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An FDA advisory committee on Tuesday voted against midomafetamine (MDMA) as an adjunct to psychotherapy in post-traumatic stress disorder (PTSD).

In a 9-2 vote, the (PDAC) said available data failed to show that MDMA was effective in treating patients with PTSD.

The committee also voted 10-1 that the risks outweigh the benefits, even with FDA's proposed risk evaluation and mitigation strategy (REMS).

"Overall, the therapy itself is still -- I would consider -- experimental," said committee member Paul Holtzheimer, MD, of the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, who voted no. "Clearly, missing safety data would be necessary to long-term safety [and] tolerability of this intervention."

"We're building the airplane while we're flying it," said John Hertig, PharmD, of the Butler University College of Pharmacy and Health Sciences in Indianapolis, Indiana, who also voted no. "When we're looking at psychedelics I can deal with that, but what I can't really deal with -- when we're building the airplane -- are the safety concerns."

Walter Dunn, MD, PhD, of the West Los Angeles Veterans Affairs (VA) Medical Center -- who cast the lone vote in favor of the drug's risk-benefit -- said that while he voted yes, he was "low on my confidence about the risk-benefit." Nonetheless, he said, "We are in dire need of new treatments for PTSD."

Dunn added that no treatment is perfectly safe, and the REMS strategy was a good starting point for further development "with the right guardrails in place."

During the meeting, drugmaker Lykos Therapeutics presented clinical data from two randomized, double-blind, placebo-controlled phase III trials of MDMA in PTSD, MAPP1 and MAPP2. Participants received three dosing sessions of MDMA in the trials, alongside psychological support sessions before and after dosing.

Those in the MDMA arms experienced significantly greater improvement in PTSD symptoms, as measured by (CAPS-5) total severity scores. In MAPP1, those on MDMA experienced an average drop of 24.4 points in CAPS-5 scores, compared with an average drop of 13.9 points for those on placebo. In MAPP2, patients in the MDMA arm had a mean change of 23.7 points in CAPS-5 scores, compared with 14.8 points for those in the placebo group.

Panelists broached concerns about the design of the two studies, saying participants could tell whether they had taken MDMA or not. FDA briefing documents noted that most patients in the treatment and placebo groups correctly guessed their assignment in a post-study survey (90% and 75%, respectively).

They also raised concerns around cardiac safety data, which they said weren't well characterized in the company's research presentation. For example, the trial had incomplete QT assessment and showed significant increases in blood pressure and heart rate.

"The cardiovascular risk is still very high, [and] it's just not well characterized," said Rajesh Narendran, MD, of UPMC Western Psychiatric Hospital in Pennsylvania and the chairperson of the committee, who voted no.

Public comments focused largely on concerns about the mission and approach of Lykos Therapeutics, which has been working on development of MDMA for decades. Several public commenters shared concerns about allegations of misconduct during the trials, specifically one incident that involved .

"I have real concerns about the validity of the data and the allegations of misconduct," said Elizabeth Joniak-Grant, PhD, of the University of North Carolina at Chapel Hill, who served as the committee's patient representative. "I can't in good conscience support something where these many harms are being reported."

In the end, many committee members agreed that MDMA has potential in PTSD, but there were too many unanswered questions about its safety to move forward with a positive recommendation.

"It's a really exciting treatment," said Holtzheimer, who is also the director of the VA Posttraumatic Stress Disorder Brain Bank. "I'm really encouraged by the results today, but I feel that both from an efficacy and a safety standpoint, it is still premature."

The FDA is expected to make a decision about the treatment by August 11. While the agency isn't required to follow its advisory committees' recommendations, it typically does.

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