The FDA issued a complete‑response decision on Regenxbio’s gene therapy for Hunter syndrome (RGX‑121), finding the pivotal program lacked reliable external controls, enrolled a heterogeneous population of uncertain phenotype, and relied on unvalidated surrogate biomarkers. The agency requested evidence of biomarker normalization or meaningful neurodevelopmental outcomes to support approval and recommended either further enrollment or new late‑stage studies with appropriate untreated or sham‑surgery controls. The letter underscores ongoing FDA scrutiny of single‑arm and externally controlled gene‑therapy programs for rare neurologic diseases.