FDA issues CRL for RGX-121 gene therapy in mucopolysaccharidosis type II

The FDA has issued a Complete Response Letter (CRL) to REGENXBIO Inc. regarding its Biologics License Application (BLA) for RGX-121 (clemidsogene lanparvovec), a gene therapy under review for the treatment of mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome.¹

In May 2025, the FDA accepted the BLA for RGX-121 under the accelerated approval pathway. According to the company, in a CRL dated February 7, 2026, the FDA stated that it had agreed to the study protocol in principle but identified several reasons for not approving the application.²

FDA cites concerns about study population and external control comparability

The FDA indicated uncertainty regarding whether the study eligibility criteria adequately defined a population with neuronopathic disease, as distinct from attenuated disease. Clear differentiation between these phenotypes is clinically relevant, as patients with neuronopathic MPS II experience progressive neurocognitive decline and early mortality.

The agency also raised concerns about the comparability of the natural history external control to the treated study population. External controls are often used in ultra-rare disease development, but differences in baseline characteristics, disease severity, and data collection methods can complicate the interpretation of treatment effects.

In addition, the FDA questioned the appropriateness of cerebrospinal fluid (CSF) heparan sulfate (HS) D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit. The agency ultimately determined that the data set did not provide substantial evidence of effectiveness to support approval.

The CRL outlined potential paths forward, including conducting a new study, treating additional patients with longer-term follow-up, or incorporating an untreated control arm. The company noted that each option presents challenges in an ultra-rare disease population.

"This decision is devastating for the families of boys living with this progressive, life-threatening disease," said Curran Simpson, president and CEO of REGENXBIO. "We are concerned about [the] FDA's feedback regarding the overall development path and evaluation of the data in the context of the urgent need for this irreversible ultra-rare disease. We remain confident in the quality and volume of evidence demonstrating the long-term potential of RGX-121 to positively change the trajectory of Hunter syndrome. This program has been in development for over 10 years. We are incredibly grateful to all the patients, their families, investigators, and site staff who have supported this program and our continued efforts to bring a much-needed new treatment option to the Hunter syndrome community. We will continue those efforts."

RGX-121 gene therapy designed to deliver IDS gene to the CNS

RGX-121 is a one-time gene therapy designed to deliver the iduronate-2-sulfatase (IDS) gene to the central nervous system (CNS). Expression of the gene within CNS cells is intended to provide a sustained source of iduronate-2-sulfatase (I2S) protein beyond the blood-brain barrier, allowing cross-correction of affected cells throughout the CNS. The expressed protein is structurally identical to endogenous I2S.

The BLA submission was supported by biomarker, functional, and safety data from the CAMPSIITE I/II/III trial, including follow-up through 12 months. According to the company, RGX-121 has been well-tolerated in all patients dosed across trial phases.

RGX-121 has received Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy designations from the FDA, as well as advanced therapy medicinal product classification from the European Medicines Agency.

MPS II remains an unmet need, particularly for neurologic disease

MPS II is a rare, X-linked recessive lysosomal storage disorder caused by a deficiency of the enzyme I2S. Enzyme deficiency results in the accumulation of glycosaminoglycans, including heparan sulfate, in tissues and organs, including the CNS. In severe forms of the disease, children may initially meet early developmental milestones, but developmental delay typically becomes apparent between 18 and 24 months. Progressive neurocognitive decline and multiorgan involvement are characteristic of neuronopathic disease.

There is no approved therapy that directly addresses the neurologic manifestations of MPS II.

"MPS II is a very complex disease, but its impact is well established, resulting in irreversible brain damage for the majority of patients; without appropriate treatments stopping this neurocognitive decline, the neuronopathic MPS II child will die prematurely, usually in their mid-teens," said Joseph Muenzer, MD, PhD, director, Muenzer MPS Research and Treatment Center, Bryson Distinguished Professor in the Division of Genetics and Metabolism, Department of Pediatrics Genetics, University of North Carolina at Chapel Hill. "I remain encouraged by the clinical data behind RGX-121. New innovations like gene therapy could make a significant impact for these patients, and time is precious for these families."

"I've seen the severe impact of MPS II on patients and their families firsthand and am extremely disheartened by today's news," said Terri Klein, president and CEO, National MPS Society. "Families know the devastating trajectory of this disease all too well and have waited 20 years for new treatment options. They cannot wait any longer. Drug development for ultra-rare disease must be streamlined to allow new medicines to reach patients. We urge the FDA to find a swift path forward so that boys living with MPS II and their families have the chance for a better life."

Company plans Type A meeting and potential BLA resubmission

REGENXBIO stated that it plans to request a Type A meeting with the FDA to discuss the CRL and a potential BLA resubmission. The company intends to provide additional evidence from global MPS II experts to further clarify the neuronopathic patient population and to submit longer-term clinical data in support of effectiveness.

The company reported that it aims to identify a path forward and resubmit the BLA as quickly as possible.

References

1. REGENXBIO. REGENXBIO Announces Regulatory Update on RGX-121 BLA for MPS II. REGENXBIO. February 9, 2026. Accessed February 11, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-regulatory-update-rgx-121-bla-mps-ii
2. REGENXBIO. REGENXBIO Announces Regulatory Update on Ultra Rare MPS Programs. REGENXBIO. January 28, 2026. Accessed February 11, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-regulatory-update-ultra-rare-mps-programs.