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An FDA advisory committee dealt a major blow last week when it rejected Lycos Therapeutics’ psychedelic MDMA-based drug candidate for treating post-traumatic stress disorder.
The FDA’s Psychopharmacological Drugs Advisory Committee Many criticisms of the treatment — Due to concerns about the abuse potential of MDMA, also known as ecstasy, Sexual misconduct allegations During clinical trials Lycos fails to recover The FDA requested information about reactions such as euphoria. Ultimately, the court voted 9-2 that combining MDMA with talk therapy is ineffective for treating PTSD, and 10-1 that the risks do not outweigh the benefits.
Despite the setback, Lycos CEO Amy Emerson said the company is moving forward with its application, which could be the first groundbreaking approval for a psychedelic treatment, and that the committee’s recommendation makes things “a little more challenging” but “doesn’t change” the steps the company needs to take to get approved on August 11. PDUFA Dates.
The FDA will take the committee’s advice into consideration but will not be bound by it in its final approval decision.
“The key was to actually get feedback, and we did. We understand the concerns,” Emerson said. “The information gained from those conversations will be taken into consideration as we continue to work with the FDA on what the REMS (Risk Evaluation and Mitigation Strategy) will look like, what the labeling will look like.”
Challenges of clinical trials of psychedelic drugs
While many of the committee’s criticisms were based on ethics, one concern they raised was so-called “functional unblinding,” a practice that has long plagued clinical trials of various psychedelic drugs.
The issue of functional unblinding — where patients and researchers know who has received the investigational treatment — is not unique to psychedelics, nor is it new, said Dr. Michael Murphy, chief medical and scientific officer and co-founder of Worldwide Clinical Trials. Any clinical trial with a valid effect can trigger functional unblinding, but the risk is amplified with psychedelics “given the nature of the experience and the highly pronounced effects,” Dr. Murphy said.
To mitigate the impact of functional unblinding in study design, companies may choose to administer sub-therapeutic doses of the active ingredient or Active Placebo Simulate the experience of using an experimental drug. FDA has implemented these and other recommendations Draft Guidance To design clinical trials for psychedelic drugs.
Another way to complement functional unblinding is to use separate assessors who are “blinded to both treatment assignment and consultation,” Murphy said, which is the approach Lycos took.
The company is working closely with the FDA to address functional blinding issues, The research The study will be conducted as a double-blind, randomized, placebo-controlled trial, with blinded independent assessors.
“Well-designed studies can alleviate some of the concerns people commonly express about the use of psychedelics.”
Dr. Michael Murphy
Chief Medical and Scientific Officer and Co-Founder, Worldwide Clinical Trials
Rather than having patients self-report their response to treatment, blinded raters assessed participants’ change in the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary outcome) and the Sheehan Disability Scale (SDS) impairment score (secondary outcome).
“That independent assessor does not attend any treatment sites or clinical trial visits other than visits to measure CAPS,” Emerson says.
Phase 3 results from both companies were positive, with one showing 71% of participants no longer DSM-5 Criteria for PTSD After 18 weeks, this increased by 10% compared with 48% in the placebo group.
Functional unblinding is also danger At the time, another hallucinogen made from esketamine, J&J’s Spravato, was being evaluated as a treatment for treatment-resistant depression.
To mitigate this risk, J&J used blinded, remote, independent assessors and took additional steps to maintain blinding, such as adding a bittering agent to placebo doses and analyzing the dissociation that esketamine sometimes causes.
after that Positive AdmissionThe FDA approved Spravato in 2019.
Emerson added that Lycos is working with the FDA to conduct a special protocol evaluation and agree on how to analyze the response data.
“It’s this whole picture of minimizing bias. It’s not about doing one thing, it’s about doing many things. This is specific to research,” she said.
But when asked if the committee “got it all figured out,” Emerson said “no.”
“The FDA understands that, and that’s key,” Emerson said. “They’ve been working on this with us for years. They’ve been there since the very beginning, when we were looking at what the Phase 3 program and the two trials within that program would look like. It’s a big deal for a committee to try to understand.”
She also noted that the FDA’s guidelines for clinical trials of psychedelic drugs were released after Lycos’ Phase 3 study was completed.
“They wouldn’t expect to see every single part of that guideline in a Phase 3 trial,” she said.
Wider impacts
The news about Lycos appears to have surprised investors, including psychedelic drug stocks. MindMed, Compass Pathways and Atai Life Sciences The pharmaceutical industry was hit hard by the Admissions Committee’s announcement, but the situation does not necessarily spell doom for the emerging drug class. Many of the Admissions Committee’s concerns were specific to Lycos, and the larger challenge of functional unblinding was not the committee’s only issue.
In addition, the FDA has approved Spravato Draft Clinical Trial Guidelines It demonstrated the agency’s support for hallucinogen-based drugs.
This area is also seeing a lot of activity, with around 70 companies participating, around 50 of which are in the clinical stage, and many of them working to treat conditions with high unmet need, such as treatment-resistant depression and substance abuse disorders.
“In psychiatry, we don’t often come across potentially transformative agents, and when we do, we don’t recognize them at first,” Murphy points out.
Lycos’ MDMA-assisted therapy candidate for PTSD, which is commonly treated with SSRIs, would address a high unmet medical need if approved, and the FDA prioritized Lycos’ New Drug Application. February Review.
The company is also exploring other potential indications for MDMA-assisted therapy.
“Think about a large unmet need, something that may have underlying trauma, like an eating disorder,” Emerson says.
The issue of functional unblinding may continue to arise in clinical trials of psychedelics, but that is Spravato’s Final ApprovalMurphy doesn’t believe functional unblinding will be a defining factor for the class as a whole.
“I don’t think this is a onerous proposition,” Murphy says. “Well-designed studies could alleviate some of the concerns that people often express about the use of psychedelics.”
