The FDA rejected a psychedelic sponsor’s bid for approval. Here are six industry takeaways

Regulatory context: Psychedelic regulation and drug development

• A growing body of evidence suggests that psychedelics may provide clinical benefit for certain purposes, especially mental health conditions. Psychedelic drugs primarily influence the way the brain processes the chemical serotonin, which can lead to vivid visions and alterations to a person’s sense of self, according to the National Institutes of Health. Classic psychedelics include serotonergic agonists such as psilocybin (from psychedelic mushrooms) and lysergic acid diethylamide (LSD). Other substances that also typically fall into this category are entactogens or empathogens, such as 3,4-methylenedioxy-methamphetamine (MDMA, or “ecstasy”).
• The road to research on psychedelic products is paved with obstacles. First, nearly all psychedelics are Schedule I drugs under the Controlled Substances Act (CSA). This means that research programs are subject to additional oversight from U.S. Drug Enforcement Administration (DEA) and companies may face difficulties obtaining sufficient supplies for studies. Second, the perceptual disturbances caused by psychedelic substances beget study design challenges like functional unblinding, response expectancy; additionally, the therapeutic presence that traditionally accompanies psychedelic administration comes with “set and setting” nuances that can dramatically affect outcomes. [ Read AgencyIQ analysis here for a detailed discussion of these issues.].
• FDA released a draft guidance in June 2023 attempting to address many of these unique aspects of clinical research on psychedelic substances. Although the agency maintains that “the substantial evidence standard for establishing effectiveness of psychedelic drugs is the same as it is for all other drugs,” it acknowledges many of the issues with devising an adequate and well-controlled (AWC) clinical study and provides some general input on alternative approaches to research in this area. [ See AgencyIQ’s analysis of the draft guidance here.].
• An AgencyIQ review of the 223 comments on that guidance shows a disconnect regarding the role of and requirements for psychological support. Many commenters took issue with the guidance’s statement that, “The contribution of the psychotherapy component to any efficacy observed with psychedelic treatment has not been characterized. Psychotherapeutic interventions have the potential to increase expectancy and performance biases. Sponsors should plan to justify the inclusion of a psychotherapy component.” Many stakeholders felt that this statement showed a lack of understanding of the research in this area, in which, at minimum, some form of psychological support is considered standard.
• Psychotherapy is considered to constitute the practice of medicine, placing regulation of its conduct outside the scope of FDA’s authority. However, the agency can describe a concomitant therapy in labeling for a product it has authority to regulate if it is essential for the therapeutic effect. While the ability to describe and specify aspects of the therapy is limited, the agency can specify the number and licensure of therapists who would participate in the MDMA treatment. The June 2023 guidance recommends that studies involve two monitors (one with graduate-level professional training and clinical experience in psychotherapy, licensed to practice independently) to observe study participants during treatment sessions.

Lykos Therapeutics’ New Drug Application (NDA) for MDMA capsules to treat post-traumatic stress disorder (PTSD)

• A lengthy regulatory history: The initial investigational new drug application for midomafetamine was filed in 2001. Lykos (formerly MAPS PBC) met with the agency in 2016 for the End of Phase 2 meeting. At that time, FDA flagged concerns with functional unblinding and inherent expectation bias. FDA suggested that the sponsor incorporate an active comparator—a recommendation that was not ultimately taken. Throughout 2017, Lykos sought feedback on the protocol for its first Phase 3 study, MAPP1, via the Special Protocol Assessment (SPA) process. SPA allows sponsors to gain regulatory perspective on whether a proposed trial design is adequate to support a marketing application, though the ultimate approval decision is based on the data submitted for review. Following some back-and-forth regarding statistical analyses and endpoints and abuse potential studies, the agency agreed to a revised SPA in July 2017.
• FDA accepted the Lykos NDA in February 2024, and the submission received priority review. The application relied on evidence from two multi-site, randomized, double-blind, placebo-controlled trials (MAPP1 and MAPP2) that compared MDMA-assisted therapy (MDMA-AT) to placebo plus therapy. Both studies measured Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) severity score at baseline and two months after the last experimental session, with assessment performed by a “centralized pool of blinded, independent diagnostic assessors.” According to results published by the firm, both studies demonstrated a statistically significant reduction in CAPS-5 total severity score. Lykos also put forth data from the exploratory, non-interventional follow-up study (MPLONG) regarding the durability of the effects.
• Importantly, midomafetamine was proposed for use in conjunction with psychotherapy. In the clinical studies, this consisted of a four-month course of treatment with three doses of MDMA administered in supervised therapy sessions. This involved preparatory therapy sessions and “integrative psychotherapeutic sessions” between medication sessions. The therapists used the nonproprietary “ MAPS Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder,” to guide therapeutic stance, but the practitioners had flexibility in terms of modality.

