Perhaps the most interesting of the pile of FDA rejection letters was for Lykos Therapeutics’ MDMA therapy. Letters sent to Stealth BioTherapeutics, Regeneron and more were also released as the agency also promised future CRLs “promptly after they are issued to sponsors.”
Going forward, the FDA will make complete response letters publicly available “promptly after they are issued to sponsors,” the agency said in a release late morning on Thursday. A the same time, the FDA released a cache of rejection letters from 2024 and 2025, following the 200 older rejections made public this summer.
Like last time, many of the complete response letters (CRLs) were heavily redacted, or rehashed drug rejections that have already been publicized.
Perhaps the most interesting of the pile was the rejection letter for Lykos Therapeutics’ midomafetamine (MDMA) therapy, which had been submitted to treat post-traumatic stress disorder. The drug went through a tumultuous advisory committee meeting in 2024, only to be rejected by the FDA in August that year.
Much of the drama surrounding the drug’s rejection has already been revealed, particularly as the company has tried to recover from the crushing blow.
In the letter, the FDA seemed to zero in on unreported safety events at two sites and the potential for abuse during the treatment process, which is conducted in an in-patient setting. The letter explains that Lykos did not submit information on events that the participant or therapist considered “positive or favorable,” which would be necessary to assess signals of abuse or patient impairment.
“There are substantial concerns about the reliability of the safety data which limit our ability to adequately assess the safety of midomafetamine for the treatment of PTSD,” the FDA wrote.
Other issues included the durability of the therapy, design issues in the study and the high proportion of patients who had reported previously using MDMA. The FDA recommended a new study to demonstrate the durability of the effect, minimize the potential for bias and characterize safety. The agency also recommended that Lykos conduct an audit of the serious safety concerns raised during the adcomm, which included allegations of a therapist abusing a patient.
Another letter provides details of Stealth BioTherapeutics’ rejection for elamipretide. The biotech had been seeking approval of the therapy for Barth syndrome, an ultra-rare genetic disorder that causes muscle weakness, fatigue and heart failure. About 85% of patients with Barth die by the age of five. In announcing the rejection in May, Stealth did not detail the FDA’s specific concerns.
In the letter, the FDA acknowledges the challenging nature of Barth syndrome and the need for an approved treatment. The agency said it evaluated the submitted packet carefully, employing “regulatory flexibility” for the rare and serious disease. Stealth had proposed using several surrogate endpoints, including left ventricle stroke volume, a measure of the amount of blood being pumped from the left ventricle during a single heartbeat. The company suggested that these could reasonably predict clinical benefit.
Nevertheless, the FDA was “unable to conclude that these approaches establish the effectiveness of elamipretide for traditional or accelerated approval.” Instead, the agency suggested that Stealth resubmit the application under the accelerated pathway using the surrogate endpoint of muscle strength of the knee extensors.
The FDA flagged that Stealth’s SPIBA-201 study did not meet its primary endpoints, noting that in Part 2 of the study the endpoints were based on patient effort and could be subject to bias if patients knew they were on the study drug. The FDA also noted deficiencies at the drug manufacturing facility.
Stealth resubmitted the application for elamipretide in August.
Elsewhere in the cache was the FDA’s short and sweet rejection of Regeneron’s odronextamab. The company had already revealed that the FDA had concerns with the manufacturing site that were not specific to Regeneron’s drug. The site in question is operated by Catalent, which was acquired by Novo Holdings and transferred to Novo Nordisk last year.
Another letter provided details of Zealand Pharma’s rejection for glepaglutide, although much of the details had been released by the biotech itself in December 2024.
The same goes for a letter explaining the controversial rejection of Replimune’s RP1. After the CRL was received in July, 22 experts involved in the clinical trial that underpinned the application responded to the FDA’s specific concerns, defending the trial design and its outcomes. At the time, analysts even alleged the possibility of political interference by Center for Biologics Evaluation and Research (CBER) Vinay Prasad.
One notable difference in the release of this cache of letters is that the letter writer’s name was redacted, whereas the previous 200 letters released in July included that information.
The FDA also released a letter rejecting Rocket Pharmaceuticals’ gene therapy Kresladi. The company at the time of the June 2024 rejection said the agency had requested additional chemistry, manufacturing and controls information to complete its review. The newly released letter is mostly redacted, with no new information revealed.
