FDA has issued a Complete Response Letter (CRL) to Lykos Therapeutics regarding its New Drug Application (NDA) for MDMA-assisted therapy in PTSD, meaning the agency is not prepared to approve it at this time.
The letter is not a complete surprise to industry insiders or Lykos itself, who had been bracing for a negative verdict from the agency amidst a number of negative appraisals in recent months. Those included one of FDA’s own advisory committees pointing to flaws in the study design and conduct, and ultimately deeming the package insufficient to warrant approval in an overwhelming ‘no’ vote.
However, even the less optimistic insiders might be surprised by just how harsh FDA’s CRL appears to have been, with the agency requesting an additional Phase 3 study—a very, very tall ask for the small company.
The Path Forward
While a CRL is a rejection of the NDA in its current form, it’s not a total snubbing of MDMA-assisted therapy. The CRL, which is transmitted directly to the sponsor and is not made available to the public, discusses why a submission is not approvable and, relatedly, how a sponsor might work to address these deficits if it wishes to resubmit.
According to Lykos, which released a statement late on Friday, the agency has requested an additional Phase 3 study to further study the safety and efficacy of the intervention. That’s very bad news for the company.
Lykos shared that it plans to request a meeting with the agency to ask it to reconsider its decision, “and to further discuss the agency’s recommendations for a resubmission seeking regulatory approval for midomafetamine capsules.”
According to the company, the issues raised in the CRL echo those raised during the AdComm in June. In its statement, Lykos stressed “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.”
“The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades,” said Lykos CEO Amy Emerson.
Jennifer Mitchell, lead author on Lykos’ Phase 3 publications, said that the agency’s decision to request another Phase 3 study “is a major setback for the field.”
For now, it’s back to the drawing board for Lykos, which may need a fresh cash injection to meet the challenge. If FDA won’t budge on its additional Phase 3 requirement, it sets Lykos back several years and presents a task that borders on Sisyphean.
The very little available data on how appeals (‘Formal Dispute Resolution Requests’, in agency parlance) over CRLs fare doesn’t paint a rosy picture, with the vast majority being officially denied. However, even appeals which are ‘denied’ might lead to a more favourable path to approvable than that dictated by the agency’s original review, as Torrente and Kaur note. As such, Lykos and its supporters might hope to find an opening through the dispute resolution process.
Early Reactions
Given this is a breaking story, we’re yet to reach out to others for comment. The markets haven’t had a chance to react yet, either, as the news came after the close.
It’s likely that other psychedelic drug developers are less surprised by the decision, however, with peers like Compass Pathways seeking to distance its clinical program design from Lykos’ in an Earnings Call earlier this month.
One area where these drug developers have often sought to differentiate themselves is in the realm of psychotherapy, with the ‘drug-assisted therapy’ part of Lykos’ submission potentially causing a headache for regulators and advisory committees alike. “There is no active psychotherapy”, Compass’ Chief Medical Officer said of its COMP360 psilocybin protocol, whereas MDMA-assisted therapy “truly is psychotherapy catalyzed by the drug.”
What’s more, a recently-published clinical trial registry entry for atai’s Phase 2 study of DMT goes so far as to list recently-initiated and current directive psychotherapy, or even plans to initiate during the study, as an exclusion criteria for would-be participants in the trial1, demonstrating just how keenly other psychedelic drug developers are attempting to distance themselves from what are perceived to be messier ‘assisted psychotherapy’ models.
Without eyes on the full CRL, however, it’s tricky to know which methodological or execution-related matters were most fateful for Lykos.
Pα: In many ways, a CRL was the expected outcome… perhaps not a few years ago, or even a few months ago; but, with increasingly pessimistic signals from independent reviews and one of FDA’s own advisory committees, it was almost a fait accompli. Despite a last-minute advocacy effort by folks as famous as Elon Musk and a bipartisan roster of lawmakers, FDA has scuppered Lykos’ first shot on goal.
It’s worth emphasising that this does not have to be the end of the road for MDMA-assisted therapy’s FDA approval hopes, or for Lykos. We should expect to gain more clarity on the nature of the course correction required, and Lykos’ next steps, in the coming weeks and months. However, if Lykos can’t convince the agency to drop the additional Phase 3 requirement, the company has a very challenging road ahead. (Other groups studying MDMA in PTSD, like the VA, have committed to continuing their efforts regardless of the outcome of the present NDA. “We will find another way to approach this”, Rep. Jack Bergman told POLITICO, while Rachel Yehuda wrote in a LinkedIn post today that in the case of a negative FDA verdict her group would “Double down on the research[,] keep generating the data and the cases.” “The nature of the challenge is, well that it is challenging”, she said, but added that the VA’s first RCT of the intervention “seems to have produced stunning and robust results”.)
What this does mean, however, is that Lykos might have missed its chance at being the first drug developer to bring a ‘psychedelic’ to market, despite taking on—and ultimately becoming ensnared by—the enormous regulatory risk that entails. But, beyond approval lies commercialisation risk… scaling up treatments from the tightly-controlled confines of clinical trial programs into the ‘real world’ in a logistically and commercially viable manner. In this newly-reconfigured timeline, might we see Lykos come to market, if at all, behind one of its formerly-trailing peers like Compass? One thing’s certain, much of the landscape-shaping responsibility (the whole ‘jamming a psychedelic peg into a square healthcare system’ bit) now shifts to Compass, which had already been telegraphing its efforts in that regard2 (through, for example, collaborations with potential treatment delivery partners).
While FDA’s negative verdict might not come as a major shocker to those close to the company and psychedelic drug development field, those who had been following MDMA’s passage from club drug to FDA-approved medicine less incessantly might be caught by surprise. The decision is sure to disappoint many patients, practitioners and advocates who had hoped to see MDMA-assisted therapy added to the lacking PTSD armamentarium, but it is worth reiterating that this might ultimately be a (hefty) delay, as opposed to the end of the road entirely.
As reactions roll in and further clarity appears, we will be sure to keep you updated via our Pα+ coverage. ∎
- Regular readers might recall that the majority of trial participants in MindMed’s Phase 2b LSD study were apparently receiving non-study psychotherapy.
- As we reported earlier this month, Lykos announced ‘new initiatives’ and noted that it is working with “top behavioral health facilities to help ensure these sites are prepared to implement the measures utilized in Lykos’ clinical trials.”
