Lykos Responds to Opposition by FDA Advisors to MDMA-Assisted Therapy
On June 4, an advisory committee to the U.S. Food and Drug Administration (FDA) voted to issue guidance that opposed the approval of MDMA-assisted psychotherapy as a treatment for adults with PTSD. The recommendation, issued by the Psychopharmacologic Drugs Advisory Committee, is expected to influence the agency’s final decision on Lykos Therapeutics’s New Drug Application (NDA), which is expected on August 11.
The advisory panel voted 9-2 that data gathered by Lykos in its clinical trials was insufficient to show that MDMA-assisted therapy is effective for PTSD. Advisors also voted 10-1 that the benefits of MDMA-AT do not outweigh the risks – even when administered within the FDA’s proposed risk evaluation and mitigation strategy (REMS).
For supporters of FDA approval for MDMA-AT, the guidance was a sobering reminder about the complexities of securing FDA approval for psychedelic therapies. It is also a comedown for those hoping that FDA approval of MDMA-AT would trigger the DEA to reconsider the drug’s status as a Schedule 1 substance with no accepted medical use.
The committee acknowledged that clinical trials for MDMA-AT, designed and carried out by the Multidisciplinary Association for Psychedelic Studies (MAPS) Public Benefit Corporation before it became Lykos Therapeutics, showed some clinically meaningful improvements. The advisors raised offsetting concerns about the data gathered during investigations into the efficacy of MDMA-AT. Foremost were issues with blinding producing bias in patients and therapists; unreported adverse events relating to MDMA abuse potential; concerns about safety data, including cardiovascular and blood pressure related outcomes; a report of sexual abuse in a clinical trial; and lack of diversity among participants.
“While we were of course disappointed by the outcome, we were not surprised by the important questions raised,” Lykos Therapeutics CEO Amy Emerson said in a statement issued on June 13. “Our work takes place against the backdrop of a national PTSD crisis, with an estimated 13 million Americans suffering from this condition. Over the coming weeks, we will continue to collaborate with the FDA and will answer all questions they have to inform their decision-making process,” Emerson added.
Bias and Missing Data
Tiffany R. Farchione, MD, director of the Division of Psychiatry in the FDA’s Office of Neuroscience noted during the public discussion of the advisory committee, “It is the lack of data collection on the subjective effects of MDMA that may [have] the greatest impact on our regulatory decision-making.” Farchione said Lykos did not collect data necessary to the evaluation of abuse potential, such as euphoria and elated mood, despite the agency’s guidance to do so.
Lykos Therapeutics told Lucid News that it “interpreted adverse events to mean untoward or unfavorable and therefore, in our Phase 3 studies, we did not capture effects deemed positive, favorable, or neutral, such as ‘euphoria’ or ‘elated mood.’ However, following dialogue with the Agency the MAPPUSX protocol as well as other ongoing clinical trial protocols have been updated to clarify that all positive, neutral, or favorable adverse events should be collected.”
David Millis, MD, clinical reviewer in the Division of Psychiatry at the FDA, characterized the lack of systematic collection of this data as a “major concern.” Millis spotlighted disagreements between Lykos and the FDA about the blinding process, proposed statistical analysis, and choice of secondary endpoint, or supportive information about the therapy’s effect. “To be considered adequate and well-controlled, a study must incorporate a design that permits valid comparison with a control condition, and measures must be taken to minimize bias,” said Millis.
“Functional unblinding is a known research challenge for psychiatric drugs with psychoactive effects,” Emerson said. “While there is no perfect solution to functional unblinding, we took many steps to minimize its potential impact, including the use of independent, blinded third-party clinician raters to assess outcomes. The weight of evidence suggests a very low likelihood that the observed [MDMA] effect can be adequately explained by functional unblinding,” she added.
Misconduct and Abuse
The advisors questioned Lykos’s ability to oversee the training of therapists, citing a well-documented sexual abuse incident involving two therapists participating in the Phase 2 clinical trials who were associated with MAPS Canada. Panel member Walter S. Dunn, MD, Ph.D., said these incidents raise serious questions. “Unfortunately, there has potentially been some misconduct that has corrupted our ability to interpret the data,” said Dunn.
