The U.S. Food and Drug Administration (FDA) has issued a complete response letter rejecting REGENXBIO’s application for accelerated approval of RGX-121, an investigational gene therapy for Hunter syndrome, an ultra-rare neurodegenerative disorder affecting boys. The decision followed a three-month delay to the original regulatory deadline and came after the agency reviewed data submitted in support of the therapy.
In its response, the FDA pointed to unresolved questions surrounding the clinical evidence package. Specifically, the regulator cited uncertainty related to how patients were selected for the pivotal study and raised concerns about the reliance on natural history data as an external control. The agency also questioned whether reductions in cerebrospinal fluid levels of the biomarker DS26 could reliably serve as a surrogate endpoint to support approval.
To enable a future resubmission, the FDA recommended that REGENXBIO conduct a new clinical trial that enrolls additional patients, includes a placebo or untreated comparator group, and follows participants for a longer duration. The company acknowledged these recommendations but stated that such requirements would be difficult to implement given the small patient population associated with Hunter syndrome. RGX-121 had been accepted into the accelerated approval pathway in May 2025.
REGENXBIO’s application was based on results from the Phase 1/2/3 CAMPSIITE study, which enrolled 48 boys between the ages of four months and five years. In a February 2024 data readout, the company reported that treatment with RGX-121 led to an 86% reduction in DS26 levels in cerebrospinal fluid at 16 weeks. In addition, 80% of patients receiving the pivotal dose were able to discontinue enzyme replacement therapy or had not required it.
Hunter syndrome, also known as mucopolysaccharidosis type II, is caused by mutations in the iduronate-2-sulfatase gene, leading to the accumulation of toxic substances in cells throughout the body. RGX-121 is designed to deliver a functional copy of this gene to address the underlying cause of the disease. The condition affects approximately 500 boys in the United States.
The FDA decision followed an earlier clinical hold related to a separate REGENXBIO gene therapy, RGX-111, after a patient developed a brain tumor years after treatment. While the FDA acknowledged awareness of this event, the agency stated that it was not cited as a reason for rejecting RGX-121.
REGENXBIO said that the FDA had previously agreed to the trial protocol and that the company had submitted additional analyses during the review process in response to agency questions. Despite this, the regulator maintained its position in the final decision.
Chief Executive Officer Curran Simpson described the outcome in stark terms, stating, “This decision is devastating for the families of boys living with this progressive, life-threatening disease.” He added that the company plans to request a Type A meeting with the FDA to discuss potential next steps and to present further evidence supporting the therapy’s effectiveness.
Following news of the rejection, REGENXBIO’s shares fell in premarket trading. The company has indicated that it intends to continue discussions with regulators and evaluate options for generating additional data to support a future resubmission.
FDA Decision on RGX‑121 for Hunter Syndrome
The U.S. Food and Drug Administration has issued a Complete Response Letter (CRL) rejecting REGENXBIO’s Biologics License Application for its RGX‑121 gene therapy intended to treat Hunter Syndrome, an ultra‑rare genetic condition also known as mucopolysaccharidosis type II (MPS II). The regulator concluded that the submission did not provide sufficient evidence of effectiveness under the accelerated approval pathway and outlined specific areas requiring further validation or study.
FDA Requests New Study to Support Hunter Syndrome Approval
In the CRL, the FDA described several concerns related to the data package supporting RGX‑121 for Hunter Syndrome, including questions about whether the trial’s study population was properly defined, whether the external natural history control arm was truly comparable to treated patients, and whether the biomarker used as a surrogate endpoint can reliably predict clinical benefit. The agency also suggested potential ways forward such as running a new controlled study or extending follow‑up with more patients.
Impacts on REGENXBIO and Hunter Syndrome Community
REGENXBIO responded to the FDA’s decision by emphasizing its intention to request a meeting to discuss the next steps and additional data that could support a future resubmission. The FDA’s rejection of RGX‑121 for Hunter Syndrome has had immediate effects in financial markets, with analyst reports noting stock volatility and lowered price targets following the regulatory setback.
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