Lykos Plots FDA Appeal: Reeling from CRL and Journal Article Retractions, MDMA Developer Hopes to Change Your Mind

As I reported on Friday evening, Lykos looks set to appeal the FDA’s decision. The company said it will request a meeting with the agency to ask that it reconsider and to “further discuss the agency’s recommendations for a resubmission”.
This often happens via the FDA’s Formal Dispute Resolution Request (FDRR) pathway, which allows an agency decision or guidance to be formally reviewed by a supervisor that sits above the review division’s ‘decision maker’. CRLs and clinical holds are common subjects of FDRRs, with the number of FDRRs filed in response to CRLs on the rise.
The vast majority of appeals are denied, which means the appeal was not granted precisely as it was requested by the sponsor. But, this headline high denial rate obscures lots of underlying utility in the process, with ‘denied’ appeals often establishing or revealing a more favourable or clear path toward eventual approval.
Before it reaches its decision in response to an appeal, the responsible supervisor can also opt to convene an Advisory Committee (AdComm) to assist in its deliberation.
This was the case with Avenue Therapeutics’ IV tramadol for moderate to moderately severe postoperative pain, which received two CRLs that it met with two formal dispute resolution requests. That AdComm ultimately voted 14-8 that the NDA did not demonstrate the benefits outweighed the risks. The company ended up designing a Phase 3 study with the FDA to address the agency’s perceived safety risks, and it said it reached a ‘final agreement’ regarding the design of that study earlier this year. For reference, Avenue received its second CRL way back in the summer of 2021, showing just how much of a time-sink the process can be.
But, given that an AdComm was already convened by the agency in the case of Lykos’ NDA, and it had an overwhelmingly negative view of MDMA-assisted therapy, it’s unlikely that FDA would convene another AdComm so soon.
Some companies aim to codify any clarity gained through the post-CRL appeal process by seeking agreement with the agency on a Special Protocol Assessment (SPA) or a Breakthrough Therapy Designation. A good example is that of Acer Therapeutics, which announced it had received a Breakthrough Therapy Designation in April 2022 and that it had reached agreement with the agency on an SPA in May 2022, around three years after it appealed a June 2019 CRL for its Edsivo (celiprolol) for vascular Ehlers-Danlos syndrome, in which the FDA had requested a fresh clinical trial.
Perhaps the bigger question, then, is: Given the fact that Lykos had already secured a Breakthrough Therapy Designation and a Special Protocol Assessment, shouldn’t the company have had substantial clarity about what the agency expected (and, if not, sufficient opportunities to check) all along? In this sense, the benefit of even a denied post-CRL appeal, which is generally thought to be gaining clarity or agreement on an expeditious path to re-submission, should have already been in-hand for the company.

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