New York Magazine published an investigative podcast together with Psymposia in 2021 which reported allegations made by trial participant Meaghan Buisson in 2018. According to The New York Times, Buisson told a meeting of the Institute for Clinical and Economic Review (ICER) that she experienced significant trauma. “The severe PTSD that brought me into this clinical trial went unaddressed and unresolved,” Buisson told a meeting of ICER advisors on May 30. “All they did was pour a concrete foundation of new traumas over the top.”
MAPS PBC, the original sponsor of the MDMA-AT investigations, addressed the allegations in 2019 and 2022 saying it reported the “ethical violation” to health officials in Canada where the conduct occurred and to the FDA. “We take all concerns around harms and clinical trial conduct and research conduct very seriously,” Alia Lilienstein, Lykos senior medical director and head of Clinical Science told the FDA advisory committee.
In her June 13 statement, Emerson said, “This was a terrible and harmful instance of malpractice that caused profound suffering to a participant.” Emerson said that Lykos banned the therapist pair associated with this case. She added that Lykos has since “carefully developed and implemented new policies and practices aimed to prevent, investigate, encourage reporting of, and thoroughly respond to potential instances of misconduct or unethical behavior. We investigate all allegations and complaints of misconduct.” Emerson said the company has “implemented independent channels for individuals to report misconduct” which will be “expanded to suit the post-marketing environment” if MDMA is approved.
Diversity Concerns
Sociologist Elizabeth Joniak-Grant, a patient representative with the FDA who served on the advisory committee, expressed concerns about the lack of BIPOC participation in the clinical trials. “The fact that this study has so many white participants is problematic because I don’t want something to roll out that only helps this one group,” Joniak-Grant said.
Lykos Therapeutics told Lucid News, “Diverse staff is critical for recruitment and retention of people of color. Trial sites were provided with an additional budget to compensate subjects for study-related costs, such as childcare and transportation which may provide additional barriers to entry. All therapists were required to attend a racial justice and microaggressions training and respond to a reflective knowledge assessment afterward. These tactics will need to be continued in any future studies.”
Significant Gaps
Members of the advisory panel raised questions about whether Lykos adequately followed the FDA’s guidance while conducting its studies. Although Farchione acknowledged that MDMA’s acute effects “make it nearly impossible to blind studies,” Millis pointed out that the agency had offered possible solutions.
Millis said the FDA suggested at the end of the Lykos Phase 2 trial that niacin or lower-dose MDMA could have been effective as active placebos. Lykos did not adopt the guidance stating that niacin could potentially worsen PTSD symptoms and lower-dose MDMA could possibly exacerbate anxiety in some trial participants. The result was that Lykos continued the studies without blinding measures considered effective by the advisors, potentially impairing the agency’s ability to evaluate the study data.
Lykos Therapeutics told Lucid News, “The dosing of the drug and the therapy component was informed by prior information and Phase 2 studies. In the Phase 2 program, we evaluated different study designs including dose response and low-dose controls to help address functional unblinding. We also tested different numbers of preparatory and integration psychotherapy visits. In Phase 2, a greater mean reduction in CAPS-4 scores was observed in participants receiving 3 medication sessions compared to two with comparable safety. No further effect was observed in Phase 2 participants receiving four to six medication sessions.
The time interval of at least 21 days between medication sessions allows for patients to process and integrate the outcomes of the prior medication session and sufficient time for 3 integration psychotherapy visits. These findings formed the basis for selection of the Phase 3 design which we developed in collaboration with FDA.”
During the advisory committee meeting, Millis also recounted disagreements between Lykos and the FDA about statistical analyses and choice of secondary endpoint documented in a special protocol assessment contained in a “SPA No Agreement letter” for the Phase 3 MAPP1 trial in 2017. The No Agreement letter stipulated that adverse events associated with potential abuse or overdose in MDMA-treated patients must be documented. It also said that all clinical safety and efficacy trials should be evaluated for central nervous system (CNS)-related adverse events, such as a “euphoria-like response.” The agency sought this data to interpret the potential for abuse.
Millis cited a review from the FDA Controlled Substance Staff suggesting that MDMA has abuse potential that parallels Schedule II narcotics, including cocaine, oxycodone, and Ritalin. “We’re actually managing more and more severe cases of MDMA overdose, and so I’m less concerned about the safety in the acute setting, but more chronically if they go on to abuse MDMA,” said advisory committee member Maryann Amirshahi, a professor of emergency medicine at Georgetown University.
