Can Lykos Therapeutics Address MDMA-AT Safety Concerns Ahead of FDA Decision?

As the August 11 deadline nears for the FDA to issue a decision on Lykos Therapeutics’ New Drug Application for MDMA-Assisted Therapy for PTSD, many observers are waiting to see if the drug company and the regulatory agency can reach agreement on the details of a Risk Evaluation and Mitigation Strategy (REMS) that would adequately address the cautions raised by advisors. 

Last month, the FDA’s Psychopharmacologic Drugs Advisory Committee (AdComm) and the Institute for Clinical and Economic Review (ICER) separately issued guidance stating that the data in the Lykos New Drug Application (NDA) is insufficient, with the risks of approval outweighing the benefits. Both independent advisory bodies cited multiple concerns about safety, bias, and oversight in the clinical trials that informed the NDA.

In the last few weeks, prominent scientists, veterans groups, and politicians pushed back on those critical reports, with a multi-pronged campaign to assure regulators and the public that MDMA-AT is ready for immediate approval, if accompanied by a suitable REMS. Concurrently, Lykos Therapeutics, formerly known as the MAPS Public Benefit Corporation, told Lucid News that it is in “ongoing discussions” with the FDA about a REMS program and “to determine the most appropriate post-marketing plans to address the outstanding questions raised.” 

In this first part of a two-part special report, Lucid News looks into the questions raised by the AdComm and ICER, the history of these concerns, and efforts by researchers and clinicians to address safety considerations that could block FDA approval of MDMA-AT. 

Breakthrough or Breakdown?

Since MDMA-AT was granted the Breakthrough Therapy designation for the treatment of PTSD by the FDA in 2017, Lykos says it has worked “in collaboration” with the agency to design the trials now being evaluated. That year, the drug company, then a wholly owned subsidiary of the MAPS nonprofit, developed an agreement with the FDA on the Special Protocol Assessment for Phase 3 clinical trials. This plan confirmed that the design, endpoints, conduct, and statistical analyses of these trials (MAPP1 and MAPP2) adequately addressed the objectives of the data required by regulators. 

The FDA guidance offered by the Breakthrough Therapy designation does not, however, guarantee a drug’s approval. Final decisions are based on a complete review of the application data in its entirety. The guidance and cooperation that the FDA provided as part of the Breakthrough Therapy designation helped Lykos navigate the regulatory process, but does not necessarily reveal how independent advisory bodies interpret the data in the application. 

The Phase 3 trials covered under the New Drug Application enrolled 194 adults with PTSD, beginning in 2018 and concluding in 2022. Participants were predominantly female (69%) and White (71%), with 85% experiencing multiple trauma sources. A total of 476 participants are included in the application’s safety database, a figure that the FDA AdComm characterizes as “small” but also says “may be adequate” for approval. ICER noted in its Final Evidence Report on the Lykos NDA that the small sample sizes and short follow-up periods reported in these clinical trials are unlikely to represent “all potential adverse effects of the therapy.”

Is MDMA-AT Safe?

The FDA’s Psychopharmacologic Drugs Advisory Committee (AdComm) evaluates the safety and efficacy of psychiatric medications, providing expert recommendations to the FDA for approval or rejection. ICER is a non-profit organization that advises insurance companies about the cost-effectiveness of new treatments. Both organizations raised a number of concerns about the safety of MDMA-AT, based upon the data in the application. 

One of the cautions raised examined the potential near and long-term adverse impacts on  cardiovascular and liver function. A consensus statement, issued on July 7th by 23 prominent researchers and clinicians who work with psychedelics, asserts that the Phase 3 trials did not produce serious events indicative of cardiovascular or hepatic risk. They highlighted that MDMA  has been studied for more than four decades, including its use with psychotherapy from the 1970s until 1985. Based on this data, they maintain that serious adverse events are rare, even in unsupervised settings. 

The researchers and clinicians argue that MDMA is “generally safe and well tolerated.” They emphasize the need for post-approval safety surveillance and studies to address any ongoing medical concerns, advising that those measures should suffice to address issues of this nature.

Would Approving MDMA-AT Potentially Increase Illicit Use?

The AdComm advisors expressed strong concerns about the abuse potential of MDMA, which is considered to be a safety issue for regulatory purposes. Their perspective is informed by the increased demand for illicit drugs produced by the prescription opioid epidemic. In a recent interview with Lucid News, Dr. Rick Dart, the director of the Rocky Mountain Poison and Drug Center, cautioned that “adverse events linked to subsequent use of illicit substances could be a significant trigger” for the FDA to block a drug’s approval. 

Dart explained that monitoring for illicit use of controlled substances became a more urgent issue due to the opioid crisis. “Traditionally, the FDA would approve a drug and leave it to doctors to use it appropriately,” says Dart. “However, with powerful and addictive drugs, the FDA realized some providers weren’t as responsible.” While MDMA does not demonstrate the same safety concerns as opiates, Dart notes that “a patient might have a positive experience with legally prescribed MDMA but later use an illicit version, leading to severe reactions. This can complicate the safety profile of the original drug.”

The FDA evaluates MDMA’s abuse potential as comparable to Schedule II narcotics, such as Ritalin, cocaine, and other amphetamines. The FDA measures specific “abuse related terms,” such as “euphoria” or “elated mood,” to “capture effects deemed positive, favorable, or neutral” verbatim from participants. Regulators use this data to assess abuse potential within a population. Lykos did not collect that data in its Phase 3 studies, despite being advised by the FDA to do so. Lykos Therapeutics told Lucid News that it did not initially collect this data because the company “interpreted adverse events to mean untoward or unfavorable.” They have since updated their clinical trial protocols to conform to this FDA guidance. 

