The U.S. Food and Drug Administration rejected REGENXBIO’s investigational gene therapy for Hunter syndrome in a Complete Response Letter issued Feb. 9, shifting attention to Denali Therapeutics, which expects an FDA decision on its own candidate next month.
Hunter syndrome, also known as mucopolysaccharidosis II (MPS II), is a rare neurodegenerative disease that primarily affects boys and can be fatal between the ages of 10 and 20. The only current FDA-approved treatment, Takeda’s Elaprase, does not address neurological symptoms because it cannot cross the blood-brain barrier.
REGENXBIO’s RGX-121 was placed on clinical hold after safety concerns emerged with a similar gene therapy. However, the FDA’s main objections focused on study design issues such as eligibility criteria and the use of natural history external controls in the pivotal trial. Scott Loiler, chief scientific officer at the National MPS Society, said, “With these rare diseases, it’s hard enough to attract companies and investors to put their energies and money into these programs because there’s not going to be a big payoff down the road. With this kind of FDA rejection, if investors can’t see or understand the timeline for when there is going to be an approved product, they’re just not going to invest.”
The agency also questioned whether cerebrospinal fluid heparan sulfate D2S6 is an appropriate surrogate endpoint likely to predict clinical benefit. Loiler disagreed with this rationale for rejection based on what he called “subjective” criteria and pointed out that research has shown CSF HS D2S6 is a clear biomarker of Hunter syndrome.
Denali Therapeutics’ tividenofusp alfa (DNL310) uses proprietary technology to deliver enzyme replacement across the blood-brain barrier. Recent Phase 1/2 data showed DNL310 reduced levels of CSF heparan sulfate by 91% after 24 weeks of treatment. Jefferies analysts estimate a 70–80% chance that Denali will receive FDA approval for its asset.
REGENXBIO plans to request a Type A meeting with the FDA and intends to resubmit its application with additional evidence from global experts and longer-term clinical data. The company said it “intends to find a path forward as quickly as possible with the goal of resubmitting the BLA.”
The outcome of Denali's pending application could have broader implications for investment in rare disease therapies and future regulatory approaches.
