FDA Publishes New Drug Rejection Letters

The FDA has released another batch of drug rejection letters, following up on the 200 complete response letters (CRLs) made public earlier this summer. The newly disclosed documents, spanning 2024 and 2025, shed light on the agency’s reasoning behind several high-profile rejections, from psychedelic therapies to ultra-rare disease treatments. The FDA said it will now publish CRLs “promptly after they are issued to sponsors” in an effort to bolster transparency.

Lykos Therapeutics’ MDMA Therapy

Among the most notable rejections was Lykos Therapeutics’ midomafetamine (MDMA) therapy for post-traumatic stress disorder (PTSD). After a tense advisory committee meeting in 2024, the FDA formally rejected the application in August of that year. The agency raised concerns about unreported safety events at trial sites, the risk of abuse during treatment, and flaws in study design.

The rejection letter emphasized that Lykos failed to report certain “positive or favorable” events, which regulators deemed necessary to evaluate potential abuse or impairment. The FDA also questioned the durability of the therapy’s effect, recommended a new trial to minimize bias, and even suggested an audit after allegations surfaced of therapist misconduct during the clinical program.

Stealth BioTherapeutics and Barth Syndrome

The cache also included details of Stealth BioTherapeutics’ rejection for its drug elamipretide, aimed at treating Barth syndrome—an ultra-rare and often fatal genetic disorder. While the FDA acknowledged the urgent need for a therapy and applied “regulatory flexibility,” it ultimately concluded that the company’s surrogate endpoints, including left ventricle stroke volume, were insufficient to establish efficacy.

The agency urged Stealth to resubmit under the accelerated pathway, focusing instead on endpoints like muscle strength. The FDA also noted that the SPIBA-201 study failed to meet its primary endpoints and raised concerns about patient bias and manufacturing deficiencies.

Other Notable Rejections

• Regeneron’s odronextamab was rejected due to manufacturing issues at a Catalent site later acquired by Novo Nordisk.

• Zealand Pharma’s glepaglutide rejection aligned with details the company disclosed in late 2024.

• Replimune’s RP1 rejection drew controversy, with clinical experts defending trial design and alleging possible political interference.

• Rocket Pharmaceuticals’ Kresladi gene therapy was rejected in June 2024 over manufacturing and controls data gaps, though the newly released letter was heavily redacted.

Why It Matters

The latest release of FDA drug rejection letters underscores the agency’s ongoing shift toward greater transparency. While many of the letters were redacted or repeated information already disclosed by companies, the detail on cases like Lykos Therapeutics provides rare insight into how regulators weigh safety, efficacy, and trial integrity. For biotechs, the disclosures highlight both the challenges of navigating FDA standards and the stakes of failing to meet them.

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