FDA advisors express skepticism as they debate MDMA therapy for PTSD

The psychedelic drug MDMA, which has been studied as a possible mental health treatment, may finally get a chance to enter mainstream health care.

Tuesday, scientific advisors to the Food and Drug Administration are deciding whether to recommend that MDMA – in combination with talk therapy – is safe and effective as a treatment for post-traumatic stress disorder.

The drug company Lykos Therapeutics, which sponsored clinical trials of the drug, has asked the FDA to approve MDMA-assisted therapy for PTSD. It’s a critical step in the drug’s path to market.

The committee is expected to vote on the strength of the evidence at 5:30 p.m. ET following public comment and discussion.

The FDA does not have to follow the committee’s recommendation.

Remarks during the meeting from FDA staff and members of the advisory panel highlighted some major stumbling blocks -- shortcomings in the clinical research that could jeopardize its shot at being approved.

Agency staff focused on uncertainties and gaps in the data, unanswered questions about its potential for abuse and a lack of evidence supporting the psychological approach used in the therapy sessions.

Some on the panel have explicitly brought up allegations that have surfaced about possible misconduct and bias in the trials that could have skewed the results.

Scientists with the FDA didn’t share details, but acknowledged the agency was investigating some of the claims, which have surfaced in a petition to the agency and outside reports on the trials.

The significance of the moment was not lost on those in attendance.

There are only two FDA-approved treatments for the condition and MDMA would be the first to come on the market in decades. It would also be a milestone for the broader effort to expand access to psychedelics.

“We are charting new territory,” said Kim Witczak, a consumer representative on the FDA’s advisory committee. “We want to set it up right.”

Representatives of Lykos emphasized the positive findings in clinical data collected during two nearly identical randomized controlled trials.

For example, one of those studies showed 67% of participants in the MDMA treatment arm no longer met the diagnostic criteria for PTSD following three dosing sessions with MDMA, compared to about 32% in the placebo group who underwent the therapy sessions but did not receive an active drug.

“In totality, these results support [that] MDMA in combination with psychological intervention provides significant and meaningful reductions in PTSD symptoms and functional impairment in patients with PTSD,” said Berra Yazar-Klosinski, chief scientific officer for Lykos.

FDA staff and outside advisors did not dwell on those rosy results, though.

While the study took steps to “blind” study participants, there was considerable discussion around the fact many of those in the study could tell they had received the experimental drug, leading to what’s known as “functional unblinding,” which can ultimately affect the results.

“Although we do have two positive studies, the results are in the context of dramatic functional unblinding,” says Dr. David Millis, clinical reviewer for the FDA.

Another potential sticking point could be the lack of data about how patients experienced the acute effects of the drug, including feelings like “euphoria” or “elevated mood.” That data helps inform the FDA’s assessments of the drug’s abuse potential.

“We noticed a striking lack of abuse-related adverse events,” said Millis, noting that the FDA had advised the study sponsors to collect this type of data.

While MDMA is currently listed as a Schedule III drug, the agency's review found it has the same abuse potential as a Schedule II stimulant, a category that includes cocaine.

“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 Maryann Amirshahi, a professor of emergency medicine at Georgetown University and a member of the committee.

About 40% of those enrolled in the MDMA study had a history of using prior to the study.

Alongside its positive findings on the short-term effects of MDMA, Lykos presented data from a follow-up observational study intended to suss out the staying power of the treatment.

While not yet published in a peer-reviewed journal, that data “suggest evidence of MDMA’s durability to at least six months,” said Yazar-Klosinski with Lykos.

However, the FDA staff highlighted various issues with that long-term data, including a dropout rate of 25% and the fact that some participants sought therapy and, in some cases, used illicit drugs, including MDMA..

Data shared from Lykos showed a range of adverse events.

The majority of those in the study had a history of suicidal ideation in their lifetime, but during the study period “the frequency of these symptoms was comparable between the two groups, said Dr. Alia Lilienstein, senior medical director for Lykos Therapeutics.

“Of note there were no suicidal behaviors or attempts reported in the MDMA group,” she said.

That point is particularly contentious because of recent allegations that certain adverse events were not reported. A petition filed with the FDAcalling for the advisory meeting outlined these concerns and others, citing an unnamed former employee of the drug company.

There is already a well-documented case of two therapists in the Phase 2 trials with a participant who said they engaged in inappropriate contact with her while she was under the influence of MDMA. The videos of the two therapists in bed with the participant were eventually made public by a podcast.

“Let's try to not gloss over this misconduct. It was sexual misconduct. That's particularly important,” said Elizabeth Joniak-Grant, a sociologist and a member of the panel.

Several other panelists asked questions along those lines.

Last month, a report from the Institute for Clinical and Economic Review, a group that evaluates clinical data and drug prices, concluded there was insufficient evidence to assess the overall net benefit of MDMA-assisted therapy, after a lengthy investigation into the trial data.

That report stated that it’s possible those involved in the trials including therapists and investigators encouraged the reporting of positive events and downplayed adverse events.

The drug company has pushed back on the allegations and said it stands behind the data.

A public comment submitted to the FDA by one trial participant said her therapist encouraged her to view "worsening symptoms as evidence of healing and 'spiritual awakening'" and that she and other participants later struggled with suicidality following the trial.

Dr. Walter Dunn, a psychiatrist at UCLA and a panelist, asked about claims in the ICER report that some participants may have been discouraged from participating in the long term durability study.

“Those were investigated as well,” said Lilienstein with Lykos, “All participants who were interested in participating were given the opportunity to review consent, and some chose not to participate after reviewing consent, but otherwise everyone was given the opportunity.”

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