Personal Reflection on the Lykos Therapeutics Complete Response Letter

The FDA's decision this month to issue a response letter instead of an approval for MDMA was a disappointment for many of us who see the promise in this medicine. My career has allowed me to stay close to the science of MDMA since almost the first publications. Across the years, I've watched the evidence accumulate that MDMA has an unusual emotional effect that facilitates self-compassion, decreases avoidance, and accelerates therapeutic processes.

I started investigating the risks of MDMA in the mid 1980s, shortly after Schuster and colleagues began publishing on so-called MDMA neurotoxicity. I then conducted investigator-initiated trials with MDMA beginning in the 90s, originally as part of the second team to get FDA permission to administer MDMA to volunteers. From around 1999 to 2001, I took time off from my career to help the parent nonprofit of Lykos get their first patient studies approved.?

I've always tried to be clear-eyed about the potential downsides of MDMA and other psychedelics. I spent much of my career working to understand whether and how MDMA-induced chronic serotonergic changes might be relevant to people. I studied MDMA-related hyponatremia because it is a major, dose-independent cause of mortality in MDMA users. And I tried to document HPPD when most psychedelic researchers doubted it existed. I didn't do this work because it was inherently interesting. I simply felt an obligation to illuminate the shadowy psychedelic spaces where people get hurt and to make those spaces safer for everyone.

This research informed the approach we take at Tactogen. Tactogen develops new MDMA-like compounds with the goal of making these treatments gentler, more effective, and more accessible. At this year's Society for Neuroscience meeting we'll show preliminary rodent data on one of our lead candidates that we believe produces acute MDMA-like effects and a possible "afterglow" without causing lasting serotonin depletions. We think this or another of our other lead candidates may prove superior to MDMA for therapeutic use.

But this does not mean I have ever considered MDMA unapprovable. Data from multiple sources suggest MDMA can be helpful and used with acceptable safety. In fact, Tactogen has several ideas for improving the product profile of MDMA, possibly reducing risks of adverse effects like suicidal ideation. And while Tactogen is nominally a competitor to Lykos, we see multiple treatment options as important for best helping people.?

The FDA's decision to ask Lykos for more data was therefore a disappointment. But it is also a reminder that science is a process with many stakeholders. It isn't enough to be right, you also need to test your beliefs in a way that convinces skeptics; you need to build consensus with a critical mass of stakeholders.

This isn't intended as a criticism of Lykos. I have my disagreements with them, of course. (Most prominently these relate to protocol design choices and their response to protocol deviations and boundary violations in Phase 2. Much of this plausibly originates from a failure to put professional drug developers in decision-making roles early on.) However, in my view, the Lykos New Drug Application has been mainly handicapped by a first mover disadvantage and not by any of the issues that received media attention.?

In essence, they got started too early. Their parent company got permission from the FDA to start patient studies in 2001. This was long before any psychedelic companies existed. Therapy for PTSD was less advanced. EMDR, for example, was considered controversial and, while other exposure therapies had research support, they were not yet widely used by therapists. For their Phase 2 trials, Lykos' parent chose to manualize the therapy methods that had already been used with apparent success during the era of legal MDMA therapy.?

The Lykos therapy manual has subsequently received significant attention from critics. Since I lack expertise here, I leave the discussion to therapists and clinicians. But I do think a fair evaluation of the therapy would analyze the manual in conjunction with the multi-day training that the study therapists received and the adherence rating manuals that operationalized the therapy.

Clinical trial progress was slow. With their annual budget initially under $1.5M, it took Lykos until 2016 —fifteen years— to complete Phase 2. In 2017, Lykos got the FDA to agree that their proposed Phase 3 study design was good enough to show efficacy. It took them another five years to complete Phase 3.?

Meanwhile, FDA and academic research continued to discuss and hash out best practices. FDA Division of Psychiatry Products developed a new concern for functional unblinding as a confound, possibly driven by the growing academic literature. Perhaps most importantly, FDA seems to have increased their concern for the durability of therapeutic benefits.

The FDA's slides at the Advisory Committee meeting indicate that FDA raised the topic of durability at a meeting with Lykos in late 2022. This would have been around the end of the second and final Phase 3 trial. The late point that durability was raised plausibly explains many otherwise puzzling aspects of the Lykos long term follow-up study design, such as the unblinding of some participants and the single, temporally inconsistent measurement time. The late point that this issue was discussed also suggests that, despite the Breakthrough Therapy designation, communications between Lykos and FDA were not entirely healthy.

Durability matters to FDA Psychiatry because it affects how much safety data they want to see. Transient benefits suggest greater drug exposures and greater potential risks. If patients improve for a few weeks and then regress back to baseline, FDA worries that real world patients will need more exposures to the medicine than occurred in the trials. FDA then wants more safety data to evaluate the risks of these additional exposures.?

Any speculation about FDA thinking is risky without having access to their formal communications with Lykos. However, the FDA's uncertainty about the durability of MDMA's benefits may be a central reason that MDMA was not approved. Aside from functional unblinding, to my knowledge, durability is the only issue that FDA raised in publicly available documents without noting a possible post-approval remedy.?

Given the evolving discourses, it is easy to stand in 2024 and criticize the 2017 trial design. This was painfully obvious at the FDA Advisory Committee meeting. Yet Lykos is not unusual in having imperfect trials. 80% of FDA approvals come with a requirement or commitment that the sponsor collect more data, strongly suggesting that FDA often finds the submitted data to be lacking.?

Plus, experience has taught me that the better study design is often a mirage that disappears as the study nears completion. Every individual study will be flawed and unconvincing to motivated skeptics. Robustness comes not from one perfect study, but from multiple independent studies.?

Happily, there are several independent ongoing studies that will add to the robustness of our understanding of MDMA's therapeutic benefits. Rachel Yehuda recently described her study of MDMA-assisted therapy for PTSD at the Bronx V.A. as producing "stunning and robust results."?

Independent studies may be reassuring, but they are immaterial to a New Drug Application. FDA made their decision based on the submitted data from Lykos. And contrary to hot takes on social platforms, it is impossible for outsiders to judge whether it was the right decision or not.?

Moreover, the wisdom of the FDA's move is surely predicated on what happens next. There are many scenarios where those currently claiming victory for science will be left unhappy, just as there are many scenarios that will leave Lykos supporters disappointed.?

How can Lykos respond? They can start a formal dispute resolution process, add the 40-something expanded access patients to their safety database, and try to argue that these data make another trial unnecessary. If they do need another trial, and I suspect they will, an adaptive design with a stopping rule may be an efficient way to collect the data.

Whatever the fate of Lykos' New Drug Application, prescription MDMA-like medicines are all-but-inevitable. MDMA-assisted therapy is moving forward internationally. And Tactogen and other companies are advancing next generation compounds that aspire to meaningfully improve on MDMA while lacking its historic baggage.?

It would be a great loss if MDMA does not ultimately receive approval in the US. There are certainly other PTSD treatments that are effective for many. However, MDMA is an innovative approach that may help those who do not tolerate or respond well to available treatments. It also has promise for many other indications that together may affect close to 1 in 4 adults.?

MDMA is also a well-understood molecule that has already been taken by 22 million people in the US. Its unusual emotional effects are documented in over 1,500 research participants in studies not supported by Lykos. This isn't a mysterious treatment. It is heartbreaking that patients must wait for legal access.