Disc Medicine receives FDA Complete Response Letter for bitopertin in EPP, citing surrogate endpoint issues despite PPIX reductions; company plans APOLLO Phase 3 data for resubmission by mid-2027.
Written By: Pharmacally Medical News Desk
Disc Medicine, Inc. a clinical-stage biopharmaceutical company advancing novel therapies for serious hematologic diseases, announced today that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the New Drug Application (NDA) of bitopertin as a treatment for erythropoietic protoporphyria (EPP). The decision impacts the drug’s pursuit of accelerated approval and participation in the Commissioner’s National Priority Voucher (CNPV) pilot program.
FDA’s Rationale: Surrogate Endpoint Concerns Despite Biomarker Success
The FDA’s decision to issue the CRL stems from its strict rules for accelerated approval, which has two key requirements for using a surrogate endpoint like “% change in whole blood metal-free PPIX” (a measure of toxic buildup in blood)
- Positive on Biomarker Effect: The FDA acknowledged robust evidence from the Phase 2 AURORA (double-blind, placebo-controlled) and BEACON (open-label) trials, where bitopertin demonstrated statistically significant reductions in whole blood metal-free PPIX levels.
- Issue with Clinical Correlation: However, the agency concluded that these trials lacked sufficient association between PPIX reduction and sunlight exposure endpoints (e.g., time in sunlight without pain). Despite strong mechanistic rationale GlyT1 supplies glycine for heme production, and PPIX buildup drives EPP symptoms the FDA deemed the surrogate insufficiently validated for accelerated approval.
The FDA suggested that results from the ongoing Phase 3 APOLLO trial could support traditional approval, providing direct clinical evidence on endpoints like pain-free sunlight exposure time.
Disc’s Strategic Response and APOLLO Momentum
Disc Medicine remains optimistic, viewing the CRL as addressable. “We are committed to delivering bitopertin to patients, knowing how critical this potentially disease-modifying therapy is to the EPP community,” said John Quisel, J.D., Ph.D., President and CEO. “While our efforts at utilizing expedited pathways to get bitopertin to patients quickly have not come to fruition, we are continuing to pursue all avenues in support of FDA approval.
Key next steps include:
- Requesting a Type A meeting with the FDA to align on a response strategy.
- Leveraging topline data from APOLLO, expected in Q4 2026, followed by an NDA resubmission.
- Filing a formal CRL response post-APOLLO, targeting an FDA decision by mid-2027.
The APOLLO trial, a confirmatory Phase 3 double-blind, placebo-controlled study, completed enrollment in March 2026 months ahead of schedule thanks to strong enthusiasm from patients and physicians. A January blinded sample size re-estimation confirmed no adjustments needed, bolstering confidence in its powering.
Financially secure, Disc reported $791 million in unaudited cash, cash equivalents, and marketable securities as of December 31, 2025, supporting operations into 2029.
Bitopertin’s Development Journey and Broader Potential
Licensed from Roche in May 2021, bitopertin has progressed through multiple EPP trials:
- BEACON: Phase 2 open-label, showed PPIX reductions.
- AURORA: Phase 2 double-blind, placebo-controlled, confirmed dose-dependent effects.
- HELIOS: Ongoing open-label extension.
- APOLLO: Phase 3 pivotal study.
Beyond EPP, bitopertin targets other erythropoietic porphyrias and hematologic conditions by supporting erythropoiesis.
EPP, a rare genetic disorder caused by a deficiency in the ferrochelatase enzyme, leads to painful photosensitivity upon sunlight exposure due to toxic accumulation of protoporphyrin IX (PPIX) in red blood cells and other tissues. Current treatments focus on symptom management, leaving a significant unmet need for disease-modifying options. Bitopertin, an oral inhibitor of glycine transporter 1 (GlyT1), aims to address this by modulating heme biosynthesis, reducing PPIX levels, and potentially enabling safer sunlight exposure.
Reference
Disc Medicine Receives Complete Response Letter from FDA for Bitopertin for the Treatment of EPP, 13 February 2026, https://ir.discmedicine.com/news-releases/news-release-details/disc-medicine-receives-complete-response-letter-fda-bitopertin