The Hunter syndrome space suffered a setback in February when the FDA turned down REGENXBIO’s investigational gene therapy, raising urgent questions about whether competitor Denali Therapeutics can clear the agency’s bar next month.
The Hunter syndrome community entered 2026 with hope that the first treatment for the disease’s neurological symptoms would be approved early this year. With the FDA rejection of REGENXBIO’s investigational gene therapy, the spotlight turned to competitor Denali Therapeutics, which is expecting a decision for its own candidate next month.
Hunter syndrome—also known as mucopolysaccharidosis II (MPS II)—is an ultrarare neurodegenerative disease afflicting mostly boys. It is caused by the lack of an enzyme called iduronate-2-sulfatase (I2S), which the body needs to digest sugar. In severe cases, the disease takes patients’ lives when they’re between 10 and 20 years of age.
REGENXBIO’s RGX-121, for which the biotech received a Complete Response Letter (CRL) on February 9, had already sustained a blow weeks earlier when a safety signal connected to a similar gene therapy in development led to an FDA hold on both programs.
Though the clinical hold provided context regarding the CRL, the FDA’s main objections centered on a number of structural reasons.
The FDA’s rationale for the CRL was surprising, Scott Loiler, chief scientific officer at the National MPS Society, told BioSpace. Rather than concerns over potential safety signals, the CRL focused on eligibility criteria and natural history external control used in the Phase 1/2/3 RGX-121-101 study, along with the appropriateness of the surrogate endpoint—points the biotech believed it had addressed with the submission of additional information and responses to questions during the application process.
This poses questions for other companies working in the field, particularly Denali Therapeutics, which has a target action of April 5 for its own Hunter syndrome treatment, tividenofusp alfa (DNL310).
REGENXBIO’s belief that it had addressed these issues, coupled with a perceived lack of FDA flexibility when reviewing rare disease applications, has Loiler “worried” about how Denali will fare.
The FDA’s decision on RGX-121 could also have a broader effect on investment in rare diseases, he added.
“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,” Loiler said. “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 REGENXBIO CRL
Earlier this month, the FDA published a redacted version of the CRL as part of a new transparency initiative introduced last summer. Within the letter, the agency said it had agreed in principle to the RGX-121-101 study protocol referenced when it accepted the biologics license application for RGX-121.
Despite this, the FDA cited uncertainty with the study eligibility criteria, specifically REGENXBIO’s ability to adequately define a population with neuronopathic (more severe) vs. attenuated (less severe) disease. In its letter, the FDA acknowledged that expert consensus is lacking to differentiate these two populations in younger patients, but said that patients in the company’s trial were only required to meet one and not all four eligibility criteria to define neuronopathic Hunter syndrome.
REGENXBIO conducted its registrational trial in patients up to the age of five years, because, Loiler said, it is important to treat the condition as early as possible to avoid worsening of symptoms. Loiler disagreed, however, with the FDA’s rationale for rejecting RGX-12 based on “subjective” criteria.
The agency’s second issue relates to the comparability of the natural history external control—in which a dataset of untreated patients acts as a baseline—to the study population, particularly noting differences in age and definitions of cognitive impairment. This would have also been agreed to during the BLA, Loiler said, adding that a natural history control is often necessary in rare indications due to the limited number of patients.
An external-control study is also at the heart of the dispute between the FDA and another rare disease-focused company. UniQure had hoped to submit for approval of its Huntington’s disease gene therapy based on a pivotal study leveraging a natural history control group, but the FDA is insisting upon an additional sham-controlled Phase 3 study before it will review AMT-130. UniQure also believed it had alignment with the FDA regarding the study design.
Finally, the FDA questioned the appropriateness of CSF heparan sulfate (HS) D2S6 as a surrogate endpoint that is likely to predict clinical benefit. For Loiler, research has already shown that CSF HS D2S6 is a clear biomarker of Hunter syndrome. Clinical trials have indicated that when levels of this marker are reduced, patients show benefits against natural history controls, he said.
Denali in Pole Position
Currently, the only FDA-approved treatment for Hunter syndrome is Takeda’s enzyme replacement therapy Elaprase. An IV infusion, Elaprase provides the enzyme that breaks down glycosaminoglycans, which accumulate inside people with the disease due to the enzyme deficiency. Elaprase is limited, however, by its inability to cross the blood-brain barrier, meaning it has no effect on the neurological symptoms of the disease.
While REGENXBIO and Denali came into 2026 neck-and-neck, RGX-121’s rejection may have put Denali in pole position to bring the first treatment for these symptoms to the market.
Like Elaprase, Denali’s tividenofusp alfa (DNL310) is an enzyme replacement therapy. However, it is able to cross the blood-brain barrier through the use of “transport vehicle” technology, Peter Chin, acting chief medical officer and head of development at Denali, told BioSpace in an email. DNL310 leverages Denali’s proprietary Enzyme TransportVehicle to carry the enzyme missing in Hunter patients, I2S, across the BBB and into other parts of the body, he explained.
Recent data from a Phase 1/2 trial showed that DNL310 met its secondary endpoint by reducing levels of CSF heparan sulfate by 91% after 24 weeks of treatment.
Notably, REGENXBIO measured a similar biomarker, CSF HS D2S6, a disaccharide fragment of HS. By comparison, DNL310 was tested against the total level of disaccharides, Jefferies analysts wrote in a March 2 note to investors.
Loiler and Jefferies agreed that as DNL310 is an enzyme replacement therapy like Elaprase, the FDA could have more confidence in its safety profile than that of a gene therapy.
While DNL310’s approval—of which Loiler remains optimistic—would represent a major step forward for patients, the drug does come with the additional burden of repeated dosing compared to the one-and-done convenience of a gene therapy.
In their note, Jefferies said the FDA’s issues with RGX-121 are “program-specific,” and calculated a 70–80% chance that Denali’s asset will receive FDA approval.
As for REGENXBIO, the FDA’s recommended path forward “would be challenging in the setting of an ultra-rare disease,” a company spokesperson told BioSpace in an email, a sentiment CEO Curran Simpson also expressed in the February 9 press release.
The FDA’s recommendations for the company include changing the relevant biomarker, performing a new clinical study or enrolling more patients into the existing study.
REGENXBIO plans to request a Type A meeting with the FDA to discuss the CRL and a BLA resubmission. The resubmission will provide additional evidence from global Hunter syndrome experts to further clarify the neuronopathic patient population and include additional longer-term clinical data to support evidence of effectiveness, according to the release. The company “intends to find a path forward as quickly as possible with the goal of resubmitting the BLA.”
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