FDA Places RGX-121 Gene Therapy for MPS II on Clinical Hold

The FDA has placed a clinical hold on clemidsogene lanparvovec (RGX-121), an investigational gene therapy for mucopolysaccharidosis type II (MPS II, also known as Hunter syndrome), after spinal MRI abnormalities were detected in 5 participants from the CAMPSIITE study (NCT03566043).^1,2 Regenxbio stated in a company update that it does not expect to resubmit a biologics license application (BLA) for the therapy in the near term.

"We believe these findings are unique and limited to our Hunter syndrome program, and require longer-term follow-up and additional data analysis to assess the benefit-risk profile of RGX-121," Curran Simpson, president and CEO of Regenxbio, said in a statement.¹ "We remain focused on our Duchenne and retinal disease candidates, which utilize a different capsid and routes of administration, with near-term catalysts that are on track, including the planned submission of the Duchenne BLA this quarter and the wet AMD [age-related macular degeneration] topline pivotal data announcement in the fourth quarter."

The imaging findings consisted of either a small nodule or a small cystic mass in participants who had received RGX-121 through intracisternal or intraventricular administration approximately 3 to 6 years earlier. Investigators classified the findings as nonserious, and reviewing radiologists considered them likely benign, according to the company. The affected participants remained asymptomatic and showed overall stability or improvement on neurocognitive and neurobehavioral assessments.

However, the cause and clinical significance of the abnormalities remain undetermined. Regenxbio reported no clinical or pathological evidence establishing that RGX-121 caused the lesions. No nodules or masses were identified on brain MRI. Because spinal MRI is not routinely performed in MPS clinical practice or trials, the underlying prevalence of comparable asymptomatic findings in this population is also unknown.

The abnormalities were detected under an expanded imaging protocol introduced after a separate clinical hold involving RGX-111, the company’s investigational gene therapy for MPS I. The revised monitoring plan included both brain and spinal MRI. Investigators currently plan to follow the 5 participants with periodic imaging rather than an intervention.

Regenxbio and partner NS Pharma are evaluating additional imaging and longer-term follow-up data. Further development decisions will incorporate FDA feedback, including the agency’s full clinical hold letter.¹ RGX-121 previously received FDA orphan drug, rare pediatric disease, fast track, and regenerative medicine advanced therapy designations, as well as advanced therapy medicinal product classification from the European Medicines Agency.

RGX-121 is designed as a one-time gene therapy that delivers a functional IDS gene to cells in the central nervous system. The therapeutic rationale is to establish a source of iduronate-2-sulfatase beyond the blood-brain barrier, potentially enabling secretion of the enzyme and cross-correction of surrounding cells. The expressed protein is structurally identical to endogenous iduronate-2-sulfatase, according to Regenxbio.¹

MPS II is a rare X-linked disorder caused by iduronate-2-sulfatase deficiency. Accumulation of glycosaminoglycans, including heparan sulfate, produces progressive cellular, tissue, and organ dysfunction that may involve the central nervous system. In severe disease, developmental delay is generally apparent by 18 to 24 months, underscoring the need for therapies capable of addressing neurologic manifestations.

"Boys with neuronopathic MPS II experience a multitude of neurodevelopmental and systemic effects. While imaging natural history is limited for this ultrarare disease, I believe that asymptomatic, likely benign findings like these may be inherent to the impact of Hunter syndrome throughout the body," Roberto Giugliani, MD, PhD, professor, Department of Genetics, Universidade Federal do Rio Grande do Sul, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, in Brazil, said in a statement.¹ "I am pleased that these patients are doing well and remain asymptomatic."

REFERENCES
1. REGENXBIO announces regulatory update on RGX-121 for MPS II. News release. Regenxbio. August 24, 2026. Accessed August 25, 2026. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-regulatory-update-rgx-121-mps-ii
2. REGENXBIO announces positive data from pivotal dose level of RGX-121 demonstrating long-term systemic effect. News release. Regenxbio. September 3, 2024. Accessed August 25, 2026. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-positive-data-pivotal-dose-level-rgx-121