FDA hits Regenxbio with CRL for Hunter syndrome gene therapy

The U.S. FDA has issued a CRL for Regenxbio’ BLA for RGX-121 (clemidsogene lanparvovec) for the treatment of Mucopolysaccharidosis II (MPS II), an ultra-rare neurodegenerative disease also known as Hunter syndrome.

The FDA had accepted Regenxbio’s BLA for RGX-121 in May 2025, granting it priority review with a PDUFA target action date of November 9, 2025. Then, in August, the agency extended its review timeline of the BLA to February 8, 2026, following the company's submission of longer-term clinical data for all patients in the pivotal study. Last month, the FDA placed both RGX-121 and RGX-111 on hold after a brain tumor was found in a 5-year-old participant in the RGX-111 trial.

In the CRL, the agency outlined several reasons for not approving the gene therapy, including uncertainty regarding the study eligibility criteria to adequately define a population with neuronopathic disease (vs. attenuated disease), the comparability of the natural history external control to the study population, and the appropriateness of CSF HS D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit.

Regenxbio says that it believed it had addressed the points raised in the CRL through the submission of additional data and responses to numerous FDA information requests. “Independent, leading global MPS and biomarker experts conducted analyses and reviews with the FDA, as well. Ultimately, the FDA did not agree the data set provided substantial evidence of effectiveness to support approval of RGX-121 for the treatment of MPS II,” stated the company in a press release.

The CRL lists several potential paths forward, including a new study, treating additional patients and conducting longer-term follow up, and using an untreated control arm. But according to Regenxbio, all of these suggestions would be challenging in an ultra-rare disease population.

Regenxbio plans to request a Type A meeting to discuss the CRL, as well as the planned BLA resubmission to provide additional evidence from global MPS II experts to further clarify the neuronopathic patient population and additional longer-term clinical data to support evidence of effectiveness.

MPS II is a rare disease where the body can't break down sugar molecules. It is caused by a variation in the IDS gene, which contains the instructions for the production of a specific enzyme, I2S. RGX-121, an AAV therapeutic designed to deliver a functional copy of the I2S gene directly to the central nervous system, is on track to be the first gene therapy and one-time treatment for the disease.