A week after an FDA committee declined to support an midomafetamine (MDMA) treatment for post-traumatic stress disorder (PTSD), Lykos Therapeutics is looking to dispel some concerns about the therapy as the discussion has taken on a life of its own beyond the biotech world.
The Psychopharmacologic Drugs Advisory Committee (PDAC) voted against MDMA capsules last week on two questions related to efficacy and safety. While the FDA does not have to follow the committee’s guidance, it typically does. After the negative vote, the conversation over drugs with psychoactive effects spilled over into the public discourse.
In a letter to shareholders, Lykos CEO Amy Emerson explained that it was time to try and set the record straight on midomafetamine, for which the company is seeking FDA approval for PTSD.
“We acknowledge that several issues raised during the PDAC meeting have now become the focus of public dialogue. This is a new and complex treatment that raises unique and important questions. We feel it is important to share the company’s perspectives related to key points which were raised,” Emerson wrote.
She addressed seven key concerns that were raised by the committee and explained how Lykos remains committed to working with the FDA.
Emerson said Lykos is confident that the application for MDMA provides evidence of clinical efficacy and was supported by two randomized, placebo-controlled phase 3 clinical trials. Both met their primary endpoints with participants showing clinically meaningful improvement in their PTSD symptoms compared to the control group. The results were statistically significant and proved durable on long-term follow up.
However, the committee had a number of concerns about whether the clinical investigators and patients could determine the use of the study drug rather than the placebo.
“Functional unblinding is a known research challenge for psychiatric drugs with psychoactive effects,” Emerson acknowledged in her letter. But Lykos worked with the FDA in 2017 to develop a special protocol assessment for the phase 3 trial design.
“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,” Emerson said. “The weight of evidence suggests a very low likelihood that the observed midomafetamine effect can be adequately explained by functional unblinding.”
The committee also wondered whether patients who had previously used illicit MDMA could be biased. Emerson said there was no meaningful difference in primary outcome measures between the subgroup of patients who had reported prior use of the street version of the drug and those who did not.
Another primary concern was the use of therapy alongside MDMA administration, which is called MDMA-assisted therapy. One committee member said the use of this talk therapy was the “greatest strength” but also its “greatest liability.” That’s because the therapy part is not under the purview of the FDA.
Emerson explained that “significant steps” were taken to ensure standardization and consistency across the trial for the therapy portion. The CEO rejected the suggestion that MDMA-assisted therapy will be unregulated if the therapy were approved.
“The practice of psychotherapy is already a regulated field with mandatory reporting requirements and oversight provided by licensing boards and professional societies,” Emerson wrote. “We expect that healthcare professionals providing psychological intervention with midomafetamine, if approved, will utilize their clinical judgment to effectively deliver treatment, with appropriate oversight from these governing bodies.”
Lykos’ MDMA therapy will also come with a Risk Evaluation and Mitigation Strategy (REMS) program, which is a drug safety program the FDA requires for certain medications to ensure the benefits outweigh the risks.
But this program itself was under question by the panelists, because the full breadth of what will be required is still being hammered out by the company and agency. So the committee never got to consider whether the REMS program will tip the benefit-risk ratio more toward the former.
Emerson directly addressed a case of therapist misconduct that occurred during a phase 2 trial in 2015 and was brought up throughout the course of the committee meeting. The incident in question involved a case of sexual abuse between a therapist and a patient after the last dose had been administered in the trial. The two therapists involved in the patient’s treatment were married, and one did not report the sexual misconduct despite being aware of it.
“This was a terrible and harmful instance of malpractice that caused profound suffering to a participant,” Emerson said. At the time, Lykos reported the matter to Health Canada, the FDA and the relevant institutional review board and the therapists were banned from future work with the company.
Committee member Walter Dunn, M.D., Ph.D., asked about the incident on multiple occasions during the meeting to ascertain how to reduce the potential for patient abuse with the MDMA-assisted therapy. Dunn, assistant clinical professor for the Department of Psychiatry at the University of California, Los Angeles, wondered whether the use of two therapists is risky because if those two people have a personal or business relationship, they may not be willing to speak up if they become aware of misconduct—as was the case in the 2015 incident.
Patient advocate Elizabeth Joniak-Grant, Ph.D., stressed that the committee “not gloss over” the misconduct and be clear that it was sexual in nature because patients with PTSD are statistically more likely to experience sexual violence.
“I think it’s important that we not say misconduct; it was more than that,” Joniak-Grant said.
Lykos has instituted new policies to prevent and detect abuse, misconduct or unethical behavior, Emerson explained.
“We investigate all allegations and complaints of misconduct. Lykos has implemented independent channels for individuals to report misconduct, and these will be expanded to suit the post-marketing environment if midomafetamine is approved,” she wrote in her letter.
Lykos also hit back at reports of sponsor and investigator bias. Stat reported last week about concerns that some investigators had failed to collect information on feelings of “euphoria” experienced with the treatment, which could be used to inform the addiction potential. Lykos also has roots as an activist organization, having rebranded from MAPS PBC, a spinout of the parent organization MAPS (Multidisciplinary Association for Psychedelic Studies).
The rebrand occurred as Lykos submitted the application for midomafetamine to the FDA at the end of 2023.
The FDA committee also had concerns about potential cardiovascular and hepatotoxicity risks associated with MDMA. Emerson pledged to work with the FDA to characterize the data or collect new information on these risks if the agency requests it. Lykos asserts that these risks can be safely managed in the post-marketing environment.
To end her letter, Emerson said Lykos will be collaborating with the FDA, which ultimately gets to decide whether MDMA is ready for the markets.
“Misinformation has been circulated about our program, and we want to clarify that the FDA has received all data and supporting documentation,” Emerson wrote.