Updated: FDA Committee, Concerned about Bias, Votes No on Psychedelic in PTSD

The FDA’s Psychopharmacologic Drugs Advisory Committee yesterday voted against recommending Lykos Therapeutics’ midomafetamine to treat patients with post-traumatic stress disorder (PTSD).

Advisory committee members voted 2 for and 9 against on whether the available data show that midomafetamine is effective in patients with PTSD. They also voted 1 yes to 10 no on the question of whether the benefits of midomafetamine with FDA's proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD.

Amy Emerson

“We remain committed to working with the FDA to address outstanding questions so that we may find a path forward to ensure the responsible and careful introduction of MDMA-assisted therapy into the healthcare system, if approved,” Amy Emerson, CEO of Lykos Therapeutics, said in a news release. “We are grateful to the advocates, clinical trial participants and people living with PTSD who shared their testimony in the open public hearing and through written comments, and will continue to do everything we can to bring this potential new therapeutic option to people living with PTSD.”

PTSD is a mental health condition affecting about 13 million Americans each year, yet currently available treatments provide only modest efficacy; there are high treatment discontinuation rates.

Midomafetamine is 3,4-methylenedioxymethamphetamine (MDMA) — commonly known as ecstasy — a class of psychoactive compounds. The FDA’s target action date is Aug. 11, 2024.

Committee members reviewed results from two phase 3 studies evaluating the efficacy and safety of MDMA. Both MAPP1 and MAPP2 both met the primary endpoint as measured by the change from baseline in Clinician-Administered PTSD Scale for DSM-5 and the key secondary endpoint of improvement in functional impairment associated with PTSD.

In MAPP1 67% of patients with severe PTSD receiving MDMA-assisted therapy no longer met the criteria for PTSD after 18 weeks of study treatment. In the MAPP2 study, 71% of patients with moderate to severe PTSD no longer met the criteria for PTSD after 18 weeks of MDMA-assisted therapy. Results from MAPP2 were published in Nature Medicine in September 2023.

Adverse effects in both trials were mild to moderate and did not include increased suicidal thoughts or actions.

In materials released ahead of the meeting, FDA officials expressed several concerns. First was the issue of whether trials of midomafetamine could be blinded, which may impact the efficacy results. Because of the alternations in mood and cognition caused by midomafetamine, the majority of patients in both the treatment arm and placebo arm were able to guess which treatment they received. “Participants experienced functional unblinding due to the effects of the drug itself. Functional unblinding can introduce bias in clinical studies,” regulators said.

Although Lykos conducted a follow up of patients six months to two years after the initial study period, about 25% of patients dropped out before the follow-up visit. Additionally, some patients had used other therapies before the follow-up visit.

FDA officials were also concerned about the safety results, saying in the briefing document that the cardiac safety results were not well characterized. Additionally, liver function studies were only done in the phase 1 and phase 2 studies and not in the phase 3 trials. Liver injury has been identified in the literature reports from illicit use of MDMA.

The committee members who voted no on the question of whether the available data show that midomafetamine is effective expressed concerns about the functional unblinding and whether that impacted efficacy.

“I felt the functional unblinding, the lack of management for expectation bias and also selection bias and not incorporating that into some kind of statistical model is meaningless,” chairman Rajesh Narendran, M.D., attending psychiatrist, resolve Crisis Services, at UPMC Western Psychiatric Hospital in Pittsburgh, said after the vote

Walter S. Dunn, M.D., Ph.D.

Of committee members who voted yes on the same question was Walter S. Dunn, M.D., Ph.D., assistant clinical professor at the University of California Los Angeles, Department of Psychiatry.

“I think there are concerns about the functional unblinding in addition to the expectation bias, potentially reducing my confidence and the effect sizes that were reported,” he said. “However, I can’t overlook the fact that the effect sizes were fairly large. This treatment plus psychotherapy can be effective for post-traumatic stress disorder.”

Martin R. Steele, cofounder of Reason for Hope and founder & President of the Veteran Mental Health Leadership Coalition, said in a statement that committee lost sight of the bigger picture. "We lose 17 to 44 Veterans every single day to deaths of despair such as suicide or overdose – often resulting from unresolved trauma in service to this country – and the problem only seems to be getting worse. Despite rates of PTSD and suicide increasing for decades, we have seen little progress with new treatments, including no new FDA approved drugs for PTSD in over 20 years."

He said the benefits of MDMA, particularly alongside a stringent REMS, outweigh the risks. "Considering the clear limitations of currently available medications such as SSRIs and talk therapies, MDMA-AT offers a seemingly obvious and logical approach to treating PTSD. The drug’s ability to rapidly establish therapeutic rapport and reduce fear response makes it easier to commit to and engage in a psychotherapeutic process that involves confronting often highly traumatic memories."

This story was updated to include comment from Martin Steele.