REGENXBIO’s gene therapy for Hunter syndrome, RGX-121, was rejected by the U.S. Food and Drug Administration (FDA) due to concerns over study design, population heterogeneity, and the use of surrogate endpoints.
The FDA detailed its reasoning in a complete response letter released on Monday. The agency stated that while it “agreed in principle” with REGENXBIO’s proposed protocol, it had “expressed concerns throughout your development program” regarding key aspects of the pivotal study.
One major issue cited was the variability within the patient group. REGENXBIO sought approval for RGX-121 across patients with different levels of disease severity. However, according to the FDA, the trial enrolled individuals with an “uncertain phenotype,” which led to doubts about whether those studied truly represented the intended treatment population.
The regulator also criticized REGENXBIO’s reliance on external controls instead of an internal placebo or untreated control group. The FDA noted these controls “lack the comparability” needed with trial participants. This challenge has been highlighted recently in other gene therapy reviews as well; uniQure’s Huntington’s disease gene therapy faced similar feedback from regulators requiring more rigorous sham surgery–controlled studies before seeking approval.
Additionally, REGENXBIO used cerebrospinal fluid levels of D2S6 protein as a surrogate marker for efficacy. The FDA found there is “insufficient evidence” that this biomarker can reliably predict clinical benefit in patients.
“Despite exercising regulatory flexibility, given the breadth of uncertainties, we are unable to conclude that the RGX-121-101 study is an adequate and well-controlled study,” wrote the agency.
For any resubmission attempt, REGENXBIO must demonstrate normalization or significant improvement in a relevant disease biomarker or neurodevelopmental outcomes. The company could either conduct a new late-stage trial or add more patients to its current one but must include an appropriate untreated control arm as recommended by regulators.
The rejection creates opportunities for competitors such as Denali Therapeutics. Analysts at William Blair commented that RGX-121’s issues appear unique to its program and suggested Denali's candidate tividenofusp alfa might be better positioned for approval due to its more targeted patient selection and broader use of biomarkers beyond D2S6. They stated: “Tivi seems better positioned for an FDA approval... We remain 70-80% confident in Tivi’s approval for Hunter syndrome.” A decision from the FDA on Denali's application is expected April 5.
This disclosure comes amid a recent push by the FDA toward greater transparency through public release of complete response letters sent to drug sponsors—an initiative started last year that has made regulatory decision-making more visible not only to patients but also investors and industry observers.
