The FDA has released the rejection letter explaining its recent refusal of Regenxbio’s gene therapy for the rare disease Hunter syndrome, providing further details into the agency’s issues with the biotech’s trial design.
RGX-121 was rejected in early February, with Regenxbio listing the primary reasons given by the FDA as concerns about the ability to properly define a patient population, the use of a natural history control arm and the use of a biomarker as a surrogate endpoint in the sole trial submitted to the regulator.
“Although we agreed in principle to the study protocol, we expressed concerns throughout your development program,” the FDA wrote in the complete response letter (CRL) dated Feb. 7.
Regenxbio plans to resubmit its application, a company spokesperson told Fierce Biotech.
“We look forward to addressing FDA feedback and discussing the challenges of developing new medicines for ultra-rare disease populations noted in the CRL in a type A meeting,” the spokesperson said.
Regenxbio submitted data from 13 patients in its ongoing Campsiite trial, all of whom were classified as having the more severe neuronopathic form of Hunter syndrome, where cognition rapidly declines during early childhood. By penetrating into the brain and delivering the gene for the enzyme iduronate-2-sulfatase (IDS)—which is missing in Hunter syndrome—RGX-121 is meant to stall cognitive decline. Hunter syndrome is also known as mucopolysaccharidosis type II (MPS II).
In its letter, the FDA took issue with how Regenxbio differentiated neuronopathic patients from those with the less severe, attenuated form of the disease. The Maryland-based biotech relied on a genetic analysis for eight of the patients and results from the Bayley Scales of Infant Development (BSID) for the other five, with one patient classified using both measures.
“Defining neuronopathic disease based on a specific genetic mutation is problematic because some mutations in the IDS gene contribute to a heterogeneous disease presentation with a spectrum of severity,” the agency wrote, adding that “expert consensus is lacking” on how to tell whether young patients have the severe or attenuated form of the disease.
At the same time, assessing severe disease by checking for a lower cognitive score on the BSID also troubled the FDA. “Patients with attenuated disease may experience mild impairment, and there is no consensus on a threshold level of cognitive impairment that distinguishes attenuated from neuronopathic disease phenotypes,” the letter said.
“It’s important to understand that MPS II disease severity is a spectrum, but the majority of patients have the neuronopathic form,” the Regenxbio spokesperson told Fierce. “The decline in these patients is irreversible, and treating early is critical.”
The genetic information alone is predictive of neuronopathic disease, Joseph Muenzer, M.D., Ph.D., a pediatrician and expert in Hunter syndrome and related diseases at the University of North Carolina, told Fierce.
“And if you have developmental delay, it doesn't matter what your genotype is,” he said, adding that he believes almost all of Regenxbio's trial patients have the neuronopathic form of the disease.
Muenzer is a consultant for both Regenxbio and Denali Therapeutics, and is also one of the principal investigators of Denali's Hunter syndrome clinical trial.
In the pivotal trial, Regenxbio sought to demonstrate that RGX-121 treatment reduces levels of a type of heparan sulfate, a large sugar molecule normally broken up by the IDS enzyme. Regenxbio and others developing new Hunter syndrome treatments, like Denali Therapeutics, are using the sugar as a biomarker in place of clinical outcomes.
The target heparan sulfate level of 100 nanograms per milliliter set by Regenxbio, though, is “compromised by lack of comparability” between the 13 trial patients and the patients whose data forms the natural history control arm, the FDA said, especially in age and level of cognitive impairment.
Beyond that, though, the FDA seems unconvinced that heparan sulfate is an appropriate biomarker for Hunter syndrome at all.
The biomarker threshold “has been proposed for the purposes of this application without external expert or scientific consensus,” the agency wrote. The type of heparan sulfate used by Regenxbio, D2S6, “is not routinely assessed as part of standard clinical practice” and “lacks support from published literature as a biomarker for this disease.”
In 2024, a group of experts published a community consensus that heparan sulfate writ large is a suitable biomarker for accelerated approval of new treatments for Hunter syndrome and other related diseases. RGX-121 was accepted for accelerated approval consideration by the FDA in May 2025.
"Heparan sulfate is a well-established biomarker for MPS II and inherent to the disease, as build-up of heparan sulfate in the brain leads to irreversible neurodevelopmental decline in these patients," the Regenxbio spokesperson said.
