Psychedelic drug developers are undeterred by the FDA’s Complete Response Letter for the company’s MDMA therapy for PTSD, and experts expect Lykos will ultimately obtain approval.
Following the FDA’s Aug. 9 decision to not approve Lykos Therapeutics’ MDMA-assisted therapy for post-traumatic stress disorder, the reaction from interested parties was swift and unwavering. While drug developers pointed to issues with this specific New Drug Application, many think the treatment could one day reach the market and most agreed the psychedelics space as a whole is undeterred.
The decision will probably turn out to be just a “delay,” said Doug Drysdale, CEO of Cybin, a company developing psilocybin-based drugs. “I think this program is fixable and will likely lead to an approval at some point,” he told BioSpace.
More broadly, players in this up-and-coming therapeutic space see the rejection as a sign of caution from the FDA, not a reflection of resistance 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 readthrough . . . to other psychedelic programs. What Lykos is doing is quite different and unique to them, and ultimately, the [Complete Response Letter] came because the NDA submission was just incomplete.”
Rob Barrow, CEO of LSD-focused MindMed, was similarly sanguine. “Certainly, for the field, it would have been great to see an approval, but it also just reinforces the need for rigor and the highest quality studies and ethics and safety in these studies to ensure that, if we’re successful in illustrating p-value and clinical response, that we can make sure that transitions into a strong case for approval.”
A Delay, Not a Rejection
In its Complete Response Letter (CRL), the FDA said Lykos’ New Drug Application (NDA) for MDMA capsules could not be approved based on the data submitted to date. The decision followed a June advisory committee meeting in which the FDA’s Psychopharmacologic Drugs Advisory Committee voted 10-1 against recommending the treatment, saying that its benefits did not outweigh its risks. The FDA has requested that Lykos complete an additional Phase III study—something CEO Amy Emerson said “would take several years.”
Fran Brown, senior vice president of drug development solutions at Certara, told BioSpace she believes the FDA made the right decision. “Once you approve something in that setting, you open it up to a much wider use case, and [FDA’s] contention was that [Lykos] had not adequately described the safety risks in the context of the benefit,” she said.
Brown pointed to missing safety information in Lykos’ current data package, including post-baseline lab assessments and data related to addiction potential. “There’s quite a lot of things . . . that the data was not available to shed light on the risk, and I think the FDA is looking to see a study design that will fill those gaps,” she told BioSpace.
A key focus area for the adcomm was functional unblinding, which occurs when trial participants are aware of whether they’ve been given the drug or a placebo because of the drug’s immediate effect. “At the end of the day,” Drysdale said, “there was missing [toxicology] data, there was missing abuse assessment data, the long-term efficacy time points were inconsistent, and there wasn’t a dose ranking study, which is part of the mitigation against functional unblinding.”
Lykos objected to the idea that its application lacked adequate support for the therapy’s approval. In a press release, the company said that “the data included in the NDA provide sufficient evidence of efficacy and durability in line with the relevant FDA guidance,” adding that it intends to meet with the FDA to “ask for reconsideration of the decision” and to seek the regulator’s recommendations for a resubmission.
While the path forward for Lykos is unclear, the details provided by the FDA in its rejection letter are a good clue, said Fluence, a continuing education organization in the field of psychedelic therapy.
“The extensive feedback typically offered in a CRL provides a clear roadmap for approval—something that would have been unimaginable four decades ago when MDMA was first banned,” the organization said in a statement sent to BioSpace. “This marks important progress in the field of psychedelic research and mental health treatment. We’ve come a long way, and that’s worth celebrating.”
Broader Lessons
This guidance is illuminating not only for Lykos, but also for other companies in the space. For Cybin, Drysdale said, “it’s actually in some ways helpful to have all this feedback from the adcomm and from the FDA because we can incorporate that into our programs ahead of time.”
For example, Drysdale noted that Lykos is not the only psychedelic drug developer dealing with functional unblinding. For its part, Cybin has designed its Phase III program to have three arms: one containing a high therapeutic dose, a second containing a sub-therapeutic dose, and a third containing a placebo. “These psychedelic-naive patients [who] come into the study won’t know if they’re getting a high dose or a mid-dose, and so they can’t figure out whether it’s the active dose or the inactive dose,” Drysdale said. “So that mitigates some of the functional unblinding,” Cybin is also using remote, independent, blinded raters.
MindMed has also leveraged multiple dose levels in its clinical trials. Barrow added that the real focus needs to be on decoupling functional unblinding from what’s known as expectancy bias. People with depression or anxiety “don’t enroll in clinical trials because they expect to not get better. They expect something,” he said, adding that it is important to hedge against patients believing they’re getting better just because they have a reaction to the drug. MindMed tries to mitigate this through an informed consent process where patients are told that they may feel nothing and get better, or that they might feel something and not get better.
Ultimately, Barrow said, Lykos’ rejection was not all bad news. “Anytime we see a demonstration of FDA independence and rigor, it’s a good thing. It also proves . . . to patients and providers that if, and hopefully when, we get in front of FDA and get an approval, there will be the highest degree of confidence that we’ve delivered a robust package that could stand up to the most intense scrutiny possible.”
Drysdale agreed, saying the delay is probably “a good thing in that if it leads to more robust studies, more robust treatments and outcomes—that’s better for the sector in the long run.”
Barrow noted that MindMed has been “very encouraged” by its interactions with the FDA and pointed to a statement released by the regulator after the CRL. “The agency recognizes that there is 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 encourage research and drug development that will further innovation for psychedelic treatments and other therapies to address these medical needs.”
