At a Glance
- FDA issued a Complete Response Letter for RGX-121 BLA in MPS II
- FDA raised concerns on patient selection, controls, and surrogate endpoint
- Longer follow-up and additional data requested
- REGENXBIO plans a Type A meeting and BLA resubmission
Written By: Pharmacally Medical News Desk
REGENXBIO has received a regulatory setback for its investigational gene therapy RGX-121 for Hunter syndrome. The U.S. Food and Drug Administration has issued a Complete Response Letter for the company’s Biologics License Application covering the one-time treatment for mucopolysaccharidosis type II.
The BLA for RGX-121 (clemidsogene lanparvovec) was accepted in May 2025 under the accelerated approval pathway. However, in a CRL dated February 7, 2026, the FDA concluded that the application could not be approved in its current form.
Key concerns raised by the FDA
While the FDA agreed with the study protocol in principle, it cited several unresolved issues. These included uncertainty around eligibility criteria to clearly distinguish neuronopathic MPS II from attenuated disease, concerns about the comparability of the external natural history control, and questions over whether cerebrospinal fluid heparan sulfate D2S6 is an appropriate surrogate endpoint reasonably likely to predict clinical benefit.
The agency outlined possible paths forward, including a new study, treating additional patients with longer follow-up, or adding an untreated control arm. REGENXBIO noted that each option presents significant challenges given the ultra-rare nature of MPS II and limited patient availability.
Company and patient community response
“This decision is devastating for the families of boys living with this progressive, life-threatening disease,” said Curran Simpson, President and CEO of REGENXBIO. He said the company remains confident in the evidence generated over more than a decade of development and raised concerns about regulatory expectations in an urgent, irreversible condition.
REGENXBIO said it believed it had addressed FDA feedback during review through additional data submissions, responses to information requests, and analyses involving independent global MPS and biomarker experts. Despite this, the FDA determined that the dataset did not provide substantial evidence of effectiveness to support approval.
Clinicians and patient advocates also expressed disappointment. Joseph Muenzer, MD, PhD, of the University of North Carolina at Chapel Hill, noted that neuronopathic MPS II leads to irreversible neurocognitive decline and premature death, often in the mid-teens, underscoring the urgency for new treatments. The National MPS Society urged regulators to identify a faster path forward for therapies targeting ultra-rare diseases.
Next steps for RGX-121
REGENXBIO plans to request a Type A meeting with the FDA to discuss the CRL and a potential resubmission strategy. The company intends to provide further clarification of the neuronopathic patient population and additional longer-term clinical data, with the goal of resubmitting the BLA as quickly as possible.
About RGX-121 and MPS II
RGX-121 is an investigational one-time gene therapy designed to deliver the iduronate-2-sulfatase gene directly to the central nervous system, enabling sustained production of the I2S enzyme beyond the blood-brain barrier. The BLA was supported by biomarker, functional, and safety data from the CAMPSIITE Phase I/II/III program (NCT03566043), with follow-up data out to 12 months. The therapy 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 in Europe.
Mucopolysaccharidosis type II is a rare X-linked recessive lysosomal storage disorder caused by deficiency of the I2S enzyme, leading to accumulation of glycosaminoglycans such as heparan sulfate.
References
REGENXBIO Announces Regulatory Update on RGX-121 BLA for MPS II, 09 February 2026, REGENXBIO Announces Regulatory Update on RGX-121 BLA for MPS II | Regenxbio Inc
CAMPSIITE™ RGX-121 Gene Therapy in Subjects with MPS II (Hunter Syndrome), ClinicalTrials.gov ID NCT03566043, https://clinicaltrials.gov/study/NCT03566043