During the meeting, Millis said that the FDA “noticed a striking lack of abuse-related adverse events” submitted with the regulatory application, which he characterized as a “major concern.” Millis added, “When we followed up with the applicant about their abuse potential assessment methodology, they clarified that they did not systematically collect abuse-related adverse events in the guidance. Rather, they only documented events identified as unfavorable. As a result of not having this data, our ability to properly describe the expected severity and frequency of these events in product labeling is affected.”
Lykos Therapeutics told Lucid News that it “understands that the abuse potential of midomafetamine is an area of concern, however, the abuse potential profile of MDMA is well-characterized by the available literature and data, including through extensive prior NIH-funded research conducted in humans and animals. Importantly, illicit MDMA use is known to be primarily episodic and rarely results in substance use disorders. While use of illicit MDMA cannot be completely prevented, approval of a controlled product would provide the opportunity to regulate and monitor the field to a greater extent than what is currently possible.”
Lykos emphasized that they are working with the FDA in developing “a REMS program to evaluate and mitigate the risk of serious harm resulting from patient impairment. Per the proposed REMS, MDMA will only be dispensed in certified healthcare settings and only with evidence of safe use conditions. This includes training for the prescribers, pharmacists, and therapists.”
Additionally, Lykos says that patients will be “counseled to support safe use, monitored DURING and AFTER the session, and will be required to be enrolled into the [MDMA] Drug Registry.”
Out of the Box
The Lykos New Drug Application for MDMA-AT focuses on a psychotherapy protocol to be administered along with MDMA, which posed challenges for the FDA evaluation. “The difficult thing,” said Farchione, “is that we don’t regulate psychotherapy, and also we don’t really have any say in the design or the implementation of the particular therapy that is going to be used.”
The Lykos MDMA-AT protocol provides therapists with discretion in how they engage with patients, adding complexity to the FDA evaluation. “The approach of these integrated sessions was not standardized,” Millis said during the advisory hearing, “and could vary considerably from therapist to therapist.” Advisors highlighted the difficulty of distinguishing between the effects of a drug and psychotherapy and separating the clinical benefits of each treatment.
The FDA’s lack of regulatory expertise with psychotherapy protocols, combined with concerns about the absence of standardization, amplified the advisors concerns about potential abuse by therapists engaged in MDMA-AT and questions about whether Lykos can adequately oversee the training of therapists.
“The design of the study was done in collaboration with the FDA,” Lykos Therapeutics told Lucid News. “The psychological intervention was the active control and allowed for us to access the potential benefit of adding MDMA to the treatment. Because this was the first drug plus therapy, it was likely complex for the panel. However, we believe that the FDA was comfortable with the design. The case of sexual abuse in our Phase 2 study did provide concern for the panel. If FDA-approved, prescription MDMA-assisted therapy will be launched with careful consideration of its potential benefits and risks, in accordance with established medical guidelines, protocols and quality standards.”
Public Comments
During a public comment period, the committee heard views from stakeholders, patients, and critics of MDMA-AT. Psychedelic Alpha’s Josh Hardman described, “20 comments broadly in support of MDMA-assisted therapy’s approval; 10 comments against; 2 neutral comments.”
Robert Grant, MD, MPH, a professor at the University of California San Francisco who worked on a Lykos sponsored study in 2022, supported approval of MDMA-AT within a REMS framework. Debbie Plotnick, Executive Vice President for State and Federal Advocacy at Mental Health America advocated for the approval of MDMA-AT and other novel mental health therapies.
Individual veterans and veterans groups also spoke. Psychedelic Alpha reports, “Those who spoke generally supported the approval of MDMA-assisted therapy, or at least further research. Individuals included Lykos trial participant Jonathan Lubecky and organizations like the Wounded Warrior Project, Veterans of Foreign Wars and Disabled American Veterans.”
Three representatives from Psymposia criticized Lykos during the comments period. Journalist Russell Hausfeld highlighted concerns regarding the treatment of veterans’ treatment by MAPS PBC and its successor, Lykos Therapeutics. Neşe Devenot, Ph.D, a senior lecturer at Johns Hopkins University, urged independent review of surveillance from Lykos clinical trials to investigate whether there are other unreported instances of therapist abuse. Brian Pace, a lecturer at Ohio State University, accused Lykos of being a “therapy cult.”
