Psychiatric Drug Developers Advise Post-Lykos Adcomm

Psychedelic drug developers have recently been prompted to reassess their trial protocols following the FDA’s Psychopharmacologic Drugs Advisory Committee’s recommendation against approving Lykos’ MDMA-assisted therapy for treating post-traumatic stress disorder (PTSD). This decision has led companies in the field to scrutinize their methodologies to avoid similar setbacks.

Joe Tucker, CEO of Enveric Biosciences, noted that the FDA had provided guidance on clinical trials involving psychedelic drugs a year earlier, indicating a willingness to support the sector. Despite this support, the advisory committee emphasized the importance of rigorous clinical trial design and evaluation.

Dan Karlin, chief medical officer of MindMed, pointed out that the FDA's reservations were more about the trial methods employed by Lykos rather than a general bias against psychedelics. The committee members focused on the design and execution of the clinical trials rather than the MDMA compound itself. Pamela Tenaerts, chief scientific officer of Medable, highlighted that while Lykos' trials showed a substantial decline in PTSD symptoms, they neglected other critical aspects, such as unrecorded symptoms, incidents of sexual misconduct, and uncertainty over endpoints.

The advisory committee identified several issues in Lykos' trials. Despite collaborating closely with the FDA under a Special Protocol Assessment, Lykos did not include data on cardiovascular and liver toxicity risks in its filings. Sam Clark, CEO of Terran Biosciences, mentioned that while this omission was not critical, it underscored the need for comprehensive data collection in future trials.

Another crucial aspect was the absence of data on the potential for abuse. Although Lykos recorded adverse events, it did not document patients' neutral or positive feelings, limiting the assessment of abuse potential. Karlin and Clark both emphasized the importance of recording all acute drug experiences to generate thorough and significant data, addressing concerns about expectation bias.

MDMA’s unique properties also posed challenges in blinding the studies. According to the Drug Enforcement Agency, MDMA acts as both a stimulant and a psychedelic, making it difficult to design a placebo that doesn't exacerbate anxiety or worsen PTSD symptoms. Despite these challenges, the FDA eventually agreed with Lykos' plan to use an inactive placebo with psychotherapy as a control, acknowledging the complexities involved in such studies.

The interplay between the drug and psychotherapy further complicated the trials. Karlin highlighted the difficulty in standardizing psychotherapy and determining whether the effects were due to the drug or the psychotherapy. Clark suggested that dose escalation studies might help differentiate between these effects, resolving issues related to functional unblinding.

The evolving understanding of psychedelics indicates that their therapeutic benefits might be linked to enhancing neuroplasticity rather than causing hallucinations. Tucker explained that increased neuroplasticity strengthens the signaling from the prefrontal cortex to the amygdala, offering a potential mechanism for treating depression and anxiety. This shift in understanding has led companies like Enveric, AbbVie, and Gilgamesh to develop neuroplastogen molecules that minimize the risk of hallucinations.

To mitigate bias, MindMed employs multiple clinical research sites and rigorous training to ensure adherence to protocols. Centralized independent raters are used to assess patients' treatments, aiming for unbiased evaluations.

Reflecting on Lykos' experience, it is clear that meticulous planning and comprehensive data collection are crucial for psychedelic drug trials. The ultimate goal, as Karlin stated, is to develop treatments that are accessible and effective, even for those who might currently be hesitant about using psychedelic drugs.