FDA rejection of Lykos delays – but does not end – psychedelic therapies

Following the FDA’s decision on August 9 do not approve The reaction from interested parties to Lykos Therapeutics' MDMA-assisted therapy for post-traumatic stress disorder was swift and unwavering. While drug developers pointed to problems with this specific new drug application, many believe the treatment could one day come to market, and most agreed that the psychedelics space as a whole is undeterred.

The decision will likely prove to be just a “delay,” said Doug Drysdale, CEO of Cybin, a company developing psilocybin-based drugs. “I think this program is feasible and will probably lead to approval at some point,” he said BioSpace.

In a broader sense, the actors of this emerging therapeutic space see the rejection as a sign of caution on the part of the FDA, not an expression of opposition to the ideas of psychedelic therapies. While the FDA's decision is “disappointing for patients” and has had a negative impact on psychedelic stocks, Drysdale said, there is “no real visibility … to other psychedelic programs. What Lykos is doing is very different and unique to them, and ultimately the [Complete Response Letter] came because the NDA submission was simply incomplete.”

Rob Barrow, CEO of LSD-focused company MindMed, was similarly optimistic. “Approval would obviously have been great for the field, but it also underscores the need for rigorous, high-quality trials, ethical and safety research to ensure that if we can demonstrate the P-value and clinical response, we can turn that into a strong argument for approval.”

A delay, not a rejection

In its Complete Response Letter (CRL), the FDA stated that Lykos' application for MDMA capsules could not be approved based on the data submitted to date. The decision followed a June advisory meeting at which the FDA's Psychopharmacologic Drugs Advisory Committee voted 10-1 against recommending the treatment because the benefits do not outweigh the risks. The FDA has asked Lykos to complete an additional Phase III trial – which, according to CEO Amy Emerson, “would take several years.”

Fran Brown, senior vice president of drug development solutions at Certara, said BioSpace She believes the FDA made the right decision. “When you approve something in this context, you open it up for a much broader use case, and [FDA’s] The claim was that [Lykos] the safety risks were not adequately described in the context of the benefits,” she said.

Brown pointed to missing safety information in Lykos' current data package, including post-baseline laboratory testing and data on addiction potential. “There are a whole lot of things … where the data were not available to shed light on the risk, and I think the FDA is looking for a study design that fills in those gaps,” she said. BioSpace.

One of the areas of focus for Adcomm was functional unblinding, which occurs when study participants know whether they have received the drug or a placebo based on the immediate effect of the drug. “Ultimately,” says Drysdale, “there was a lack of [toxicology] data, abuse assessment data were missing, long-term efficacy time points were inconsistent, and there was no dose evaluation study, which is part of the mitigation against functional unblinding.”

Lykos complained that its application lacked sufficient support for approval of the therapy. Press releaseThe company stated that “the data contained in the NDA provide sufficient evidence of efficacy and durability consistent with relevant FDA guidelines,” adding that it intends to meet with the FDA to “request a review of the decision” and seek the regulator's recommendations for resubmission.

While the path forward for Lykos is unclear, the details provided by the FDA in its rejection letter are a good starting point, says Fluence, an educational organization in the field of psychedelic therapy.

“The extensive feedback typically offered in a CRL provides clear guidance for approval – something that would have been unimaginable four decades ago when MDMA was first banned,” the organization said in a statement to BioSpace“This is an important advance in the field of psychedelic research and mental health treatment. We have come a long way and this is a cause for celebration.”

Broader lessons

This guidance is insightful not only for Lykos, but also for other companies in the space. For Cybin, says Drysdale, “it's actually helpful in some ways to have all this feedback from Adcomm and the FDA because we can incorporate it into our programs up front.”

For example, Drysdale noted that Lykos is not the only psychedelic drug developer looking into functional unblinding. Cybin, on the other hand, has designed its Phase III program to have three arms: one with a high therapeutic dose, a second with a subtherapeutic dose, and a third with a placebo. “These psychedelic-naive patients [who] “The study participants do not know if they are receiving a high dose or a medium dose, so they cannot determine if it is the active or inactive dose,” said Drysdale. “This somewhat weakens the functional unblinding,” said Cybin. Cybin also uses independent, blinded assessors remotely.

MindMed has also used multiple dosing levels in its clinical trials. Barrow added that the real focus needs to be on decoupling functional unblinding from what is known as expectation bias. People with depression or anxiety “don't enter clinical trials expecting not to get better. They expect something,” he said, adding that it's important to protect patients from believing they're getting better just because they respond to the drug. MindMed tries to mitigate this through an informed consent process in which patients are told they might not feel anything and get better, or they might feel something and not get better.

Ultimately, Barrow said, the Lykos rejection isn't all bad news. “Any time we see a demonstration of FDA independence and rigor, it's a good thing. It also proves to … patients and providers that when – and hopefully if – we go before the FDA and receive approval, there will be the highest level of confidence that we've delivered a robust package that can withstand the most intense scrutiny possible.”

Drysdale agreed, saying the delay was probably “a good thing because if it leads to more meaningful studies, more meaningful treatments and outcomes, that's better for the sector in the long run.”

Barrow noted that MindMed was “very encouraged” by its interactions with the FDA, pointing to a statement the regulator released following the CRL. “The agency recognizes that there is a great need for additional treatment options for mental health conditions such as PTSD,” the FDA said, according to The Washington Post“We will continue to support research and drug development that advances innovation in psychedelic treatments and other therapies to meet these medical needs.”