The advisory committee meeting

• FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) met June 4 to weigh in on the Lykos Application. As AgencyIQ discussed in-depth at the time, the committee grappled with data flaws and gaps within the context of positive trials and high unmet need. Specifically, the data showed evidence of functional unblinding, as participants were able to accurately guess their treatment assignment most of the time. In addition, the studies collected limited clinical laboratory data to inform the safety profile and did not systematically document adverse events that could contribute to abuse potential.
• FDA raised concerns about the psychotherapy component, since its use in both trial arms meant that its specific contribution to efficacy could not be quantified. Panel members flagged potential issues with variability between providers.
• Separate from statistical concerns, PDAC had questions regarding potential misconduct within the development program. These concerns stemmed from a March 2024 Draft Evidence Report from the Institute for Clinical and Economic Review (ICER) related to the MAPP studies. “Based on public reports, there is no question that, despite the trial requiring dual treatment by one male and one female therapist, boundaries, including sexual boundaries, were severely crossed with at least one patient,” according to the report. In addition, the report alleged that “Concerns have been raised by some that therapists encouraged favorable reports by patients and discouraged negative reports by patients including discouraging reports of substantial harms, potentially biasing the recording of benefits and harms.” Lykos personnel responded by stating that internal investigations led to policy changes and additional training regarding boundary setting for patients and providers. FDA added that the agency had inspections ongoing and reiterated the importance of licensure of study personnel.
• The agency proposed a Risk Evaluation and Mitigation Strategy (REMS) framework in case of approval. This would be necessary because of the “expected patient impairment from midomafetamine administration.” The proposed elements to ensure safe use (ETASU) plan included four components: (1) dispensing only in certain healthcare settings, (2) dispensing to patients with documentation of safe-use conditions, (3) monitoring each patient using the drug, and (4) enrolling each patient using the drug in a registry. The plan would also include an implementation system and timeline for assessment submission.
• Ultimately, the panel voted 9-2 and 10-1 against the efficacy and risk-benefit ratio of Lykos’ drug. Lykos responded to the outcome of the meeting in a press release. Further, Lykos expressed confidence in the rigor of its study design, and asserted that clinical laboratory data regarding cardiovascular and hepatotoxicity risks could be addressed in the postmarket environment. Regarding the case of misconduct discussed at the meeting, the firm emphasized that it “reported this violation to Health Canada, the FDA, and the relevant Institutional Review Board and banned the therapist pair associated with this case from all future work.”

In early August, FDA aligned with its advisors and issued a Complete Response Letter (CRL) for the application

