Lykos to Appeal MDMA Drug Rejection
Lykos Therapeutics says it will pursue FDA’s dispute resolution process after the agency issued an 8/9 complete response letter on its NDA for midomafetamine (MDMA) capsules for a proposed indication of treating post-traumatic stress disorder (PTSD). The agency’s Psychopharmacologic Drugs Advisory Committee (PDAC) voted in June not to recommend approval due to safety and efficacy concerns.
The panel voted 2 (yes) to 9 (no) on whether the available data are sufficient to show that MDMA is effective in patients with PTSD. They also voted 1 (yes) to 10 (no) on whether the benefits of MDMA with FDA's proposed risk evaluation and mitigation strategy outweigh its risks.
An FDA briefing document released before the panel met noted several safety-related issues that reviewers were raising. “For example,” it said, “the cardiac safety profile of midomafetamine is not well characterized and the QT-assessment is incomplete. Significant increases in both blood pressure and pulse were observed and were considered adverse events of special interest (AESI). This has the potential to trigger cardiovascular events, which have been described in literature reports of illicit MDMA use. Additionally, there are limited clinical laboratory data available for review.”
FDA also seemed bothered that liver function assessments were conducted in just one Phase 1 study and two Phase 2 studies, but these were not collected in the Phase 3 studies. However, the agency says, the NDA designated hepatotoxicity to be an AESI based on cases of severe liver injury from literature reports of illicit MDMA use. The agency pointed out that hepatotoxicity had not been previously identified as a safety signal prior to or during the conduct of the clinical trials and hepatotoxicity was not designated as an AESI in the protocols.
On the efficacy side, FDA’s document noted that the treatment itself makes it complicated to properly assess. “First, midomafetamine produces profound alterations in mood, sensation, suggestibility, and cognition,” the agency says. “As a result, studies are nearly impossible to blind. Although participants were randomized to either drug or placebo, the vast majority (approximately 90% of those assigned to drug and 75% of those assigned to placebo per a poststudy survey) were able to accurately guess their treatment assignment — the study was designed and conducted as a double-blind trial, but participants experienced functional unblinding due to the effects of the drug itself. Functional unblinding can introduce bias in clinical studies.”
Regarding the complete response letter, FDA requested that Lykos conduct an additional Phase 3 trial to further study MDMA’s safety and efficacy. “Lykos plans to request a meeting with the FDA to ask for reconsideration of the decision and to further discuss the agency's recommendations for a resubmission seeking regulatory approval for midomafetamine capsules,” a company statement says, adding that it has additional concerns around the structure and conduct of the panel meeting, including the limited number of subject matter experts in the discussion, “which at times veered beyond the scientific content in the briefing documents.”
“Lykos believes that the data included in the NDA provide sufficient evidence of efficacy and durability in line with the relevant FDA guidance,” the company says. “In addition, Lykos had aligned with the FDA in the Special Protocol Assessment (SPA) in 2017 on a variety of bias minimization measures in the study design,” it argues.