The FDA has issued a complete response letter (CRL) for Disc Medicine’s New Drug Application (NDA) seeking approval of bitopertin for the treatment of erythropoietic protoporphyria (EPP).
A CRL indicates that the FDA has completed its review and is requesting additional information before approval.
Bitopertin was under review for accelerated approval for EPP, which is a rare genetic disorder that causes severe pain and skin damage when patients are exposed to sunlight. EPP is most often diagnosed in childhood, and symptoms can persist throughout life.
Bitopertin was also included in the National Priority Voucher (CNPV) pilot program. According to Disc Medicine, the FDA agreed that data from the Phase II AURORA and BEACON trials showed that bitopertin significantly reduced whole blood metal-free protoporphyrin IX (PPIX), the proposed surrogate biomarker.
However, the agency concluded that the trials did not show that reductions in PPIX levels translated into measurable improvements in sunlight tolerance. This assessment was based on the clinical endpoints used in those studies.
While the FDA cited strong mechanistic and biological plausibility supporting PPIX as a biomarker, it indicated that additional clinical evidence would be needed to support approval. This means the biomarker’s role in the underlying biology of protoporphyria is well understood, but clinical confirmation is still required.
The FDA stated that results from the ongoing Phase III APOLLO trial could serve as the basis for a traditional approval of bitopertin.
APOLLO is a double-blind, placebo-controlled confirmatory study. Topline data are anticipated in the fourth quarter of 2026.
Disc Medicine said it plans to request a Type A meeting with the FDA to discuss its regulatory approach and next steps.
The company also reported that a blinded sample size re-estimation of the APOLLO trial was conducted in January 2026. No changes to the sample size were required based on the analysis. Enrollment in the study is expected to be completed in March 2026.
In a statement, John Quisel, JD, PhD, President and CEO of Disc Medicine, said the company remains focused on advancing bitopertin. He noted that the expedited review pathway did not lead to approval at this time. The company, he said, remains confident in the ongoing Phase III program.
Following completion of the APOLLO study, Disc expects to submit a response to the CRL. If accepted, the company said it would anticipate an updated FDA decision by mid-2027.
Bitopertin is an oral inhibitor of glycine transporter 1 (GlyT1) being developed to modulate heme biosynthesis in patients with EPP. The therapy has been evaluated across multiple clinical studies in this population, including the Phase II AURORA and BEACON trials, as well as an open-label extension study, HELIOS.
Bitopertin remains an investigational therapy and is not approved for use in any jurisdiction worldwide.
Recent FDA Review Actions and Company Responses
In recent months, several drug developers have reported FDA review actions that changed the status or timing of their applications.
Outlook Therapeutics said it requested a Type A meeting after receiving a CRL for its wet age-related macular degeneration program to discuss the FDA’s request for additional evidence of effectiveness. Biohaven said it plans to engage with the agency to determine next steps after receiving a CRL for its application in spinocerebellar ataxia.
More recently, Moderna reported that the FDA agreed to review a modified application for its investigational mRNA influenza vaccine. The agency had previously issued a Refusal to File, but agreed to proceed with review after discussions with Moderna and submission of a revised regulatory approach addressing FDA feedback.
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