• On August 9, Lykos announced that FDA issued a CRL for its midomafetamine application. The release discussed the agency’s justification for the decision somewhat ambiguously, saying that “the issues expressed in the CRL echo those raised during the FDA Advisory Committee meeting on June 4, 2024.” However, the firm also clarified that “FDA has requested that Lykos conduct an additional Phase 3 trial to further study the safety and efficacy of midomafetamine.”
• Lykos’ announcement enumerated several of the firm’s concerns related to the PDAC roster and discussion, referring to “concerns around the structure and conduct of the Advisory Committee meeting, including the limited number of subject matter experts on the panel and the nature of the discussion, which at times veered beyond the scientific content in the briefing documents.” The meeting’s roster included five voting members from PDAC, six temporary voting members, and one non-voting industry representative. Areas of expertise included psychiatry, post-traumatic stress disorder, emergency medicine, pharmacy and medication safety, and statistics. Lykos also referenced ongoing efforts within the agency to reform the advisory committee process, although these are general, agency-wide efforts to “tune up our Advisory Committee system in a way that enables our experts to get the best advice possible,” as FDA Commissioner ROBERT CALIFF recently said. [ Read AgencyIQ analysis of a recent listening session on the topic here.].

Where does Lykos go from here?

• Immediate next steps for Lykos will involve “a meeting with the FDA to ask for reconsideration of the decision and to further discuss the agency’s recommendations for a resubmission.” This meeting will likely be a Type A meeting under the Prescription Drug User Fee Act (PDUFA) [ See AgencyIQ analysis of a September 2023 guidance on these formal meetings.]. Regarding timing, FDA committed in PDUFA VII to respond to Type A meetings within 14 days and schedule them within 30 days of the initial request. After this meeting is held, Lykos says it expects to provide an update.
• If resubmission is pursued, a new review cycle will be triggered. Resubmissions are categorized into Class 1 and Class 2 resubmissions, with Class 1 submissions requiring a new 2-month review cycle and Class 2 submissions requiring a new 6-month review cycle. The classification of a potential Lykos resubmission could depend on whether a new Phase 3 trial is undertaken.
• Lykos maintains that a new trial may not be necessary. Lykos CEO Amy Emerson stated in the press release that “While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature.” Still, the design of a new Phase 3 trial would offer insights into how the agency wants to improve the data issues and gaps discussed during the June PDAC meeting. Regarding the psychotherapy component of the protocol, the release stated that “Lykos remains committed to continuing development of this integrated approach.”
• Lykos currently has other midomafetamine studies registered on ClinicalTrials.gov that could provide some clues regarding future directions. Lykos has contemplated alternative psychotherapy paradigms, as evidenced by the withdrawn Phase 2 clinical study that sought to characterize the feasibility and safety of MDMA-Assisted group therapy. Per the record, the study was withdrawn prior to enrollment of any patients due to “transfer of sponsorship.” Lykos may look again at different approaches to therapy to reduce variability and better characterize its contribution to efficacy. To address issues in the safety realm, the firm has currently registered an active, but not yet recruiting, open-label Phase 1 study that will “collect quantitative data on mood, psychological status, self-compassion, professional quality of life, and professional burnout” in a target of 150 healthy volunteers receiving midomafetamine. This study is planned to start in late 2024 and conclude in late 2025. Lykos also registered an additional open-label Phase 1 pharmacokinetics study of midomafetamine and metabolites in patients with moderate hepatic impairment to understand if a dose adjustment is necessary in that population. Potential hepatic risk was one data gap discussed at the advisory committee meeting. The study is planned to begin in 2026 and conclude in 2028.
• Per its press release, the firm also plans to “take advantage of agency processes to resolve scientific disagreements.” This implies that Lykos is considering leveraging FDA’s Formal Dispute Resolution (FDR) process [ See AgencyIQ’s in-depth explainer here]. In addition to withdrawing or resubmitting their application, sponsors who receive a CRL can “request review of scientific controversy by an appropriate scientific advisory panel.” If the request is denied, the denial should be communicated by the FDA to the sponsor in writing. A denial may then be escalated to a higher office through a “request for review of the denial” by the FDA’s “Chief Mediator and Ombudsman.” [ For an FDR case study, see AgencyIQ’s analysis of Intarcia’s years-long battle over ITCA-650]. This process could culminate in circling back to yet another PDAC meeting as a final step. According to a 2017 final guidance document on this process, sponsors should not simultaneously pursue several different administrative remedies at the same time. This means that Lykos will likely initiate the FDR process based on the outcome of the abovementioned Type A meeting with the agency.
• The FDR process is often time- and resource-intensive but does afford companies certain rights, and even potential benefits. As AgencyIQ has previously discussed, the communication obtained through the dispute process can offer additional, favorable information about how to obtain subsequent approval that may not have been previously available or made clear in the CRL process.