Calling out D2S6 is a red herring, Muenzer said, because heparan sulfate is never measured directly. Heparan sulfate is made up of different kinds of sugars, four of which are usually all measured and summed to calculate heparan sulfate levels. One of these is D2S6.
Physicians don't regularly measure heparan sulfate or D2S6 because assays aren't yet commercially available, Muenzer explained, but should start becoming available in a month or two.
"Heparan sulfate is a very potent, reliable surrogate marker for neuronopathic and all MPSes, not just MPS II," he said.
The issues raised in the CRL are being used as a “smokescreen” by Vinay Prasad, M.D., the FDA’s top regulator of gene therapies, to reject submissions through the accelerated approval pathway, Muenzer speculated. Prasad has long been a vocal critic of accelerated approval, a pathway frequently used in rare diseases where large placebo-controlled trials are costly and unethical.
“Dr. Prasad, as author of the FDA’s draft guidance to accelerate approvals for individualized gene therapies, is doing more than any CBER leader in history to help speed up the development of ultra-rare disease cures for the American people,” Department of Health and Human Services spokesperson Rich Danker told Fierce.
It was “the FDA primary review team of career scientists” who decided to reject RGX-121, Danker added. Regenxbio “must identify a new, reliable biomarker or demonstrate that patients live longer and experience meaningful clinical improvement,” according to the federal official.
Typically, when dealing with rare diseases or other specialized scientific topics, the FDA convenes an advisory committee of outside experts to provide input. But the number of such committees has plunged 65% from 2024 to 2025, Annie Kennedy, chief mission officer for EveryLife Foundation for Rare Diseases, testified at a Senate hearing on Feb. 26. No advisory committees have been held since July 2025.
Since the beginning of last year, the FDA has handed down 23 rejections for new rare disease treatments, Kennedy said, adding that many of those candidates were under accelerated approval, suggesting a “hesitation to apply regulatory flexibility through surrogate endpoints, natural history studies and external controls.”
Regenxbio’s share price took another hit in the wake of the published rejection letter, dropping from $9.24 at yesterday’s close to $8.69 at 11 a.m. ET. The stock was consistently trading above $10 per share, sometimes nearing $16, before RGX-121’s rejection was first announced in early February.
As Regenxbio tries to salvage its Hunter syndrome hopes, Denali is next up to face a regulatory decision in the disease. The FDA is slated to reach a verdict on Denali’s brain-penetrating enzyme replacement therapy tividenofusp alfa by April 5, a deadline that has already been pushed back from January.
Analysts from Jefferies are still 70% to 80% positive that tivi will be approved, they wrote in a March 2 note, because many of RGX-121’s issues seem specific to the design of its key trial.
Denali’s phase 1/2 trial for tivi enrolled 47 patients compared to the 13 in Regenxbio’s submission, the analysts wrote, and neuronopathic patients were defined using more criteria. Denali is also measuring more forms of heparan sulfate as a biomarker, and the biotech has long-term data exceeding four years compared to less than two years for Regenxbio.
The Jefferies analysts caveated their note by pointing out that Denali’s submission is being evaluated by the Center for Drug Evaluation and Research or CDER, while Regenxbio’s gene therapy was reviewed by the Center for Biologics Evaluation and Research (CBER). CBER Director Vinay Prasad, M.D., has garnered a reputation for demanding randomized, double-blind, placebo-controlled trials that measure clinical outcomes over the use of biomarkers or single-arm studies that are popular—and sometimes necessary—in rare diseases.
Muenzer, for his part, is concerned about the fate that awaits Denali.
Denali has "normalized brain levels of heparan sulfate,” Muenzer said, and will provide a "key test” of the accelerated approval pathway under Prasad.
"You have to be concerned,” he added.
The FDA has faced increasing scrutiny for its handling of rare diseases during the second Trump administration. At the same time, the agency has promised new approval pathways and regulatory flexibility, but numerous applications for new medicines have been denied, often while contradicting past guidance from the regulator.
A recent editorial from the Wall Street Journal, published after Regenxbio’s rejection was announced, declared that “as long as Vinay Prasad is running the biologics shop and has such broad influence at the FDA, faster cures will die in his bureaucratic reviews.”
Editor's note: This story was updated at 3:45 p.m. ET on March 3 with comment from Regenxbio and a Hunter syndrome expert, and at 4:50 p.m. ET with comment from the Department of Health and Human Services.