Tabula Rasa Ventures Opinion | FDA Advisory Committee Review for MDMA-assisted therapy for PTSD

On June 4, 2024, the FDA held its first Meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) to review the new drug application (NDA) for MDMA-assisted therapy for PTSD, submitted by Lykos Therapeutics. While the PDAC provides valuable independent scientific advice to the FDA, the FDA is not obligated to follow its recommendations but often does. The final FDA decision is anticipated on August 11, 2024.

As a big surprise for the psychedelics space, almost unanimously, the PDAC voted against this novel treatment deeming that:

• the available data do not show the intervention is effective in patients with PTSD (No: 9; Yes: 2), and?
• when administered within the context of FDA's proposed risk evaluation and mitigation strategy (REMS), MDMA-assisted therapy's benefits do not outweigh its risks for the treatment of PTSD (No: 10; Yes: 1).

Background

MDMA-assisted therapy was granted FDA Breakthrough Therapy Designation in 2017 which led to a collaborative engagement between FDA and MAPS/Lykos to develop the Special Protocol Assessment for Phase 3 clinical trials. In 2021 (MAPP1) and 2023 (MAPP2), MAPS/Lykos published results from two multi-site, randomized, placebo-controlled Phase 3 clinical trials, demonstrating a significant reduction in PTSD severity, including:

• MAPP1: 67% of participants in the MDMA-assisted therapy group no longer met diagnostic criteria for PTSD, compared with 32% of participants in the placebo group
• MAPP2: 71.2% of participants in the MDMA-assisted therapy group no longer met diagnostic criteria for PTSD, compared with 47.6% of participants in the placebo group

These results were particularly significant given that PTSD remains with a substantial unmet need, with an estimated 13 million Americans suffering from this condition, including veterans and survivors of sexual abuse. No new effective therapy options have been approved since 2001, when Sertraline (Zoloft) and Paroxetine (Paxil) were introduced. Notably, only 20% to 30% of patients achieved full remission with these treatments.?

“It felt strange to vote no,” says committee member Satish Iyengar, a statistician at the University of Pittsburgh in Pennsylvania, given that the drug’s effects seemed so strong. “There were just too many problems with it.”

So, what happened??

Over the past month, there has been extensive commentary on the PDAC meeting results by the public on LinkedIn, Twitter, and WhatsApp groups as well as major news media. We spoke with numerous attendees and attended multiple lectures at the ICPR Conference in Haarlem, Netherlands. Additionally, we participated in webinars, and reviewed numerous media publications. This opinion piece reflects these insights and our decade-long experience in the pharmaceutical industry and the psychedelics sector since 2018.

One of the most diligent dissections of the PDAC results I have observed came from a webinar featuring Matthew Baggott, Ph.D., CEO of Tactogen (which is in fact a competitor to MAPS/Lykos), hosted by Dragonfly 44 Capital. You can access the presentation here.

For our detailed analysis, please check out:

FDA Advisory Committee Review for MDMA-assisted therapy for PTSD - TRV Opinion

TL;DR

This was a sobering moment for the psychedelics space, but the PDAC outcome is not as negative as it might seem. Reactions in the media have focused heavily on the PDAC decision without considering the full context of the NDA submission and full FDA Briefing Document. Below we provide a summary of the key concerns raised and our opinion.

PDAC Comments: Efficacy

1. Functional Unblinding & Study Design: PDAC raised concerns that the trials design led to functional unblinding which makes it difficult to evaluate the results. However, trials were designed in partnership with the FDA. Despite challenges with functional unblinding, both Phase III studies demonstrated significant reductions in PTSD severity and functional impairment with MDMA-assisted therapy compared to placebo as supported by the data, indicating robust treatment effects beyond placebo influence.?
2. Prior Experience w/ MDMA: Another concern was that approximately 40% of participants in MAPS/Lykos Phase 3 program had prior MDMA experience, which may skew results; however, trials show significant PTSD symptom reduction regardless of prior use, emphasizing the need to include experienced users for representative outcomes in wider rollout.
3. Treatment Durability: Despite a ~25% dropout rate and variable follow-up conditions in the Phase 3 studies, preliminary results indicate that participants showed improvements in PTSD symptoms at least six months after the final dosing session. More data is needed, though dropout rates for long-term follow-up psychiatric studies range from 30%-45%.
4. Psychotherapy: The PDAC was concerned that it is difficult to standardize psychotherapy and it is not under the regulatory remit of the FDA. Despite challenges in standardizing psychotherapy and therapist training, the integrated approach of MDMA-assisted therapy shows significant promise and highlights the need for evolving multi stakeholder-aligned, personalized psychiatric care beyond the traditional "pill-popping" model. Lack of regulation should not block innovation and life-saving therapies from patients.

PDAC Comments: Safety

1. Missing Clinical Labs: Despite no observed adverse liver effects and low proarrhythmic potential suggested by nonclinical studies, the PDAC highlighted the need for more comprehensive long-term clinical data on cardiovascular issues and hepatotoxicity. Post-marketing safety evaluations, including extensive laboratory tests, can be conducted through an extensive REMS program if approved, which may delay commercial rollout but should not cause FDA rejection.
2. “Positive Side Effects” & Abuse Potential: Given the necessity of positive effects for treatment efficacy and the supervision requirements akin to those of FDA-approved Spravato (esketamine), the potential for abuse for MDMA should not deter FDA approval, especially when compared to the higher abuse potential of widely prescribed Schedule II opioids. Moreover, given the proposed MDMA-assisted therapy administration solely in a medical setting by trained professionals should greatly minimize abuse risk.
3. Commentary From the Public: During the PDAC meeting, public commentary primarily focused on perceived deficiencies in the trial design, including a lack of diversity and ethical concerns regarding sexual misconduct allegations. Despite these concerns, Lykos has implemented measures to enhance participant diversity and address misconduct. Such public comments are unlikely to deter FDA approval, given the efforts to ensure ethical standards and regulatory compliance.
4. Safety Risk Mitigation: The PDAC emphasized the need for a comprehensive REMS to manage the safety risks associated with MDMA-assisted therapy, indicating that while the current proposal is promising, it requires further refinement to fully address the committee's concerns?

Conclusion

“I think there’s some clearly missing safety data”, Holtzheimer said, but feels “pretty confident this could be done with postmarketing studies”.

Most of the PDAC comments focused the clinical trial design, which was developed with the FDA, and on missing safety data, which can be collected post-marketing. There was little discussion on the significant efficacy results and the unprecedented unmet need in PTSD that MDMA-assisted therapy could address.

In the US, approximately 20 veterans die by suicide each day, highlighting the critical need for effective treatment and support for individuals suffering from PTSD. The FDA will face significant criticism if it does not thoughtfully consider all aspects of MDMA-assisted therapy in its decision due on August 11, 2024.

This situation raises important questions about our medical community's priorities: Should we adhere to outdated practices that could deny life-saving treatments, or should we innovate and embrace new approaches when there is clear empirical evidence supporting clinical outcomes for our most vulnerable populations??

Incremental innovation in drug development, while contributing to gradual improvements and refinements, is often criticized for its limited impact on groundbreaking advancements. Some of the biggest blocks to true innovation in drug development include the high costs and risks associated with research and development, stringent regulatory hurdles, and the pharmaceutical industry's focus on short-term profitability over long-term breakthroughs.

While the FDA's decision on August 11 is uncertain, there is a strong chance of approval. A complete rejection seems unlikely; however, a delay for additional information may occur.