REGENXBIO's Hunter syndrome gene therapy RGX-121 receives CRL as FDA questions trial design and biomarker endpoint

The FDA on February 7, 2026 issued a Complete Response Letter for RGX-121 (clemidsogene lanparvovec), REGENXBIO's intracisternal AAV gene therapy for neuronopathic Hunter syndrome (mucopolysaccharidosis type II). The CRL raised three concerns: whether the trial's eligibility criteria adequately differentiated neuronopathic from attenuated disease, whether the external natural history control group was sufficiently comparable to treated patients, and whether CSF heparan sulfate D2S6 levels are reasonably likely to predict clinical benefit as a surrogate endpoint.

Less than two months later, on March 25, 2026, the FDA granted accelerated approval to Denali Therapeutics' AVLAYAH (tividenofusp alfa) for the same disease—a contrast that highlights the diverging regulatory fortunes of two programmes targeting the same ultra-rare condition through different modalities. While Denali's enzyme-replacement therapy demonstrated consistent CSF biomarker reductions across multiple heparan sulfate species, the FDA questioned whether REGENXBIO's reliance on a single biomarker (D2S6) was sufficient to establish a surrogate endpoint.

Hunter syndrome is a rare, X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase (I2S), leading to progressive accumulation of glycosaminoglycans (GAGs) in tissues and organs. The severe, neuronopathic form—representing roughly two-thirds of all cases—involves progressive neurodevelopmental decline and is typically fatal in the first or second decade of life. Existing enzyme replacement therapy with idursulfase (Elaprase) addresses peripheral symptoms but cannot cross the blood–brain barrier, leaving the devastating CNS component untreated.

RGX-121 was designed to address this gap by delivering a functional I2S gene directly to the CNS via intracisternal injection. In the CAMPSIITE Phase I/II/III trial, 26 patients were dosed across dose-escalation and pivotal cohorts. At the pivotal dose level, treated patients showed an 85 % median reduction in CSF heparan sulfate D2S6 levels sustained through two years, with neurodevelopmental skill acquisition or stability observed across all subscales of the Bayley Scales at one year. The BLA was filed under the accelerated approval pathway and had received Priority Review designation.

The FDA's objections centred on trial design rather than the clinical observations themselves. The agency found the study population "heterogeneous" and expressed concern that the external natural history control did not sufficiently match the characteristics of the treated group. REGENXBIO had sought a broad label covering patients with various severity levels, but the FDA questioned whether the enrolled population was truly representative of the intended neuronopathic target. The FDA outlined potential paths forward, including conducting a new study, enrolling additional patients with longer follow-up, or incorporating an untreated control arm.

The CRL fits a wider pattern of FDA scepticism toward single-arm trials with external controls—particularly for gene therapies seeking accelerated approval. For the estimated 500 boys living with neuronopathic Hunter syndrome in the US, the rejection left the one-time treatment out of reach. REGENXBIO said at the time that it was evaluating the FDA's feedback and considering its options.

Sources: REGENXBIO; FDA; CAMPSIITE trial data.