After years of industry buzz and forward momentum in psychedelic drug development, the two leading companies in the space are stumbling.
Earlier this year, an FDA advisory panel voted against Lykos Therapeutics’ MDMA drug for PTSD due to a litany of complaints including a failure to submit requested data, concerns about the drug’s abuse potential and sexual misconduct during the trials. The treatment was ultimately rejected by the agency. Major company layoffs followed, but Lykos officials recently met with the FDA with the lingering hope of getting the therapy across the finish line.
In the wake of the Lykos decision, Compass Pathways, which has the most clinically-advanced psilocybin treatment for depression, recently delayed its timeline to report phase 3 results to ensure the trial can withstand the high level of scrutiny related to trial blinding. The company also announced plans to axe nearly a third of its staff.
The setbacks are a reminder that industry hype doesn’t spare biotechs from the hot glare of regulatory scrutiny. But if one psychedelic company can make it across the finish line, it will be easier for others to follow, said Dr. Mwango Kashoki, senior vice president and global head of regulatory strategy at Parexel, a global CRO and biopharmaceutical services company.
Creating a road map
With the road looking rocky for up-and-coming psychedelics companies, Parexel recently released a report outlining research best practices. A cornerstone of its advice: Companies embarking on psychedelic trials need open communication channels with regulators. In particular, the report recommends companies set the stage through an initial engagement meeting in the early stages of development to help inform the road ahead.
Another critical component of this early planning is ensuring appropriate dose selection, Kashoki said. This is particularly crucial for psychedelic drug trials, which carry safety risks. Testing ascending doses and exploring various dosing regimens can help sponsors settle on the most effective dose that minimizes undesirable effects.
Companies also shouldn’t try to expedite dose selection by relying exclusively on clinical data, she said.
“The assumptions that we have seen some companies make about an appropriate dose often are more extrapolation from published literature and clinical studies,” Kashoki said. “They do this without appropriate early-phase evaluation to explore for dose response from a pharmacokinetic, pharmacodynamic [and] physiologic effects perspective.”
One of the biggest challenges in trials for psychedelic drugs, which can have an acute and apparent dissociative effect, is blinding subjects and researchers. One study of psychedelic trials found that nine of 10 studies carried a high risk of bias, according to Parexel.
“If these important considerations and concerns can be satisfactorily addressed, then there’s no reason for the FDA to not consider the products as therapeutic medications."
Dr. Mwango Kashoki
Senior vice president, global head of regulatory strategy, Parexel
“The studies were compromised by small sample sizes, non-diverse patient populations, unsuccessful or unreported blinding and high dropout rates. Most did not provide protocols or statistical analysis plans,” the report stated.
Two strategies can help. One is to enlist a blinded independent person, not the study investigator, to capture safety and efficacy information. The second is to use a comparative drug that has a similar effect in the placebo group.
“One approach could be to use a low dose of the same investigational drug that through early studies has been determined not to be the efficacious dose,” Kashoki said.
The patient will experience a psychoactive effect, which reduces the potential for bias.
Ultimately, it will take some false starts before companies work out the kinks in psychedelic trials, Kashoki said.
Despite the recent setbacks, the FDA still appears willing to consider the value of these drugs.
“There is a plausible mechanism of action of these drugs in various psychiatric and substance use disorders. Why not study them? If these important considerations and concerns can be satisfactorily addressed, then there's no reason for the FDA to not consider the products as therapeutic medications,” Kashoki said.
