Lykos Therapeutics Restructures After FDA Setback, Commits to Progressing MDMA Therapy for PTSD

Along with the continued efforts of Lykos, researchers and community organizations have expressed their dedication to achieving approval for MDMA-AT and providing those with PTSD more options for treatment.

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Lykos Therapeutics has announced a strategic reorganization aimed at advancing its mission to provide innovative treatments for post-traumatic stress disorder (PTSD).¹ The company is refocusing efforts following the FDA's decision to deny approval of its new drug application (NDA) for midomafetamine (MDMA) capsules in combination with assisted therapy (MDMA-AT) for adults with posttraumatic stress disorder (PTSD).

Along with the company reorganization, Lykos announced it will be reducing its workforce by approximately 75%, with the remaining team focused on continuing efforts in clinical development, medical affairs, and engagement with the FDA.

Lykos has established an Independent Advisory Board to guide these efforts, ensuring continued collaboration with behavioral health facilities and patient groups like veterans and survivors of sexual violence.

"The team at Lykos has been part of a pioneering effort to bring forward the first clinical trials for midomafetamine, and we are sincerely grateful for their efforts," Amy Emerson, CEO of Lykos, stated. "As we prepare to address the FDA decision, we need to focus on delivering the FDA the robust clinical data necessary to support the approval of this potential new treatment."

David Hough, MD, has been appointed to lead the clinical development and FDA engagement for MDMA-AT, bringing extensive expertise from his tenure at J&J Innovative Medicine, notably leading projects like esketamine nasal spray (Spravato). His role will focus on navigating the FDA requirements and advancing toward approval. With the FDA’s complete response letter regarding MDMA-AT for adults with PTSD, the agency requested Lykos conduct a third phase 3 trial to better assess the drug’s safety and efficacy profile.

"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 in the statement.

Following the FDA’s complete response letter, Emerson expressed disappointment in the decision and the agency’s request for additional research.²

"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 two decades," she said in Lykos’ statement on August 9. Conducting an additional phase 3 study would take several years, Emerson stated, and many requests discussed with the FDA had already been addressed with existing data, post-approval requirements, or through reference to the scientific literature.

“With MDMA-assisted therapy, we have an intervention that is roughly 4 times as potent as any existing medication treatment option for PTSD,” MAPP1/2 study investigator Scott Shannon, MD, CEO of the Board of Psychedelic Medicine and Therapies, and founder of Wholeness Center, explained to The American Journal of Managed Care^® (AJMC^®). “Our effect size was 0.91, and the effect size for SSRIs is, according to 2 different studies, 0.23 or 0.28, both of which are relatively poor in terms of effect sizes, or considered a small effect size, which is almost trivial clinically.”

Phase 3 Study Data and PTSD Challenges

The NDA was submitted with data from 2 phase 3 studies, demonstrating that MDMA-AT significantly reduced PTSD symptoms compared with placebo. The studies used the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) to measure outcomes. Despite the promising results, the FDA’s rejection delays potential treatment for millions suffering from PTSD, a condition with a significant impact, especially among veterans.

Throughout the multiple phases of research evaluating MDMA-AT, the FDA worked with Lykos in pioneering rigorous clinical trial methods and practices to address the novel therapeutic approach. Upon acceptance of Lykos’ NDA, the agency granted a breakthrough therapy designation.

PTSD affects millions annually, with profound impacts on mental health and quality of life, and no new treatment options in more than 20 years.^3,4 Current treatments, though effective for some, often fall short of addressing all symptoms, highlighting the urgent need for new therapeutic options.

Leaders involved in psychedelic research and community organizations focusing on veteran’s health have pointed out the evidence of the therapy’s effectiveness compared with selective serotonin reuptake inhibitors (SSRIs), the current standard of treatment. According to findings from the phase 3 studies MAPP1 and MAPP2, MDMA-AT exhibited a much higher effect size in reducing PTSD symptoms compared to SSRIs.

MAPP1: MDMA-AT in Severe PTSD Cases

The MAPP1 trial focused on patients with severe PTSD and showed significant reductions in PTSD symptoms with MDMA-AT compared with placebo. Participants in the MDMA group showed a significant reduction in CAPS-5 scores compared with the placebo group, with a mean (SD) change of −24.4 (11.6) in the MDMA group versus −13.9 (11.5) in the placebo group (d = .91; P < .0001). The secondary end point measuring the total score of SDS also exhibited a significant reduction (P = .0116; d = .43).

