FDA Places Clinical Holds on Regenxbio Gene Therapies for Rare Metabolic Disorders
The FDA placed clinical holds on Regenxbio's RGX-111 and RGX-121 gene therapies following a tumor case in an MPS I patient. The company's stock fell nearly 18% on the news.
REGENXBIO Inc. announced on January 28, 2026 that the U.S. Food and Drug Administration placed a clinical hold on its investigational gene therapy, RGX-111, for the treatment of MPS I, also known as Hurler syndrome, following preliminary analysis of a single case of neoplasm (intraventricular CNS tumor) in a participant treated in its Phase I/II study. The FDA also placed a clinical hold on RGX-121, for the treatment of MPS II, also known as Hunter Syndrome, citing the similarities in products, study populations, and shared risk between the clinical studies.
The case was identified during a routine brain MRI of an asymptomatic five-year-old participant who received intracisternal RGX-111 four years prior. Preliminary genetic analysis of the resected tumor detected an AAV vector genome integration event associated with overexpression of a proto-oncogene (PLAG1), which is known to be susceptible to chromosomal rearrangements. The investigation to determine if this SAE is drug related is ongoing. The causality has not been established. The participant continues to be asymptomatic, with positive developmental advancements noted by the treating physician.
No evidence of neoplasm has been reported in the nine other participants treated with RGX-111 nor in the 32 participants treated with RGX-121.
The company's stock price plummeted almost 18% to close at $11.01 on January 28, the day the biotechnology company announced the FDA action. An investor filed a proposed class action alleging the company overhyped the safety and efficacy of its rare genetic-disease treatment to investors before regulators paused its study.
The President and CEO of REGENXBIO stated the company was surprised by FDA's decision to place the RGX-121 program on hold while the investigation of this single, inconclusive incident in RGX-111 continues. The CEO noted these are separate therapies, and the positive safety profile of RGX-121 in more than 30 patients treated, including those dosed nearly seven years ago, remains unchanged. The CEO emphasized that patient safety is the company's top priority, and that the company, its investigators, and the patient community remain confident in the benefit-risk ratio of RGX-121 and are highly encouraged by the meaningful efficacy profile demonstrated in the pivotal trial.
The CEO further stated that RGX-121 presents an opportunity to address the urgent, significant unmet medical need in this ultra-rare disease community, and continued delay means continued neurodevelopmental decline in boys with MPS II. REGENXBIO has not yet received the full clinical hold letter and awaits additional details from the FDA.
RGX-121 is a potential one-time gene therapy for the treatment of boys with MPS II, designed to deliver the iduronate-2-sulfatase (IDS) gene to the central nervous system. Delivery of the IDS gene within cells in the CNS could provide a permanent source of secreted iduronate-2-sulfatase (I2S) protein beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS. RGX-121 expressed protein is structurally identical to normal I2S. RGX-121 has received Orphan Drug Product, Rare Pediatric Disease, Fast Track and Regenerative Medicine Advanced Therapy (RMAT) designations from the FDA and advanced therapy medicinal products (ATMP) classification from the European Medicines Agency.
RGX-111 is designed to use the AAV9 vector to deliver the α-l-iduronidase (IDUA) gene to the central nervous system. Delivery of the IDUA gene within the cells in the central nervous system could provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS. By providing rapid IDUA delivery to the brain, RGX-111 could potentially help prevent the progression of cognitive deficits that otherwise occurs in MPS I patients. RGX-111 has received orphan drug product, rare pediatric disease and Fast Track designations from the FDA.
MPS II, or Hunter Syndrome, is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme I2S leading to an accumulation of glycosaminoglycans (GAGs), including heparan sulfate (HS) in tissues which ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system. In severe forms of the disease, early developmental milestones may be met, but developmental delay is readily apparent by 18 to 24 months. Specific treatment to address the neurological manifestations of MPS II remains a significant unmet medical need. Key biomarkers of I2S enzymatic activity in MPS II patients include its substrate CSF HS D2S6, which has been shown to correlate with neurocognitive manifestations of the disorder.
MPS I is a rare autosomal recessive genetic disease caused by a deficiency in the lysosomal enzyme alpha-L-iduronidase (IDUA), leading to an accumulation of glycosaminoglycans (GAGs) including heparan sulfate (HS) in tissues which ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system.