Six takeaways: What does the outcome mean for the psychedelic ecosystem?

• First: Psychotherapy is a major quandary at best, and a landmine at worst. This class-wide issue been an ongoing point of discussion both in the U.S. and in Europe. At a recent workshop addressing regulatory issues with psychedelic medicines, MARION HABERKAMP, an EMA committee member and on staff with the German regulator BfArM, identified the question of whether psychotherapy and psychological support are integral to psychedelic therapy as one of the “main challenges” in the field. The FDA’s MARTA SOKOLOWSKA, who attended the EMA workshop in person, reiterated that the FDA does not regulate the practice of medicine, and hence cannot regulate psychotherapy [ Read AgencyIQ’s full analysis of that workshop here.].
• Second, the challenges associated with integrating psychedelics with psychotherapy may lead some sponsors to drop the latter. Prior to the Lykos CRL, TIME Magazine reported that the CEO of Compass Pathways, a firm investigating psilocybin for multiple mental health conditions, said, “If and when we get to the point of filing, we will be filing for [only] a drug.” Compass has studied psylocibin for PTSD in an open-label, Phase 2 setting. According to a company press release, the drug was administered with “psychological support” from a licensed medical professional that involves more of a supervisory role in “preparing participants for the treatment session, observing and being present with patients during the session and supporting them after the session.”
• Next, sponsor-FDA agreement on trial designs via SPA should be taken with a grain of salt. Receiving the agency’s nod through this process indicates “adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, and planned analyses) for a study intended to support a future marketing application,” according to a 2018 final guidance on the topic. However, the agency makes clear that “an SPA agreement does not indicate FDA concurrence on every protocol detail.” The SPA did seem to benefit Lykos as they designed the trial. That said, recommendations received during this process should be followed closely.
• Fourth, sponsors should anticipate a stringent REMS requirement. Through the advisory committee, the field learned FDA’s position that a REMS is unequivocally necessary for midomafetamine due to the perceptual impairment caused by the drug. As a result, most sponsors in this drug class should expect this requirement to come into play. The contours of the midomafetamine REMS laid out by FDA in the proposed ETASU, such as dispensing only in certain healthcare settings, can be incorporated into future study designs.
• Also, the Lykos outcome could inadvertently chill some academic research. Following the announcement of the CRL, the editors of Psychopharmacology issued a retraction notice for a pooled analysis of Phase 3 trials of MDMA-assisted psychotherapy for PTSD. The notice explained that the retraction follows the discovery of undisclosed “protocol violations amounting to unethical conduct at the MP4 study site by researchers associated with this project” and undisclosed potential competing interest. Separately, in an unusual move made at an interesting moment, the FDA withdrew its plans for a behavioral economics study of real-world use of psychedelics and kratom the same day it issued the Lykos CRL. The exploratory study was intended to study risk and safety considerations for people who use “Kratom and Psychedelics alone and in combination with other substances,” to inform proactive work of the agency’s Controlled Substances Program (CSP) [ Read AgencyIQ analysis of the original announcement here.]. Per the withdrawal notice, “FDA no longer intends to proceed with the proposed study as described because circumstances occurred necessitating changes to the scope of the study.”
• Last thoughts: Political pressure will likely continue—and heighten. Dozens of legislators had asked the FDA to consider approval for the drug in light of its potential benefits to veterans and others with PTSD. Given this attention, AgencyIQ would not be surprised to see FDA leadership called before Congress to explain the Lykos decision.

Featuring previous research by Alexander Gaffney.

To contact the author of this item, please email Amanda Conti ( aconti@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

Key Documents and Dates

• Lykos Therapeutics Press Release, August 9, 2024