March 04, 2026-
U.S. Food and Drug Administration has released the complete response letter explaining its recent rejection of Regenxbio’s investigational gene therapy RGX-121, offering deeper insight into the agency’s concerns regarding the therapy’s clinical trial design and supporting evidence.
RGX-121 is an AAV9-based gene therapy designed to treat Hunter syndrome, also known as Mucopolysaccharidosis Type II. The therapy aims to deliver a functional copy of the iduronate-2-sulfatase (IDS) gene to the brain, enabling production of the missing enzyme responsible for breaking down harmful sugar molecules that accumulate in patients with the disease. By restoring enzyme activity, the therapy seeks to slow the cognitive decline associated with the severe neuronopathic form of Hunter syndrome.
In the response letter dated February 7, the FDA cited three main concerns that led to the rejection. These included difficulties defining the appropriate patient population in the submitted trial, reliance on a natural history control arm, and the use of a biomarker as a surrogate endpoint in the single pivotal study supporting the application. The agency noted that while it had initially agreed to the study protocol in principle, concerns about these elements were raised repeatedly during the therapy’s development.
Regenxbio’s submission relied on data from 13 patients enrolled in the ongoing CAMPSIITE trial, all classified as having the severe neuronopathic form of Hunter syndrome. However, the FDA questioned the company’s methods for distinguishing these patients from those with the milder attenuated form of the disease. The company used genetic analysis for eight patients and cognitive assessments using the Bayley Scales of Infant Development (BSID) for five others, while one patient was categorized using both approaches.
According to the agency, defining disease severity based solely on specific IDS gene mutations is problematic because the disease often presents across a broad spectrum. Similarly, the use of cognitive scores to classify patients raised concerns, since mild cognitive impairment may also occur in individuals with the attenuated form. The FDA emphasized that there is currently no widely accepted clinical consensus on how to reliably distinguish between the two disease phenotypes in young patients.
Another major point of contention involved the biomarker used in the trial, specifically a form of heparan sulfate called D2S6, which Regenxbio used to demonstrate treatment response. The company attempted to show that RGX-121 reduced heparan sulfate levels in patients’ cerebrospinal fluid, suggesting restoration of enzyme activity. However, the FDA questioned whether the proposed biomarker threshold had sufficient scientific consensus and noted that the specific biomarker used is not routinely measured in clinical practice and lacks strong support in published literature as a validated surrogate endpoint.
The agency also raised concerns about the comparability between trial participants and the natural history control group, citing differences in age and baseline cognitive impairment. These discrepancies, the FDA said, weaken the reliability of the proposed biomarker threshold used to support the application.
Despite the rejection, Regenxbio indicated that it plans to resubmit its application after addressing the agency’s feedback and intends to request a Type A meeting with the FDA to discuss the path forward. The company maintains that reducing heparan sulfate remains a scientifically meaningful indicator of treatment activity, particularly because accumulation of this moleculein the brain drives the neurodegenerative process in Hunter syndrome.
The regulatory decision highlights broader challenges facing ultra-rare disease drug development, where patient populations are small and traditional randomized controlled trials are often difficult or impractical to conduct. As more companies pursue gene therapies and other advanced treatments for rare diseases, regulators and developers continue to navigate how best to balance scientific rigor with the need for regulatory flexibility.
