As reported on FierceBioTech, the U.S. Food and Drug Administration has released its complete response letter (CRL) detailing why it declined to approve Regenxbio’s experimental gene therapy, RGX‑121, for Hunter syndrome, a rare and progressive pediatric disorder. The document sheds light on longstanding regulatory concerns around trial design, patient classification, and the use of biomarkers in ultra-rare diseases.
RGX‑121, an adeno-associated virus (AAV) gene therapy, is designed to deliver the missing enzyme iduronate‑2‑sulfatase (IDS) directly to the brain in patients with mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome. The therapy aims to slow or halt the irreversible cognitive decline seen in the severe, or neuronopathic, form of the disease. The FDA rejected the application in early February, citing multiple deficiencies.
Questions around patient population definition
A central issue raised by the FDA was Regenxbio’s approach to defining its intended treatment population. The company’s application relied on data from 13 patients enrolled in the ongoing Campsiite study, all labeled as having neuronopathic MPS II. However, the agency said the methods used to distinguish severe disease from the attenuated form were inconsistent and lacked broad scientific consensus.
Regenxbio classified patients using a mix of genetic mutation analysis and cognitive testing with the Bayley Scales of Infant Development (BSID). According to the FDA, neither approach is sufficient on its own. Certain IDS gene mutations can be associated with a wide range of disease severity, while cognitive testing thresholds do not clearly separate attenuated from neuronopathic disease, particularly in very young children.
The agency emphasized that MPS II exists along a spectrum, complicating efforts to define a uniform study population. Without a clear and reproducible way to identify patients with severe disease, the FDA said it could not confidently interpret the trial results.
Reliance on a natural history control
The FDA also criticized Regenxbio’s use of an external natural history cohort as a control arm. Differences in age, baseline cognitive function, and disease progression between treated patients and historical controls undermined the comparability of the data, according to the CRL. These limitations were particularly relevant given the small number of patients in the pivotal study.
In rare diseases, natural history studies are often used when randomized trials are impractical or unethical. However, the FDA signaled that such approaches must still demonstrate sufficient alignment between treated and control populations to support regulatory conclusions.
Biomarker concerns and accelerated approval
Regenxbio pursued accelerated approval based on reductions in heparan sulfate, a complex sugar that accumulates in MPS II due to IDS deficiency. While the agency has previously acknowledged heparan sulfate as biologically relevant to the disease, it questioned both the specific biomarker selected and the proposed threshold for clinical benefit.
The FDA noted that the D2S6 subtype of heparan sulfate used in RGX‑121’s application is not routinely measured in clinical practice and lacks strong support in published literature as a surrogate endpoint. The agency also stated that the proposed target level was not backed by external expert consensus.
Regenxbio and several academic experts counter that heparan sulfate accumulation is fundamental to MPS II pathology and that individual subtypes are commonly measured together as part of total heparan sulfate burden. They argue that the absence of commercially available assays reflects technical limitations rather than scientific weakness, and that broader consensus statements have endorsed heparan sulfate as a reasonable biomarker for accelerated approval in Hunter syndrome.
Broader regulatory context
The rejection comes amid heightened scrutiny of the FDA’s approach to rare disease therapies, particularly those seeking accelerated approval based on surrogate endpoints. Advocacy groups and clinicians have raised concerns about a decline in the use of advisory committees and what they view as increasing reluctance to apply regulatory flexibility in ultra-rare conditions.
Regenxbio has said it intends to resubmit its application and plans to meet with the FDA to discuss the feedback outlined in the CRL. Meanwhile, the company’s shares fell following publication of the letter, extending losses that began when the rejection was first announced.
Attention is also turning to Denali Therapeutics, which is awaiting an FDA decision on tividenofusp alfa, a brain‑penetrating enzyme replacement therapy for Hunter syndrome. Analysts have suggested that Denali’s larger dataset, broader biomarker measurements, and longer follow‑up may help differentiate its application, though uncertainty remains.
Taken together, the RGX‑121 decision highlights the persistent challenges of developing and regulating treatments for ultra-rare pediatric diseases, where small trials, heterogeneous populations, and reliance on biomarkers are often unavoidable, but regulatory standards remain exacting.
