The FDA's recent rejection of Lykos Therapeutics' MDMA-assisted therapy for post-traumatic stress disorder (PTSD) has sent ripples through the psychedelic drug development community, prompting companies to re-evaluate their strategies and prioritize alternative assets.
FDA's Concerns Lead to Setback
On August 9, 2024, the FDA issued a complete response letter (CRL) to Lykos Therapeutics, rejecting their new drug application (NDA) for midomafetamine, Lykos’ proprietary formulation of MDMA, as a treatment for PTSD. The FDA requested an additional Phase 3 trial to further study the efficacy and safety of MDMA. This decision followed a meeting of the FDA’s Psychopharmacology Drugs Advisory Committee, which voted 9-2 that the available data did not demonstrate the effectiveness of midomafetamine and 10-1 that the benefits did not outweigh the risks.
The FDA Advisory Committee raised concerns regarding the “functional unblinding” of the study design, as the cognitive and sensory effects of MDMA made it easy for participants to discern whether they received the drug or a placebo. Additionally, the FDA does not regulate psychotherapy, making it challenging to assess the efficacy of the combined drug and therapy approach.
Industry Response and Pipeline Reprioritization
The rejection has led some psychedelic drug developers to reassess their pipelines. Matthew Baggott, co-founder and CEO of Tactogen, stated that the setback primarily reflects on Lykos’ trial design rather than MDMA itself. Tactogen is now considering prioritizing its novel compounds and waiting to move forward with its MDMA product. Similarly, atai Life Sciences is prioritizing its MDMA-based asset, EMP-01, for social anxiety disorder and will monitor Lykos' progress before further pursuing MDMA for PTSD.
Addressing Safety Concerns and Improving Therapeutic Potential
Several companies are focusing on improving the safety profile of MDMA. Tactogen is exploring fixed-dose combinations to reduce side effects and is also investigating a program combining MDMA with citalopram, a selective serotonin reuptake inhibitor (SSRI), for PTSD. atai Life Sciences is focusing on one of MDMA's two enantiomers, (R)-MDMA, in its candidate EMP-01, aiming to improve the therapeutic index by potentially reducing cardiovascular risks associated with the stimulant effects of the (S) enantiomer.
Unmet Need and the Future of Psychedelic Therapies
Despite the setback, experts emphasize the high unmet need for effective PTSD treatments. The delay in approving MDMA-assisted therapy is seen as a “loss of opportunity” to lower the death rate from PTSD-related suicides, particularly among veterans. According to the U.S. Department of Veterans Affairs, seven out of every 100 veterans will have PTSD, and in 2021, there were over 17 veteran suicides per day.
Other countries have taken a different approach. Australia approved the use of MDMA for PTSD in 2023, and a Dutch panel recommended MDMA to its government for PTSD treatment. These decisions highlight the growing recognition of the potential benefits of psychedelic therapies, even as regulatory hurdles remain in the United States.
The Path Forward
While the FDA's rejection of Lykos' MDMA therapy represents a setback, it also provides an opportunity for companies to refine their approaches, address safety concerns, and improve the therapeutic potential of psychedelic treatments. The industry remains optimistic about the future of psychedelic therapies, with ongoing research and clinical trials paving the way for potential breakthroughs in mental health care.
