The FDA declined to approve midomafetamine (MDMA) capsules for post-traumatic stress disorder (PTSD), calling for another trial to evaluate the drug’s efficacy and safety, developer Lykos Therapeutics announced on Friday.
Lykos said the agency determined that the investigational psychedelic “could not be approved based on data submitted to date” and requested another phase III trial. The company plans to ask FDA to reconsider.
Though hotly anticipated, the decision was largely expected after a negative review by an FDA advisory committee in June. In a 9-2 vote, the Psychopharmacologic Drugs Advisory Committee 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 a proposed risk evaluation and mitigation strategy (REMS).
Ahead of the June meeting, FDA reviewers listed concerns with cardiac safety, including significant increases in blood pressure and pulse, which could potentially trigger cardiovascular events. There were also additional safety concerns, including prolonged impairment and vulnerability or potential for abuse.
A report from the Institute for Clinical and Economic Review (ICER) in March rated the publicly available trial data on MDMA-assisted therapy as “insufficient.”
But in recent days pressure had been building on the FDA to approve the product.
Earlier this week, over 60 bipartisan lawmakers penned a letter to the Biden administration urging approval, describing a “grave need for new and better treatment options like MDMA-assisted therapy” for veterans and service-members. The condition affects an estimated 5{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of the U.S. population in any given year, according to the Veterans’ Administration National Center for PTSD, but is more prevalent among military personnel.
“The FDA request for another study is deeply disappointing,” said Lykos CEO Amy Emerson. “Our heart breaks for the millions of military veterans, first responders, victims of sexual and domestic abuse, and countless others suffering from PTSD who may now face more years without access to new treatment options.”
FDA said Friday the MDMA application had “significant limitations” that “prevent the agency from concluding that the drug is safe and effective for the proposed indication.” The agency said it will continue encouraging “innovation for psychedelic treatments and other therapies to address these medical needs.”
If it had been approved, MDMA — also known as ecstasy or molly — would have become the first illegal psychedelic to become a federally approved medicine.
It also would have been the first new PTSD therapy in over two decades. The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are currently the only treatments to hold FDA approval for PTSD. Other evidence also supports use of the SSRI fluoxetine and venlafaxine, a selective serotonin-norepinephrine reuptake inhibitor. However, it has been shown that usually less than 20{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} to 30{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of patients achieve full remission on SSRIs.
Both of the phase III supporting clinical trials conducted by Lykos met their primary endpoints of a significant improvement in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score. The participants received three dosing sessions of MDMA with additional psychological support sessions before and after dosing.
In MAPP1, the MDMA and psychotherapy group saw an average drop in CAPS-5 score of 24.4 points compared with an average drop of 13.9 points in those receiving psychotherapy alone. By the end of the third experimental session, 30{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of the MDMA group achieved PTSD remission, 60{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} achieved a loss of diagnosis, and 80{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of the group were considered responders to treatment. On the other hand, less than 5{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of the psychotherapy-only group achieved PTSD remission, with only half responding to treatment.
MAPP2 reported similar findings, with an average 23.7-point reduction in CAPS-5 score in MDMA-treated patients compared with a reduction of 14.8 points in the psychotherapy-only group. In both trials, patients taking MDMA also achieved the prespecified secondary endpoints.
FDA’s decision to request another phase III trial “is a major setback for the field,” said MAPP investigator Jennifer Mitchell, PhD, of the University of California San Francisco, in the release from Lykos.
MDMA is the first in a series of psychedelics that are expected to be reviewed by the FDA in coming years as part of a resurgence of interest into their therapeutic potential.
The idea of using psychedelics to enhance psychotherapy is not new. A handful of therapists in California used MDMA during the 1970s and 1980s — when it was still legal — to facilitate couples therapy sessions.
Lykos is essentially a corporate spinoff of the nation’s leading psychedelic advocacy group, the Multidisciplinary Association for Psychedelic Studies (MAPS), which was founded in 1986 to oppose a federal decision placing MDMA in the same ultra-restrictive drug category as heroin, LSD, and other illegal psychedelics.
MAPS’ studies of MDMA began more than a decade ago. Since then, dozens of small, startup drugmakers have entered the field, studying other substances like psilocybin and LSD for conditions including depression, addiction, and anxiety. Those studies are generally larger and more rigorous than the MDMA studies submitted to the FDA.
Two drug developers, Compass Pathways and Usona Institute, are conducting late-stage studies of psilocybin — the active ingredient in magic mushrooms — for severe depression.
Enterprise and Investigative Writer Michael DePeau-Wilson and the Associated Press contributed to this report.