MAPP2: MDMA-AT in a Diverse Population

The MAPP2 trial, which included a broader population of patients with PTSD, evaluated the same primary end point, with the SDS functional impairment score as the key secondary end point. The results of MAPP2 were consistent with those of MAPP1. The least squares (LS) mean change in CAPS-5 score was −23.7 (95% CI, −26.94 to −20.44) for the MDMA-AT group, compared with −14.8 (95% CI, −18.28 to −11.28) for the placebo group (P < .001; d = .7). The SDS score also showed significant improvement, with an LS mean change of −3.3 (95% CI, −4.03 to −2.60) for the MDMA group vs −2.1 (95% CI, −2.89 to −1.33) for the placebo group (P = .03; d = .4).

FDA Advisory Committee

Prior to the FDA’s decision this month, an independent FDA Psychopharmacologic Advisory Committee reviewed the data and health a public hearing before it voted against supporting the effectiveness of MDMA-AT and the proposed risk mitigation strategy, influencing the FDA's decision.⁵ Although, the FDA retained the discretion to make the final decision independently.

Concerns around the trials’ procedures were brought up by community members as well as the committee, leading to questions of whether the benefits outweigh the risks of the therapy—which was ultimately cited as the reason for the complete response letter by the agency, stating that it could not grant approval based on the current data submitted and that the efficacy and safety profile warranted further data.

MDMA-AT ICER Report

The Institute for Clinical and Economic Review (ICER) evidence report on MDMA-AT was also a key component of the discussion prior to the agency’s decision.⁶ The comprehensive report, published in May, concluded that the therapy demonstrated significant efficacy in reducing PTSD symptoms and improving overall patient outcomes, and exhibited association with substantial treatment effects, as indicated by the CAPS-5 scores, showing promise in enhancing health-related quality of life and work productivity for those with PTSD.

However, the review also emphasized that while the studies included showed a generally low risk of bias, some concerns were noted in certain domains warranting further research and consideration in clinical practice

The Future of Lykos and Psychedelic Therapy for PTSD

This reorganization positions Lykos Therapeutics to advance midomafetamine toward regulatory approval, offering hope for improved outcomes in PTSD treatment, according to the company's announcement.¹

"After 38 plus years of work, I'm profoundly saddened by the FDA decision around this critically needed therapy, but am heartened that Lykos will still move forward continuing clinical research that addresses the FDA's questions," Rick Doblin, founder, president of MAPS, and former board member of Lykos, said in the announcement. "I can speak more freely as a public advocate by resigning from the Lykos Board. 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."

Along with the continued efforts of Lykos, researchers and community organizations have expressed their dedication to achieving approval for MDMA-AT and providing those with PTSD more options for treatment.²

“We, at Reason for Hope, are going to continue working tirelessly to help get this over the finish line, because there are far too many people who are going to continue suffering, and unfortunately, too many lives that are going to be lost in the interim,” Brett Waters, attorney, cofounder and executive director of Reason for Hope, told AJMC in an interview. “So, we're committed to making sure that this gets approved, and we’re really disappointed that the FDA made the wrong decision here.”

References

1. Lykos Therapeutics announces reorganization to address FDA's recent decision on midomafetamine capsules for PTSD. New release. Lykos Therapeutics. August 15, 2024. Accessed August 16, 2024. https://www.prnewswire.com/news-releases/lykos-therapeutics-announces-reorganization-to-address-fdas-recent-decision-on-midomafetamine-capsules-for-ptsd-302223812.html

2. Grossi G. MDMA-assisted therapy receives a complete response letter from the FDA. AJMC. August 9, 2024. Accessed August 9, 2024. https://www.ajmc.com/view/mdma-assisted-therapy-receives-a-complete-response-letter-from-the-fda

3. How common is PTSD. PTSD: National Center for PTSD. US Department of Veterans Affairs. Accessed August 16, 2024. https://www.ptsd.va.gov/understand/common/common_adults.asp

4. What is posttraumatic stress disorder (PTSD)? American Psychiatric Association. November 2022. Accessed August 16, 2024. https://www.psychiatry.org/patients-families/ptsd/what-is-ptsd

5. Jacobs A. FDA panel rejects MDMA-aided therapy for PTSD. New York Times. June 4, 2024. Accessed August 16, 2024. https://www.nytimes.com/2024/06/04/health/fda-mdma-therapy-ptsd.html

6. ICER. Midomafetamine-assisted psychotherapy for post-traumatic stress disorder evidence report. Published May 14, 2024. Accessed August 16, 2024. https://icer.org/wp-content/uploads/2023/11/PTSD_Revised-Report_For-Publication_05142024.pdf