Psychedelic drug developers got a wake-up call when the FDA’s Psychopharmacologic Drugs Advisory Committee recommended against approving Lykos’ MDMA-assisted therapy to treat post-traumatic stress disorder. Now, companies in this space are scrutinizing their own protocols to ensure they don’t make the same mistakes.
“It’s really a shot over the bow,” Joe Tucker, CEO of Enveric Biosciences, a neuropsychiatric drug developer, told BioSpace. “The FDA gave guidance specifically on clinical trials involving psychedelic drugs one year ago. When I read it, I remember thinking, ‘The FDA is basically bending over backwards . . . to help.' To me, that says the FDA really wants companies in this sector to be successful.”
This desire, however, pales in the face of unsatisfying clinical safety and efficacy. And, based on its recommendation, it’s clear the advisory committee insists on conducting and evaluating clinical trials “the right way,” Tucker said.
Dan Karlin, chief medical officer of MindMed, which is developing an LSD therapeutic, agreed that the FDA seems open to psychedelic drugs in general. “Committee members didn’t necessarily seem biased against psychedelics, so much as they had real reservations around the methods MAPS [now Lykos] had employed,” Karlin told BioSpace.
Focus on Trial Design
At the Lykos adcomm meeting, committee members seemed to focus more on the clinical trial than the company’s midomafetamine (MDMA) drug itself. “I think the issue was a trial issue, and not a compound issue,” Pamela Tenaerts, chief scientific officer of Medable, which designs digital trial software, told BioSpace.
Lykos showed post-traumatic stress disorder (PTSD) symptoms declined substantially, but Tenaerts said “it did less of a good job [with] the things surrounding that endpoint.” As examples, she cited symptoms that weren’t recorded, a case of sexual misconduct and uncertainty over endpoints “because they didn’t track the positive side effects, like the euphoria.” Additionally, “there are indications of patients being told that maybe they were contributing to making history,” which may have affected their perceptions of their experiences, she said.
The adcomm pointed out several issues in the trials, to which Lykos responded. Despite working closely with the FDA under a Special Protocol Assessment, the FDA did not require data regarding cardiovascular and liver toxicity risks, and Lykos did not include such information in its filings.
The lack of this physiologic safety data wasn’t a make-or-break omission, though. “The safety profile is already known and MDMA is only dosed three times in therapy . . . so that kind of safety data can be recorded in post-marketing surveillance Phase IV trials,” Sam Clark, CEO of Terran Biosciences, which develops therapies for neurological and psychiatric diseases, told BioSpace. Additionally, “companies can [design] a comprehensive risk evaluation and mitigation program to mitigate safety risks.” Nonetheless, he said, that data should be collected and submitted going forward. “Future trials should include those labs.”
Data regarding the potential for abuse also was absent from Lykos’ regulatory filings.
Although Lykos recorded adverse events during trials, it generally didn’t record patients’ neutral or positive feelings, such as elevated moods or euphoria, according to the FDA briefing document. This “limits the assessment of abuse potential,” the FDA noted. “However, there is an extensive literature in both animals and humans and other available data . . . to inform the assessment.”
Relying on that data, however, proved inadequate for the committee. Clark and Karlin both recommend recording all acute experiences with the drug, whether they’re expected or unexpected, positive, negative or neutral, to generate more thorough data and, thus, more significant information. Recording positive experiences, Clark explained, is important because that data helps address criticism around expectation bias.
Functional Unblinding
The Drug Enforcement Agency notes that MDMA acts as both a stimulant and a psychedelic. As Karlin explained, “MDMA is not a [classic] psychedelic. It’s an entactogen or empathogen.”
Unlike psychostimulants or hallucinogenics, MDMA promotes profound introspection rather than “trips,” according to research from the University of North Carolina at Chapel Hill.
The “profound alterations in mood, sensation, suggestibility and cognition” make these types of studies “nearly impossible to blind,” the FDA said in its briefing document. The agency recommended using niacin or other stimulants or low-dose MDMA, each of which Lykos rejected, arguing that those options could exacerbate anxiety or worsen PTSD symptoms, according to the same document.
But, Clark pointed out, “functional unblinding is not uncommon in drugs in psychiatric trials.” Therefore, the FDA eventually agreed, despite concerns, with Lykos’ plan to use an inactive placebo with psychotherapy as a control.
The Role of Psychotherapy
Alterations in mood, etc., pose a bigger issue than merely unblinding a study. Their occurrence means that such guided therapies are conducted alongside psychotherapy, which makes it difficult to determine whether results were caused by the drug or the psychotherapy, the FDA briefing document noted.
“No one has suggested that MDMA, in the absence of psychotherapy, would be an effective treatment,” Karlin underscored. “Psychotherapy research is hard to standardize. It’s hard to know how to do an appropriate control condition.” Lykos, he said, was “in a tough spot . . . because now you have two different interventions that are not well controlled and not really well-understood.”
Dose escalation studies can help differentiate between the effects of the drug and those of psychotherapy. “There could potentially be a dose-dependent response,” Clark said, which may resolve the issue of functional unblinding.
If drug-assisted psychotherapy is a part of a trial, companies should also clarify what “psychotherapy” means in that context. “In Lykos’ situation,” Tucker said, “it seemed there was a lot of variability in what psychotherapy meant, how it was administered and how it was monitored.”
Neuroplasticity Over Hallucination
The original thinking around psychedelics was that, as a patient, “You took a drug, had a hallucination, and psychotherapy helped you process it. That solved your trauma, and you were cured,” Tucker told BioSpace.
In the past five years, however, scientists have proposed an alternative mechanism called neuroplasticity. “In people with depression or anxiety, the prefrontal cortex has lost some of its ability to calm the amygdala,” Tucker said.
By enhancing the brain’s neuroplasticity, existing neurons make more connections with other neurons, he explained. This “strengthens the signaling from the prefrontal cortex (which governs logical thinking) to the amygdala (which governs emotions).” Under that theory, the hallucination is a side-effect, and the benefit is the increased neuroplasticity.
For biopharma, this makes psychiatric therapies more appealing, Tucker said. Enveric, as well as AbbVie and Gilgamesh—which announced a collaboration in May—are developing neuroplastogen molecules, which minimize the risk of hallucinations.
The Risk of Bias
Sponsor and investigator bias was another issue for the Lykos adcomm. To minimize this, MindMed is working with “20 different clinical research sites to minimize bias [in its trials] . . . and to ensure results aren’t overweighted by one site or another,” Karlin said. Extremely rigorous site training also helps, as does meticulous oversight to ensure adherence to protocols.
MindMed and Lykos both use centralized independent raters to talk with patients about their treatments. “We use an off-site service to do the primary efficacy assessments,” Karlin said. Because they are not in the room during the sessions and are blinded to visit number, he suggests their assessments are more likely to be unbiased.
Given Lykos’ experience, Clark advised companies in this space to plan their trials meticulously to minimize the risk of encountering similar objections from future adcomms.
The ultimate goal, Karlin said, is “to develop the drug in such a way that people who would never in a million years today think about taking [psychedelic drugs] can have a medical and psychiatric evaluation and access an [effective] treatment."
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