With MDMA on Hold, What’s Next for Psychedelics?
The FDA instead issued a CRL for MDMA-assisted psychotherapy for PTSD, requesting an additional phase 3 trial to examine safety and efficacy. Other psychedelic compounds are proceeding with trials for psychiatric conditions. Learn more here.
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In what could have been a landmark approval, the US Food and Drug Administration instead issued a complete response letter (CRL) for midomafetamine (MDMA)-assisted psychotherapy (MDMA-AT) for posttraumatic stress disorder (PTSD), requesting an additional phase 3 trial to examine safety and efficacy.1
As this issue went to press, Lykos Therapeutics told Psychiatric Times that they were seeking a meeting with the FDA and were committed to finding a path forward. Lykos has asserted that the requests and questions could be addressed “with existing data, post-approval requirements or through reference to the scientific literature.”1
More in the Pipeline
As Lykos and the FDA continue their tango, other psychedelic compounds are proceeding with trials for psychiatric conditions. Hot on the heels of the MDMA-AT announcement, Atai announced positive preliminary results from their phase 1b trial of VLS-01/VLS-01-BU, an oral transmucosal film formulation of N,N-dimethyltryptamine (DMT) indicated for treatment-resistant depression (TRD). Previous research has indicated that intravenous DMT, a partial agonist of the 5-HT 1A/2 A /2 C receptors, can result in rapid-acting and durable antidepressant effects in patients with major depressive disorder (MDD). The company expects the buccal film formulation to be as effective as IV administration, with the added convenience of not needing a needle.2
The phase 2 study is anticipated to start at the end of 2024. It will consist of 2 treatment periods and will be a randomized, double-blind, placebo-controlled trial assessing the safety, efficacy, and durability of response of repeated doses.
Numinus is also pioneering psychedelic-assisted therapy. Following the FDA’s CRL decision, Payton Nyquvest, Numinus Founder and CEO, told the press, “While this is a blow to all the incredibly positive and encouraging work that has been done to advance safe access to psychedelic therapy... we remain unwavering and committed to doing all we can to make these important therapies available for all those suffering who need it most.”3
Numinus recently announced it will be a study center for a phase 3 trial of Cybin’s CYB003, a proprietary deuterated molecule related to psilocybin that was granted breakthrough therapy designation for the treatment of moderate to severe depressive disorder.4
Meanwhile, COMP360, a synthetic form of psilocybin, is being investigated for several psychiatric disorders. In May, Compass released results of an open-label multicenter phase 2 study of PTSD, which found “early and clinically meaningful improvement,” improvement over time, and met the primary safety endpoint.5
“We are pleased to see the strong signal in PTSD, which, along with our prior data in treatment-resistant depression, lead us to believe that COMP360 has the potential to become an important treatment option for patients across a broad set of mental health conditions,” Kabir Nath, CEO of Compass Pathways, said in a statement.5
Similarly, MindBio is studying MB22001, a proprietary titratable form of lysergic acid diethylamide (LSD) available in microdoses.6 They completed a successful phase 2a clinical trial for MDD earlier this year. MB22001 is also in clinical trials for premenstrual dysphoric disorder and distress/depression associated with cancer.
As part of their goal “to deliver on the therapeutic potential of psychedelics and other novel compounds,” MindMed completed a phase 2 multi- center randomized, double-blind, parallel-group dose finding trial of MM-120 (LSD D-Tartrate) for the treatment of generalized anxiety disorder (GAD).7 They expect to initiate a phase 3 clinical trial program for the orally disintegrating tablet version of MM-120 for GAD this year.
“Few treatment options have shown robust activity in GAD,” Daniel R. Karlin, MD, MA, MindMed Chief Medical Officer, said in a statement.8
They also are examining MM120’s potential for treating MDD. That study is expected to start in 2025, with data available in late 2026.
In August, Awakn screened its first patient in the MORE-KARE phase 3 trial of AWKN-001 for severe alcohol use disorder. Participants in the blinded trial will be randomized to receive different doses of ketamine infusion and a form of psychosocial support. The largest study of ketamine-assisted therapy, MORE-KARE follows a successful phase 2 trial that found an 86% abstinence rate.9
These are just the tip of the iceberg. A search of clinicaltrials.gov found 185 clinical studies on psilocybin, 104 for MDMA, and 58 for LSD.
