An FDA advisory panel dealt a significant blow to Lykos Therapeutics’ psychedelic MDMA-based drug candidate last week when it rejected the treatment for post-traumatic stress disorder.
The FDA’s Psychopharmacologic Drugs Advisory Committee piled a host of criticisms onto the treatment — from concerns about the abuse potential of MDMA, also known as ecstasy; to allegations of sexual misconduct during one of the clinical trials; to Lykos failing to collect FDA-requested information about reactions such as euphoria. Ultimately, it voted 9-2 that MDMA combined with talk therapy is not effective in treating PTSD and 10-1 that the risks don’t outweigh the benefits.
Despite that setback, Lykos CEO Amy Emerson said the company is moving ahead with its application, which has been closely tracked as a potential landmark first approval for a psychedelic-assisted therapy. Although the panel’s recommendations make the situation “a bit more challenging,” it “doesn’t change the steps” that the company needs to take ahead of its Aug. 11 PDUFA date.
While the FDA takes the panel’s advice into consideration, it’s not bound by the recommendation in its final approval decision.
“The important part is to actually get feedback, and that happened. We understand where there are concerns,” Emerson said. “The information elicited during those discussions will be taken into consideration as we keep working with FDA on what a REMS [risk evaluation and mitigation strategies] would look like and what a label would look like.”
The challenge with psychedelic trials
Although many of the panel’s criticisms were based on ethics, one concern they raised has long vexed clinical trials for a range of psychedelics: so-called “functional unblinding.”
The issue of functional unblinding, which is when patients and investigators can tell who received an investigational therapy, is not new nor unique to psychedelics, said Dr. Michael Murphy, chief medical and scientific officer and co-founder of Worldwide Clinical Trials. Although any clinical trial with an active effect could trigger functional unblinding, that risk is “amplified” with psychedelics, “given the nature of the experience and the very pronounced effect” of the drug, Murphy said.
To mitigate the effects of functional unblinding in trial design, companies can use a sub-therapeutic dose of the active ingredient or an active placebo that simulates the experience of using the experimental drug. The FDA included these recommendations and others in its new draft guidance for designing psychedelic clinical trials.
Another way to compensate for functional unblinding is to use a separate assessor “who is blinded to both treatment assignment and visit,” Murphy said —and that’s the approach Lykos took.
The company worked closely with the FDA to address the issue of functional unblinding and designed its studies to be double-blinded, randomized and placebo-controlled, while also using blinded independent assessors.
“With a well-designed study, it is possible to mitigate some of the concerns that people have commonly expressed with the use of psychedelics.”
Dr. Michael Murphy
Chief medical and scientific officer, co-founder, Worldwide Clinical Trials
Rather than having patients self-report their response to the therapy, blinded assessors rated participants for changes in their Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (the primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (a secondary endpoint).
“That person, that independent rater, is never part of the therapeutic setting or any of the clinical trial visits, other than the visit to measure the CAPS,” Emerson said.
The results from both of the companies’ phase 3 studies were positive, with one showing that 71% of participants no longer met the DSM-5 criteria for PTSD after 18 weeks compared to 48% on placebo.
Functional unblinding was also a risk when another psychedelic, J&J’s Spravato, which is made from esketamine, was being evaluated for treatment-resistant depression.
To mitigate that risk, J&J used blinded, remote, independent graders. It took additional steps to maintain the blind, such as adding a bittering agent to the placebo dose and analyzing the dissociation that esketamine can sometimes produce.
After a positive adcomm, the FDA approved Spravato in 2019.
Emerson added that Lykos worked with the FDA on a Special Protocol Assessment to agree on how the data from the measures would be analyzed.
“It’s this whole picture that creates bias minimization. It’s not one thing that you do. You do many things, and it’s specific to your study,” she said.
When asked whether the panel “got” all that, however, Emerson said, “No.”
“FDA understood it, and that’s what’s important,” Emerson said. “FDA’s worked on this for years with us. They were there at the beginning as we were working through what a phase 3 program and what the two trials within that program would look like. It’s a lot for a panel to try and absorb.”
She also noted that the FDA’s guidance for psychedelic clinical trials came out after Lykos’ phase 3 studies were done.
“They wouldn't expect to see all the parts of that guidance in the phase 3 studies,” she said.
The wider impact
Although the news about Lykos seemed to spook investors and psychedelic medicine stocks including MindMed, Compass Pathways and Atai Life Sciences took a hit following the adcomm news, the situation doesn’t necessarily spell doom for the emerging drug class. Many of the adcomm’s concerns were specific to Lykos, and the larger challenge of functional unblinding wasn’t the panel’s only issue.
Moreover, the FDA’s approval of Spravato and draft clinical trial guidance have demonstrated the agency’s support for psychedelic-based drugs.
The category is also brimming with activity, including about 70 companies, around 50 in the clinic, and many that are working on treatments for conditions with high unmet need, such as treatment resistant depression and substance abuse disorder.
“It isn't often that we get potentially transformative agents in psychiatry, and even when we see them, we don't recognize them at first,” Murphy noted.
Lykos’ MDMA-assisted therapy candidate for PTSD, which is generally treated with SSRIs, would also address a high unmet medical need if approved, and the FDA gave Lykos’ new drug application priority review in February.
The company is also considering other potential indications for MDMA-assisted therapy.
“Think of high unmet need; things that might have trauma at the root, things like eating disorders,” Emerson said.
Although the issue of functional unblinding could continue to arise in psychedelic clinical trials, it didn’t stand in the way of Spravato’s eventual approval. Murphy doesn’t think functional unblinding will be a deal-breaker for the class as a whole, either.
“I don't think it represents an untoward challenge,” Murphy said. “With a well-designed study, it is possible to mitigate some of the concerns that people have commonly expressed with the use of psychedelics.”
