FDA Rejects Lykos’ MDMA-Assisted PTSD Therapy After Negative Adcomm

After months of anticipation and lobbying by veterans and lawmakers, the FDA late Friday rejected Lykos Therapeutics’ New Drug Application for its midomafetamine (MDMA)-assisted therapy for post-traumatic stress disorder.

In its Complete Response Letter (CRL), the FDA said the application “could not be approved based on data submitted to date” and requested that Lykos conduct an additional Phase III trial to glean more information on the safety and efficacy of MDMA.

For its part, Lykos intends to request a meeting with the regulator to “ask for reconsideration of the decision” and to seek FDA’s recommendations for a resubmission.

Lykos noted in its press release that the issues raised in the CRL “echo” those raised during the June meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee, which voted 10-1 against recommending the treatment. The committee members were particularly concerned about possible selection bias and functional unblinding, as participants could tell whether or not they’d been given the drug.

In its press release, Lykos said it “believes that the data included in the NDA provide sufficient evidence of efficacy and durability in line with the relevant FDA guidance.”

Originally published August 5, 2024

On Aug. 11, the FDA is expected to make one of the year’s most highly anticipated decisions: whether or not to approve Lykos Therapeutics’ MDMA-assisted treatment for post-traumatic stress disorder.

Stakeholders and industry experts recently expressed concern over the therapy, with an advisory committee recommending against its approval. Yet some are still optimistic about its potential—particularly given the continued need for new treatments for post-traumatic stress disorder (PTSD).

There are currently more than 13 million individuals in the U.S. living with PTSD, many of whom are veterans or victims of domestic abuse. One of the major issues for this patient population is a stark lack of available and effective treatments. Moreover, according to Lykos, 40% to 60% of patients never achieve remission.

The FDA has not approved a new treatment for patients with PTSD in nearly 25 years.

“Given the high dropout rate with current therapies and the evident need for better treatments . . . I strongly believe that there is a consensus about need,” said Jerry Rosenbaum, a professor of psychiatry at Harvard Medical School. “The notion that MDMA renders psychotherapy for PTSD to be more efficacious appears to have been demonstrated,” he told BioSpace.

Lykos is seeking FDA approval to utilize MDMA—more commonly known as ecstasy—as oral tablets to treat patients with PTSD, when combined with supportive mental health services like psychotherapy.

“We believe that the Agency sees there is a significant unmet medical need for those living with PTSD,” a Lykos representative told BioSpace in an email. “We plan to work with top-tier behavioral health centers that can meet the FDA-proposed patient monitoring requirements.”

The representative added that if it is ultimately approved, Lykos will consider studying the treatment in patients with other psychiatric disorders.

Lykos’ application is largely based on the results of a pair of pivotal Phase III studies, MAPP1 and MAPP2.

In the MAPP2 randomized, double-blind study, investigators compared the treatment to placebo in 104 adults with moderate or severe PTSD who met full DSM-5 criteria for the disease and had a CAPS-5 total severity score of at least 28 and symptom duration of at least six months. CAPS-5 is considered the gold standard PTSD assessment scale.

The patients were randomized to receive either a split dose of 80 mg or 120 mg MDMA hydrochloride separated by 1.5 to 2 hours followed by 40 or 60 mg during three sessions of therapy or placebo with extended sessions of therapy. Investigators assessed outcomes from baseline to the primary endpoint 18 weeks post-baseline visit.

Patients treated with Lykos’ MDMA-assisted therapy had better outcomes than those treated with placebo. The treatment resulted in a reduction in CAPS-5 total severity score from baseline to Week 18 of -23.7 compared to a CAPS-5 total severity score change of -14.8 for the placebo during the same time period.

The safety analysis showed that muscle tightness, nausea, decreased appetite and excessive sweating were all common adverse events in the treatment group, but they were mostly transient and mild or moderate in severity.

Similar to the MAPP1 study, there were no new major safety issues reported and no reports of MDMA abuse or dependence.

Despite these data, in June, the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) voted 10-1 against recommending the treatment, saying the benefits of the drug do not outweigh the risks, even with a strict risk evaluation and mitigation strategy.

The committee also voted 9-2 that Lykos had not provided enough data showing the efficacy of the therapy in treating patients with PTSD.

But Rosenbaum said the negative advisory committee meeting might not necessarily mean the FDA will opt against approving the treatment.

“The one-sidedness of the committee’s vote does represent a barrier to the FDA approving the drug,” he said. “Nonetheless, the relative lack of sophistication of the committee’s discussion and arguments will make it easier to override some of their concerns.”

One of the main issues raised during the adcomm meeting was the way in which Lykos conducted its clinical trials. Among the concerns posed by the FDA and adcomm committee members were selection bias, with a substantial number of participants having previously used MDMA, and functional unblinding.

“Because a person can feel the drug, they are no longer blinded to the treatment condition,” said Dan Karlin, chief medical officer of MindMed, which is also developing psychedelic therapies. “That unblinding may lead to the change. We think that is overblown because [in] essentially all psychiatric drug trials, functional unblinding happens.”

Rosenbaum agreed that functional unblinding during its clinical trials is the biggest impediment for Lykos. However, during the adcomm, the FDA expressed a desire to find a suitable solution to this issue, which many companies developing new psychiatric drugs are also grappling with.

Rosenbaum suggested the functional unblinding issue could be solved by using blinded, remote ratings, robust effect sizes, plausible mechanisms of action, the weight of all open and controlled trials and human experience, and safety or credible risk mitigation strategies.

Another issue is that it is difficult for the FDA to disentangle the effect of the drug and the effect of the psychotherapy, Karlin said. While this concern is not uncommon for potential psychiatric therapies, it is especially pronounced in this class of drugs, he added.

The majority of existing studies have shown that investigational MDMA is better when it’s accompanied by psychotherapy, Karlin noted.

“What MDMA doesn’t do is help on its own,” he said. “So, while MDMA induces an acute change in people, it doesn’t seem to lead to lasting change without psychotherapy. So, really, it is the combination of the two.”

On the safety front, the PDAC raised questions regarding potential cardiovascular issues and hepatoxicity related to administration of the therapy. The FDA did not require data regarding cardiovascular and liver toxicity risks, and Lykos did not include such information in its filings.

In a press release following the adcomm, Lykos stated, “We will continue to work with the FDA to characterize the data and/or collect new data to address these potential risks, if required. As we stated during the PDAC meeting, we are confident that these can be safely addressed in a post-marketing environment.”