FDA Raises Safety/Efficacy Issues with Lykos PTSD Drug
An FDA advisory committee briefing document shows reviewer concerns about safety and efficacy issues in a Lykos Therapeutics NDA for midomafetamine (MDMA) capsules for a proposed indication of treating post-traumatic stress disorder (PTSD). The agency’s Psychopharmacologic Drugs Advisory Committee is set to convene 6/4 to discuss the overall benefit-risk profile of MDMA, including the potential public health impact. MDMA has historically been known as the party drug Ecstasy or Molly. The agency has set an 8/11 user fee review action target date.
The submission is based on data from two randomized, double-blind, placebo-controlled Phase 3 studies (MAPP1 and MAPP2) evaluating the efficacy and safety of MDMA used in combination with psychological intervention versus placebo with therapy in participants diagnosed with severe or moderate to severe PTSD, according to the company. Both MAPP1 and MAPP2 studies met their primary and secondary endpoints and were recently published in Nature Medicine.
Regarding safety, the briefing document says this assessment presented numerous challenges. “For example,” it says, “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 seems 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. It points 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 notes 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.”
Additionally, FDA says that an “expectation bias” was likely contributing to efficacy interpretation difficulties because patients who believed that they received active treatment expected that they would experience a clinical benefit, and those who received placebo fared worse due to disappointment when they did not experience anticipated effects from the treatment. Also, it is likely that study monitors could deduce a participant’s treatment assignment based on that participant’s behavior during sessions.
“Thus,” FDA continues, “both the participant and the study staff were likely aware to which treatment arm a given participant was assigned. It is reasonable to assume that functional unblinding and expectation bias has impacted treatment effects observed in the clinical trials with MDMA to some extent.”
Meanwhile, the briefing document notes that despite the complex review issues, the NDA does include “two positive studies in which participants in the midomafetamine arm experienced statistically significant and clinically meaningful improvement in their PTSD symptoms, and that improvement appears to be durable for at least several months after the end of the acute treatment period despite no additional doses of midomafetamine.”