The FDA accepted the gene therapy’s application under the accelerated approval pathway in May 2025.
The CRL indicated that the FDA agreed in principle with the study protocol and cited several reasons for not granting approval at this stage.
Issues addressed included uncertainty over study eligibility criteria used to define neuronopathic versus attenuated disease populations, comparability of the natural history external control data to the study population, and whether cerebrospinal fluid heparan sulphate D2S6 (CSF HS D2S6) is an appropriate surrogate endpoint likely to predict clinical benefit.
The FDA outlined several potential ways forward in the CRL, which included conducting a new study, treating additional patients with extended follow-up, or incorporating an untreated control arm, each option presenting significant challenges given the ultra-rare nature of MPS II.
During ongoing discussions throughout the BLA process, REGENXBIO believed it had provided sufficient responses and additional data to address points raised by the FDA.
Independent global MPS and biomarker experts also reviewed and analysed data with the FDA.
However, the agency concluded that substantial evidence of effectiveness was not demonstrated by current data to support approval.
REGENXBIO plans to request a Type A meeting with the FDA to discuss the CRL and its planned resubmission of the application.
The company intends to provide more evidence from global MPS II experts and additional longer-term clinical data to further clarify patient populations and demonstrate effectiveness, aiming to resubmit as soon as possible.
REGENXBIO president and CEO Curran Simpson said: “This decision is devastating for the families of boys living with this progressive, life-threatening disease. 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 programme has been in development for over ten years.”
In January 2025, REGENXBIO entered a strategic collaboration worth $810m with Japan-based Nippon Shinyaku to advance gene therapies targeting the rare MPS.