In 2023, Lykos produced an analysis of these types of adverse events as part of the MAPPUSX open-label extension study, which regulators evaluated in the NDA. ICER contends that the data “indicated increased illicit use and adverse events that may reflect non-trial therapeutic use or abuse.” The FDA concurred, stating that the study provides “a clear signal of abuse potential.” 

Moving forward, Dart observes that “The safety of MDMA and other psychedelic treatments hinges on meticulous post-marketing surveillance, tracking patient outcomes and behaviors, and distinguishing between controlled and illicit substance effects. This ensures these treatments remain safe and effective for the broader patient population.”

Does MDMA-AT Present Unacceptable Risks to Patients?

The FDA recognizes the Lykos NDA as a “first-in-class treatment for PTSD and a novel treatment paradigm” that combines a Schedule I drug with a new course of therapy developed for this application. Both the drug and the treatment are novel in the regulatory context. The FDA regulates drugs, not the practice of medicine, which is a limitation that the AdComm met with a deference towards caution and calls for more data.

ICER’s focus on evaluating therapies to inform payers resulted in guidance about the safety of psychological interventions. Their analysis is critical of the MDMA-AT treatment asserting that “Even in carefully controlled clinical trials with two therapists of different sexes, therapist misbehavior occurred.” These concerns refer to abuse allegations made by trial participant Meaghan Buisson in 2018 and documented in an investigative podcast produced by New York Magazine and Psymposia in 2021. ICER characterized this matter as a “case of high safety concern.” AdComm committee member Walter Dunn, MD, Ph.D. said the case raises serious questions that “corrupted our ability to interpret the data.”

In addition to veterans, one of the largest cohorts of patients in some clinical trials for MDMA-AT for PTSD are people who have experienced sexual assault.  “Nearly everyone we spoke with discussed how MDMA breaks down barriers, heightens suggestibility, and creates a substantial risk with any therapists who might choose to take advantage of patients,” said ICER’s final report. The group is calling for a review of Lykos’s guidelines for MDMA-AT, “including ethical standards and other measures to minimize risk of therapist misconduct,” particularly considering “the unique nature of therapy with MDMA.” Signers of the consensus statement of psychedelics researchers agreed that “therapist misconduct is a serious risk” and concurred with the call to review Lykos’ delivery guidelines. 

Lykos Therapeutics told Lucid News, “We regret what happened with these therapists in our study, and the safety of our participants is of utmost importance. Since then, we have carefully developed and implemented policies and practices aimed to prevent, reasonably detect, investigate, report and thoroughly respond to allegations of misconduct. Lykos continues to assess practices regarding the safety of patients through a code of ethics, compliance procedures, a robust quality system, ongoing reviews of clinical trial processes, and ongoing risk assessments.”

ICER suggests that these measures may not go far enough. In its policy recommendations, the organization asserted that “Rigorous certification and oversight of providers is of the highest importance and should include entities other than the manufacturer, such as the American Psychiatric Association and American Psychological Association, to reduce potential conflicts of interest in maintaining the highest standards.” Signers of the psychedelics researcher consensus statement also acknowledge that, if approved, “the delivery of this treatment will likely be governed by a combination of state licensing boards, payers, and professional associations.” 

ICER allows that the manufacturer, in this case Lykos, may play a role, but should not be “the sole agent of certification.” They suggest a possible two-step process for certification that could begin with the manufacturer and be followed by a professional association. “Training, certification, and oversight is needed for both the medical providers who will prescribe psychedelic agents and for the therapists who will provide psychedelic-assisted psychotherapy,” said ICER’s final report. “This is of utmost importance because psychedelic agents can increase patient vulnerability.”

More than 70 clinical professionals who worked on the Phase 3 trials of MDMA-AT, including clinical investigators, clinicians, supervisors, trainers, and monitors strongly rebutted ICER’s analysis of this incident’s implications in an April 22 comment letter submitted in response to ICER’s Draft Report. While acknowledging that “the potential for ethical transgressions in this emerging field should not be minimized,” they caution that “treatment-emergent adverse events should not be confused or conflated with malpractice.” 

“The Phase 3 trials of MDMA-AT for PTSD included a number of features that were intended to protect the participants from undue harm,” write the clinical professionals. They identify best practices and standardization procedures that, in their view, “met, and in some cases exceeded, the accepted standards in the field of psychotherapy research.” The letter identifies these as: 

• “First, the principle of active, ongoing informed consent was embedded in the research protocols, and explicitly assessed in therapist training and adherence rating.
• “Second, the therapeutic approach centered the participant’s autonomy and empowerment, and aimed to minimize power imbalances between participants and therapists. 
• “Third, Phase 3 therapists were either licensed psychotherapists or on the path to licensure, which ensured a level of personal and professional training and accountability even outside the study framework. 
• “Finally, study-specific therapist training and supervision efforts addressed ethical considerations in the practice of MDMA-AT; therapists were expected to adhere to the MAPS Code of Ethics; and challenging cases were discussed in multi-site consultation calls during the Phase 3 trials.”

As the FDA completes its final analysis of MDMA-AT in preparation for its final decision next month, regulators will decide whether these measures and others will be sufficient to override the advisor’s recommendations that the clinical trial data do not balance the risks associated with the proposed treatment. 

Part two of this series will explore potential bias arising from pro-psychedelics advocacy and functional unblinding, concerns raised about Lykos management and the company’s response, comments from stakeholders with PTSD, statements by veterans groups, and the pressing need for new effective treatments for PTSD.