The FDA issued a complete response to Disc Medicine, finding that the surrogate biomarker reduction used in the company’s submission—percent change in whole-blood metal-free PPIX—was not a reasonably likely predictor of clinical benefit for erythropoietic protoporphyria (EPP). Disc disclosed the CRL in an SEC filing and said the agency’s concerns are "readily addressable," while analysts called the decision surprising given the drug’s selection for an accelerated review pilot. Disc’s stock plunged after the announcement and analysts noted uncertainty about the FDA’s interpretation of the biomarker magnitude and its linkage to clinical endpoints. The agency recommended an adequate, well-controlled study measuring direct clinical outcomes; Disc is already conducting the Phase 3 APOLLO trial that will include sunlight-exposure endpoints in addition to PPIX measurements. The decision highlights regulatory skepticism toward surrogate-driven approvals in rare-disease settings and underscores the need for robust linkage between biomarker changes and patient-centered outcomes when sponsors seek expedited pathways.