FDA Denies Approval of New Drug Application for MDMA and Requests Additional Study

Lessons and Next Steps for Other Psychedelics in Development

As the therapeutic potential of psychedelics continues to gain traction in the medical community, recent developments surrounding the U.S. Food and Drug Administration’s (FDA) decision on Lykos Therapeutics’ MDMA new drug application (NDA) have sparked considerable debate. This article explores the implications of the FDA’s decision, lessons for developers, and the future trajectory of psychedelic therapies.

On August 9, 2024, Lykos Therapeutics announced that the FDA had issued a complete response letter (CRL) rejecting Lykos’ NDA for midomafetamine (MDMA) for the treatment of post-traumatic stress disorder (PTSD).¹ The FDA also requested an additional Phase 3 study from Lykos to further evaluate MDMA’s safety and efficacy. Although Lykos has not made the CRL public, the company reported that the concerns communicated in the CRL are similar to those raised during the FDA’s Psychopharmacologic Drugs Advisory Committee Meeting (Advisory Committee Meeting) on June 4, 2024.² Some of the issues included functional unblinding, where participants can recognize if they received the study drug or placebo; expectation bias due to the inclusion of participants with prior MDMA use; durability of MDMA treatment effect; contribution and necessity of psychotherapy to MDMA treatment effect; limited information on cardiac safety profile and limited clinical laboratory data, such as liver function testing; and allegations of therapist misconduct.³

The FDA’s request for an additional Phase 3 study may indicate lingering concerns about MDMA’s long-term efficacy and safety, particularly in light of the controversy over several studies. The agency may also be cautious due to the complex nature of psychedelic-assisted therapies, which combine pharmacological and psychotherapeutic components.

Impact of Psychopharmacology Retractions

On August 10, 2024, the day after FDA issued its CRL rejecting Lykos’ NDA, the journal Psychopharmacology retracted three studies on MDMA-assisted psychotherapy due to “protocol violations amounting to unethical conduct” by researchers at one of the study sites.^4,5,6 The journal’s retraction notices stated that the “[t]he authors have subsequently confirmed that they were aware of these violations at the time of submission of this article, but did not disclose this information to the journal or remove data generated by this site from their analysis.”⁷ In addition, some of the authors “did not fully declare a potential competing interest” of their affiliation with the Multidisciplinary Association for Psychedelic Studies (MAPS) or its subsidiary, the Multidisciplinary Association for Psychedelic Studies Public Benefit Corporation (MAPS PBC), now known as Lykos Therapeutics.⁸

The retraction of these key studies could significantly undermine both public and regulatory confidence in MDMA as a treatment for PTSD. These events underscore the importance of rigorous ethical standards and transparency in clinical research, which are critical to maintaining the integrity of the approval process.

Lykos’ Next Steps

In response to the FDA’s decision, Lykos announced its plans “to request a meeting with the FDA to ask for reconsideration of the decision and to further discuss the agency’s recommendations for a resubmission seeking regulatory approval.”⁹ Amy Emerson, Chief Executive Officer (CEO) of Lykos, emphasized that “[w]hile 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.”¹⁰

Lykos also addressed concerns raised during the Advisory Committee Meeting, which concluded in a 9-2 vote that the available findings did not show MDMA to be effective for PTSD and a 10-1 vote that the potential benefits of MDMA do not outweigh the potential risks.¹¹ The company defended the sufficiency of its data to demonstrate durability of treatment effect, noting that its “Phase 3 studies collected endpoint data at 18 weeks, with additional exploratory endpoints collected six months or more later[,]” in line with FDA guidance.¹² Lykos pointed out that the company was “aligned with the FDA in the Special Protocol Assessment (“SPA”) in 2017 on a variety of bias minimization measures in the study design.”¹³ Regarding issues related to expectancy bias due to the inclusion of participants with prior MDMA use, Lykos noted that information, such as that nearly 30% of participants in its Phase 2 studies reported prior MDMA use, was shared with the FDA prior to the establishment of inclusion/exclusion criteria for its Phase 3 trial designs and “was not previously viewed as detrimental” by the agency.¹⁴

Regarding the concerns around psychotherapy and the recommendations by some panelists to further characterize psychotherapy’s contribution and necessity, Lykos stated:

“Lykos acknowledges that midomafetamine-assisted therapy represents a novel combination of drug and therapy that raises unique research questions and will continue to engage the FDA as appropriate on these challenges. Lykos remains committed to continuing development of this integrated approach.”¹⁵

Regarding the three retracted studies in the journal Psychopharmacology, CNN quoted Lykos’ statement:

“The ethical violations at issue were reported to the FDA, Health Canada, and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), and a public statement was issued in May 2019. However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing. The journal also raised an issue regarding disclosure around conflict of interest, however, the authors did appropriately disclose contributions, funding sources, and affiliations.”¹⁶

The FDA’s request for further study and the controversy surrounding the retracted studies may require Lykos to adopt a more transparent and cautious approach in its interactions with the agency. The ethical challenges highlighted by the retracted studies point to the critical need for rigorous oversight in psychedelic research. Moving forward, companies must prioritize transparency and ethical integrity to ensure that their findings are credible and that patient safety is not compromised.

According to reporting by CNN, Lykos stated that the concerns should have been resolved through corrections instead of retractions, and that it has filed a complaint “with a third party to review the process through which the journal came to this decision.”¹⁷

According to CNN, Lykos’ statement also clarified: “It is important to note that these are not the efficacy data that was submitted to the FDA, and this was not the basis for their decision to issue a Complete Response Letter.”¹⁸

On August 15, 2024, Lykos announced a reorganization of the company as it works on the resubmission of its NDA for MDMA, including reducing its workforce by about 75%, the exit of MAPS Founder and President Dr. Rick Doblin, and the appointment of former Johnson & Johnson executive Dr. David Hough as senior medical advisor to lead the clinical development program and FDA engagement pertaining to the resubmission.¹⁹

Dr. Hough was previously the compound development team leader for Spravato (esketamine nasal spray), a prescription medication approved by the FDA in 2019 to be used along with an antidepressant in adults for treatment-resistant depression (TRD) and depressive symptoms with major depressive disorder (MDD) with suicidal thoughts or actions.²⁰ Although not a classical psychedelic, Spravato is sometimes grouped in this category due its dissociative properties. The FDA requires that Spravato is only available through a restricted program, a Risk Evaluation and Mitigation Strategy (REMS), which, among other stipulations, requires the administration of the medication in a certified health care setting under the direct observation of a healthcare provider with monitoring by a health care provider for at least two hours after administration. Notably, unlike MDMA, Spravato administration does not require an accompanying psychotherapy component. Jeff George, Chairman of the Lykos Board, views Dr. Hough’s experience in the recent approval of Spravato as “greatly relevant” to Lykos.²¹

In addition, Lykos noted that their recently created Independent Advisory Board “will also provide overall support and guidance to the management team throughout the resubmission process.”²²

On September 5, 2024, Lykos announced that Amy Emerson will step down from her role as CEO, with the company’s Chief Operating Officer Michael Mullette stepping in to become the company’s Interim CEO.²³