The FDA issued a complete response letter rejecting Regenxbio’s gene therapy for Hunter syndrome, explicitly faulting trial population heterogeneity, inadequate external controls and reliance on an unvalidated surrogate biomarker. Agency reviewers told Regenxbio the RGX‑121 pivotal study did not provide adequate and well‑controlled evidence to support approval. The agency asked Regenxbio to demonstrate either normalization of a relevant disease biomarker or meaningful neurodevelopmental outcomes in a resubmission. The FDA’s letter details shortcomings in trial design and advises options ranging from new late‑stage studies to supplementing the existing cohort. The decision reflects growing agency scrutiny of externally controlled and surrogate‑based submissions for rare disease gene therapies and signals sponsors may need tighter controls or additional clinical endpoints to secure approvals.