a letter to the president from Representatives Jack Bergman (R), J. Luis Correa (D), Morgan Luttrell (R), et al, officials call for the approval of MDMA therapy to enhance treatment of post-traumatic stress disorder (PTSD) for veterans.² They stated, "Hope is on the horizon. Promising new treatments like MDMA-assisted therapy (MDMA-AT) have the clinically proven potential to bring veterans who have long suffered with PTSD a treatment that works."

In February 2024, the FDA accepted the new drug application (NDA) for midomafetamine capsules (3,4-Methylenedioxy-methamphetamine [MDMA; Lykos Therapeutics]) as an adjunct therapy in combination with psychological interventions, which included psychotherapy and other services from a health care provider.³

The NDA submission was based on the MAPP1 and MAPP2 studies, which met both primary and secondary outcomes, including changes in symptom severity measured by Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), improvement in functional impairment associated with PTSD measured by the change in baseline in Sheehan Disability Scale (SDS). The studies included patients that were randomly assigned treatment of either MDMA or the placebo, combined with 3 preparatory and 9 integrative therapy sessions. They found that MDMA led to a significant and robust attenuation of CAPS-5 score when compared to the placebo, as well as significant decreases in the total SDS scores.³

On August 1, 2024, Lykos Therapeutics announced new initiatives and measures for additional oversight for MDMA in combination with psychological intervention. The company stated that the health care professional who is providing psychological intervention will use their clinical judgement to deliver the treatment, with appropriate oversight from governing bodies in addition to requirements and controls set by product labeling and Risk Evaluation Mitigation Strategies.⁴

There are 3 new initiatives: establishing an independent advisory board; working with top behavioral health facilities; and collaborating on training. The advisory board will be external experts in corporate, medical ethics, innovation, psychiatry, and military and veteran health to inform the company on the commercial launch of the drug. To ensure preparations of sites for the therapy, all sites will have to meet all the FDA and Drug Enforcement Administration requirements, including nationally accredited centers, veteran health care facilities, and medical centers with medical and behavioral health care oversight. Further, the company will look to external perspectives from institutions and health systems on training initiatives. The company is currently discussing how to begin training to appropriate needs to those delivering treatment. The independent advisory board will also advice on therapist training and delivery.⁴

"There's a lot of themes around seeing these as a way to shift and modify new behaviors that are more adaptive and provide more resilience against anxiety, depression, and substance use disorders," said Kelan Thomas, PharmD, MS, associate professor of clinical sciences at Touro University California College of Pharmacy, in an interview with Pharmacy Times. "That's the major theme that I'm seeing is this whole new paradigm of adding psychotherapy comes with a lot more complexity than just a simple drug approval like just tak[ing] the drug and you'll get the result. This has this added aspect of psychotherapy, and that's a whole very new concept in terms of the drug approval process—having studies that are looking at drug plus psychotherapy."⁵

Previously, an independent advisory panel for the FDA recommended rejecting the use of MDMA-assisted therapy for PTSD, citing concerns of the reliability of the clinical trial data and stating that the benefits do not outweigh the risks with therapy. The study designs were questioned, specifically whether the patients were able to correctly guess if they received either MDMA or the placebo, according to an article in Pharmacy Times. There were also concerns about potential for drug abuse as well as potential cardiovascular effects of the drug.⁶

“There are pushes globally to reconsider how psychedelic medicines are evaluated by regulatory bodies. There’s growing recognition of their potential therapeutic benefits. Different countries are exploring various models to integrate these compounds into medical and therapeutic settings more effectively,” Al-Olimat said in an interview with Pharmacy Times.⁷

He added that Australia has recently moved to allow the use of MDMA and psilocybin for medical treatments, and Europe has also been working to establish regulatory guidelines for the use of psychedelic medicine. Further, Canada has also been proactive on the issue, Al-Olimat said, noting that psilocybin has been used for end-of-life care and other specific cases that are exempt from normal regulations.⁷

“These developments indicate a significant shift from the tight controls placed on these compounds historically, suggesting that regulatory bodies are beginning to respond to the therapeutic potentials of psychedelics, albeit with a careful and structured approach to ensure safety and control,” Al-Olimat said.⁷

The Multidisciplinary Association for Psychedelic Studies (MAPS) issued a statement on the CRL of MDMA-assisted therapy.

“MAPS and our supporters have been advocating for the development and supporting the FDA-approved research of MDMA-assisted therapy for more than 38 years; MAPS will continue working towards safe, legal access to this therapy for the more than 350 million people living with PTSD worldwide," Rick Doblin, PhD, founder and president of MAPS, said in the statement. "Our collective commitment to MDMA-assisted therapy remains unwavering. MAPS remains fully focused on supporting culturally appropriate research, rigorous science, and drug policy reform that empowers citizen advocacy in all areas of the world including those with high incidences of trauma and limited resources.”⁸

References

1. Lykos Therapeutics announces complete response letter for midomafetamine capsules for PTSD. News release. Lykos Therapeutics. 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. Correa, Bergman, Luttrell, Panetta lead colleagues in highlighting breaking through therapy for veterans. News release. Representative Lou Correra. August 5, 2024. Accessed August 9, 2024. https://correa.house.gov/news/press-releases/correa-bergman-luttrell-panetta-lead-colleagues-in-highlighting-breakthrough-therapy-for-veterans

3. Gallagher A. FDA Accepts New Drug Application for MDMA-Assisted Therapy for PTSD. Pharmacy Times. February 13, 2024. Accessed July 18, 2024. https://www.pharmacytimes.com/view/fda-accepts-new-drug-application-for-mdma-assisted-therapy-for-ptsd

4. Lykos Therapeutics announces new initiatives and measures for additional oversight for midomafetamine-assisted therapy, if FDA approved. News release. Lykos Therapeutics. August 1, 2024. Accessed August 8, 2024. https://news.lykospbc.com/2024-08-01-Lykos-Therapeutics-Announces-New-Initiatives-and-Measures-for-Additional-Oversight-for-Midomafetamine-Assisted-Therapy,-if-FDA-Approved

5. Pharmacy Times. Expert: MDMA is very likely to be FDA-approved for PTSD by the end of 2023. November 8, 2021. Accessed August 8, 2024. https://www.pharmacytimes.com/view/expert-mdma-is-very-likely-to-be-fda-approved-for-ptsd-by-the-end-of-2023

6. Antrim A. FDA Advisory panel rejects MDMA-assisted therapy for PTSD. Pharmacy Times. June 4, 2024. Accessed July 18, 2024. https://www.pharmacytimes.com/view/fda-advisory-panel-rejects-mdma-assisted-therapy-for-ptsd

7. Al-Olimat S. What does the FDA Panel’s MDMA rejection mean for the future of psychedelic medicines? Pharmacy Times. June 19, 2024. Accessed July 18, 2024. https://www.pharmacytimes.com/view/what-does-the-fda-panel-s-mdma-rejection-mean-for-the-future-of-psychedelic-medicines-

8. MAPS Statement on FDA Complete Response Letter on MDMA-Assisted Therapy for PTSD New Drug Application. News release. MAPS. August 9, 2024. Accessed August 12, 2024. https://maps.org/2024/08/09/maps-statement-on-fda-complete-response-letter-on-mdma-assisted-therapy-for-ptsd-new-drug-application