The FDA has declined to approve Disc Medicine’s bitopertin for erythropoietic protoporphyria (EPP), issuing a complete response that questioned whether the drug’s surrogate biomarker reliably predicts clinical benefit. The agency flagged the modest percent reduction in whole-blood metal-free protoporphyrin IX (PPIX) and requested an adequate, well-controlled study using clinical endpoints. Disc has publicly said the concerns are addressable and is already running the Phase 3 APOLLO study, which will include sunlight-exposure clinical endpoints in addition to PPIX. The rejection is notable because bitopertin had been selected for an accelerated review voucher, underscoring that expedited programs do not guarantee approval. Market reaction was swift: shares fell after the CRL and analysts questioned how the agency weighed biomarker changes versus patient-centered outcomes. The FDA’s letter reinforces scrutiny of surrogate endpoints and signals potential higher evidentiary bars for rare-disease approvals moving forward.