Ifetayo Harvey, executive director of the People of Color Psychedelic Collective, criticized the lack of diversity and boundary violations in the trials, urging the psychedelic field to use this moment to hold itself to a higher standard.
Michael Abrams, senior health researcher at Public Citizen’s Health Research Group said there needs to be more clarity about the contribution of psychotherapy to the study outcomes. He urged against approval due to risks.
Jonathan Alpert, chair of the American Psychiatric Association’s Council on Research acknowledged MDMA’s potential but cited significant issues with the available evidence, and called for more research.
“There were a substantial number of people and advocates testifying to support the approval of MDMA-assisted therapy,” Lykos Therapeutics said. “We want to thank them for sharing their personal stories. For those who were critical, we hear you and we continue to investigate all allegations. We take them seriously and investigate them appropriately. While there have been a number of allegations, we continue to find that our studies were properly conducted with the appropriate controls in place.”
A Measured Vote for Caution
Despite broad concerns about the need for better treatments for PTSD, the panel overwhelmingly determined that the risks of approving Lykos’s New Drug Application outweigh potential benefits. “I think we are charting new territory, and we want to set it up right,” said Farchione.
“It felt strange to vote no,” said committee member Satish Iyengar,a statistician at the University of Pittsburgh in Pennsylvania, acknowledging the drug’s promise in treating PTSD. “There were just too many problems with it,” she said. Advisor Dr. Paul Holzheimer of the VA’s National Center for PTSD said, “I think this is a really exciting treatment and I’m encouraged by the results, but from a safety and efficacy standpoint I feel it’s still premature.”
Advisory committee chair Rajesh Narendran, a professor at the University of Pittsburgh School of Medicine, said “there’s a lot of holes in this dataset” and added his opinion that illicit use “is gonna soar” if MDMA-AT is approved. Other committee members also voiced similar views. “It seems like there are so many problems with the data — each one alone might be OK, but when you pile them on top of each other … there’s just a lot of questions I would have about how effective the treatment is,” said Dr. Melissa Decker Barone, a psychologist with the Department of Veterans Affairs.
Joniak-Grant concurred. “I have real concerns with the validity of the data and the allegations of misconduct,” she said. “I can’t in good conscience support something where these many harms are being reported.”
“Going forward, for psychedelics to be approved,” Narendran said, “there need to be more complex models.”
Staying the Course
Despite the comments that emerged during the advisory committee meeting, Lykos remains positive about the trajectory of their application. “Our confidence in the potential approval of MDMA-assisted therapy comes from our belief in the regulatory process and our ongoing collaboration with the FDA,” Lykos Therapeutics said.
Betty Aldworth, director of Communications and Post-Prohibition Strategy for the MAPS non-profit organization, told Lucid News, “MAPS’ multi-pronged approach recognizes that, regardless of the law, people have and will continue to use psychedelics in a variety of settings. In addition to incubating and funding leading-edge psychedelic science, we continue our legacies of educating professionals and the public and advocating for policy that supports the dignity and rights of people who use psychedelics and other drugs. Our movement building activities will continue to support direct-service harm reduction providers, like the Zendo Project, alongside a variety of nonprofits that similarly contribute to the many elements required to build safe, just, and equitable approaches to psychedelics and the people who use them.”
Lykos Therapeutics added, “MDMA-assisted therapy offers statistically significant and clinically meaningful improvement in PTSD symptoms and functional impairment compared to placebo across two phase 3 trials with evidence of durability over time. This is a novel combination of a limited exposure to [a] drug which catalyzes psychological intervention. The adverse events experienced were as expected for MDMA and were mostly mild and self-limited. The careful screening and monitoring of prospective patients—and the selection and rigorous training of therapists — will be essential for mitigating risks. Overall, given the efficacy and safety data, and the substantial unmet medical need for treatment of a serious and life-threatening disorder – MDMA, in combination with psychological intervention, we believe could provide a potential new option for PTSD if approved.”
“We are grateful to the Agency for organizing the PDAC meeting and the panelists who provided their valuable time and perspectives,” Lykos Therapeutics said. “The input will be valuable to the FDA as we work through a REMS plan and potential post-marketing studies.”