FDA's Psychedelic Reckoning
By Ben Comer, Chief Editor, Life Science Leader
The number of psychedelic drug developers reaching Phase 2 and Phase 3 clinical trials is growing, in recognition of the level of unmet need in many mental health disorders and other conditions. Those candidates are progressing despite two setbacks that occurred this year: the first began with a contentious and emotional FDA Advisory Committee meeting on Lykos Therapeutics’ breakthrough therapy-designated MDMA candidate, and ended with an FDA Complete Response Letter (CRL) declining to approve the therapy-assisted drug without further study.
The second setback arrived with Compass Pathways’ announcement of a delay in top line data from a Phase 3 pivotal trial of COMP360, Compass’s breakthrough therapy-designated psilocybin candidate targeting treatment-resistant depression. Both Lykos and Compass announced significant layoffs following those setbacks.
Considered in isolation, it might appear that the buzz around psychedelic medicines has begun to wear off. A different signal, however, points to a different conclusion: Johnson & Johnson’s Spravato, a ketamine-derived product (esketamine) administered via nasal spray and first approved by the FDA in 2019, is expected to reach blockbuster status this year, and could reach as much as $5 billion annually, according to the Wall Street Journal. Aside from that precipitous growth in sales, the increased usage of Spravato has helped to build the infrastructure needed to administer new psychedelic medicines, such as expanding the number of available clinics and practitioners licensed to treat patients.
Cybin’s CBY003, also a breakthrough therapy designee, has benefited substantially from its breakthrough therapy status, says Drysdale. After meeting with the FDA in February, following the end of the CBY003 Phase 2 trial, Cybin went back to the agency in August — after the Lykos CRL announcement — for a Type B Breakthrough Therapy meeting. “We really had to dig into the details and understand the consequences of the Lykos decision,” says Drysdale. “The timing kind of worked out for us, and we were able to incorporate all of those concerns and learnings into our Phase 3 program, and to align with FDA.”
Give The FDA What It Wants
What were some of the items that FDA wants to see in a Phase 3 trial of a potent psychedelic drug? “Timing and endpoints … FDA wants a short primary endpoint, six weeks in our case, and then they also want to see 12 weeks of double-blinded, placebo-controlled data,” says Drysdale. “They were also eager to have a psychedelic naïve population.” Because MAPS began its clinical investigations into MDMA so long ago (an original IND for MDMA was accepted by the agency in 1992), it was perhaps more difficult for the organization to anticipate shifts in agency thinking, such as a need for psychedelic naïve patients to help control for expectation bias, posits Drysdale.
Overall blinding is another issue the FDA cares about. Patients participating in Cybin’s CYB003 clinical trials are monitored for four to six hours, and they wear an eye mask and headset cued up with a playlist Cybin put together in combination with investigators and therapists (“calm instrumental stuff, no heavy rock”). For the monitors in the room, most of the time it is pretty clear that a patient is having a psychedelic experience, versus receiving a placebo, says Drysdale. The monitors are responsible for “collecting the patient’s experience, adverse events, any abuse-related terms like euphoria, and all of that goes into the report form,” he says. “But it’s blinded to the raters, who rate the patient’s depressive score before and after the session … they don’t get to see any of that information, so they can’t have any insight into the patient experience or what they took, and I think that’s important.”
Cybin is further addressing patient safety by recording all trial sessions, including interactions with facilitators and monitors in the study. “We’re using manual auditing of those videos, and we’re using AI real-time auditing to make sure that the facilitators and monitors stick to the script, both for fidelity and to make sure they aren’t influencing the patient in any way, or adding any bias or abuse liability,” says Drysdale. “If a monitor said something inappropriate, like ‘Would you like a hug?’ that would be flagged immediately, and we have a whole process for addressing that kind of behavior.”
Drysdale says Cybin has been using its breakthrough therapy designation “to the fullest extent,” and the fact that Lykos and Compass had issues arise prior to the launch of Cybin’s pivotal Phase 3 clinical program has been exceedingly fortunate. “I’ve never been involved with a breakthrough therapy treatment before, and the difference in FDA interactions is marked, it’s completely different,” he says. “You get real discussions rather than vague, yes and no kinds of responses … they tend to give real input.” For example, “FDA might say, ‘We think you might want to rethink that end point definition,’ and ‘Let's talk about patient population’ … it’s a real dialogue. I think we have truly benefited from that.”
Expanding Infrastructure And A New HHS/FDA Regime
Spravato, J&J’s esketamine product, which is indicated for both treatment-resistant depression and MDD, has a REMS program that controls how patients and physicians use and administer the drug. Drysdale suspects that a REMS program for CYB003 would be more or less a “cut and paste” of the Spravato REMS, based on meetings with FDA and a proposed REMS for Lykos’s MDMA product. “We’ll propose a REMS program as part of our application based on the data we have, and not just the pivotal studies, but other studies” covering things like toxicology, abuse, liability, and clinical pharmacology, he says.
In terms of venues for commercial drug administration, the growing use of Spravato has led to the emergence of “treatment centers that have multi-modalities … such as transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and esketamine,” says Drysdale. “Spravato has established itself in 4,500 centers, and that number is going to grow by the time we come to market. We see CYB003 dropping into that infrastructure.” Because CYB003 would be administered much less frequently, perhaps twice a year (if approved — Cybin hopes to file an NDA for CYB003 in 2027) compared with 26 doses a year for Spravato, there would be space to accommodate patients, says Drysdale.
At the time of our conversation, Marty Makary had not yet been nominated as the Trump administration’s pick for FDA Commissioner, but Drysdale was optimistic about the potential implications of Robert F. Kennedy Jr. as HHS Secretary. “He has been quite positive about psychedelics, and he also has made it clear that he considers it a priority to make psychedelics available in a regulated way,” says Drysdale. “But not retail legalization, so he seems to be aware of the challenges and the positives. I think that's very, very good for us.”