Lykos Makes Moves
Meanwhile, all eyes remain on Lykos and the FDA to see what’s next for MDMA-AT. The company has undergone a reorganization, which included reducing their workforce by 75% as well as focusing remaining staff on the issue at hand. As part of the plan, David Hough, MD, was newly appointed as senior medical advisor. Hough has roots in psychiatric drug development, having served as compound leader for Invega, Invega Trinza, and Spravato.
“My hope is to build on the strong foundation Lykos has created and leverage my experience in the industry to ensure a productive ongoing dialogue with the FDA and oversee the clinical work that needs to be done to address the Agency’s questions which will allow us to serve patients safely and effectively,” Hough said.10
In addition, Rick Doblin, PhD, founder of MAPS, exited Lykos. “I can speak more freely as a public advocate by resigning from the Lykos Board,” he told press. “The FDA delays make it more important than ever that I work at MAPS toward developing global legal access to MDMA and other psychedelics for public benefit through MAPS’ multidisciplinary research, education, and drug policy reform.”10
References
1. Lykos Therapeutics announces complete response letter for midomafetamine capsules for PTSD. August 9, 2024. Accessed August 20, 2024. https://news.lykospbc.com/2024-08-09-Lykos-Therapeutics-Announces-Complete-Response-Letter-for-Midomafetamine-Capsules-for-PTSD
2. atai Life Sciences announces positive preliminary results from phase 1b trial of VLS-01 (buccal film DMT). August 13, 2024. Accessed August 20, 2024. https://ir.atai.life/news-releases/news-release-details/atai-life-sciences-announces-positive-preliminary-results-phase
3. Numinus Wellness comments on FDA decision on new drug application for MDMA-assisted therapy for PTSD. August 12, 2024. Accessed August 20, 2024. https://www.investors.numinus.com/news/news-details/2024/Numinus-Wellness-Comments-on-FDA-Decision-on-New-Drug-Application-for-MDMA-Assisted-Therapy-for-PTSD/default.aspx
4. Cedar Clinical Research selected as clinical research site for Cybin’s phase 3 study of CYB003. April 17, 2024. Accessed August 20, 2024. https://www.investors.numinus.com/news/news-details/2024/Cedar-Clinical-Research-selected-as-clinical-research-site-for-Cybins-Phase-3-Study-of-CYB003/default.aspx
5. Compass Pathways announces durable improvement in symptoms through 12 weeks in open-label phase 2 study of COMP360 psilocybin in post-traumatic stress disorder. May 8, 2024. Accessed August 20, 2024. https://ir.compasspathways.com/news-releases/news-release-details/compass-pathways-announces-durable-improvement-symptoms-through
6. MindBio begins landmark phase 2B take-home microdosing (MB22001) clinical trial in patients with major depressive disorder. March 20, 2024. Accessed August 20, 2024. https://www.mindbiotherapeutics.com/clinical-trials
7. MindMed reports second quarter 2024 financial results and business updates. August 13, 2024. Accessed August 20, 2024. https://ir.mindmed.co/news-events/press-releases/detail/158/mindmed-reports-second-quarter-2024-financial-results-and-business-updates
8. MindMed announces constructive end-of-phase 2 meeting with U.S. FDA for MM120 in generalized anxiety disorder (GAD). June 20, 2024. Accessed August 20, 2024. https://ir.mindmed.co/news-events/press-releases/detail/149/mindmed-announces-constructive-end-of-phase-2-meeting-with-u-s-fda-for-mm120-in-generalized-anxiety-disorder-gad
9. Awakn announces first patient screened in phase 3 clinical trial of AWKN-001 for severe alcohol use disorder. August 9, 2024. Accessed August 20, 2024. https://awaknlifesciences.com/awakn-life-sciences-announces-first-patient-screened
10. Lykos Therapeutics announces reorganization to address FDA’s recent decision on midomafetamine capsules for PTSD. August 15, 2024. Accessed August 20, 2024. https://news.lykospbc.com/2024-08-15-Lykos-Therapeutics-Announces-Reorganization-to-Address-FDAs-Recent-Decision-on-Midomafetamine-Capsules-for-PTSD
