Regulatory & Policy

FDA accepts Ultragenyx's UX111 gene therapy resubmission for Sanfilippo syndrome Type A treatment

Edited by Robert McTiernan··4 min read

Ultragenyx Pharmaceutical has submitted a resubmitted Biologics License Application to the US FDA for UX111 (rebisufligene etisparvovec), an AAV9 gene therapy intended as a treatment for patients with Sanfilippo syndrome Type A (MPS IIIA). The US FDA has accepted the resubmission for review, as announced by the company, and has set a PDUFA action date of September 19, 2026. If the application is successful, UX111 would become the first approved therapy for MPS IIIA, a disease for which no pharmacological treatment currently exists anywhere in the world.

The FDA previously issued a Complete Response Letter (CRL) to Ultragenyx's original approval filing for UX111 in July 2025, citing CMC-related issues. The BLA resubmission seeks accelerated approval for UX111 as a one-time intravenous infusion for patients with MPS IIIA. The US FDA had previously granted the application Priority Review in February 2025. The filing is supported by updated long-term clinical data representing up to eight years of follow-up, the company said, including data presented at the WORLD Symposium in 2026. During a prior late-cycle review, the US FDA acknowledged that the neurodevelopmental outcome data were robust and that biomarker data provided supportive evidence, according to Ultragenyx.

The clinical evidence underpinning the submission draws on the Phase I/II/III Transpher A trial, a study of UX111 in children with MPS IIIA. Sponsor-reported data from the trial, disclosed in February 2026, showed that in younger or earlier-stage patients (n=17), Bayley-III cognitive raw score treatment effects versus natural history reached +23.2 (p<0.0001) over 24 to 60 months. Other Bayley-III domain treatment effects included receptive communication +8.1 (p=0.0076), expressive communication +11.1 (p=0.0008), and fine motor +9.0 (p=0.0026). On the biomarker side, at the 3×10¹³ vg/kg dose in an overall efficacy set of 27 patients at a September 2025 data cutoff, the company reported a median cerebrospinal fluid heparan sulfate reduction of 63.98% (p<0.001), with 81.5% of patients overall achieving at least a 50% reduction. The most common treatment-emergent adverse events were liver enzyme elevations, which were described as mostly mild to moderate and resolving spontaneously, the company said. A peer-reviewed interim report of the Transpher A trial has also been published.

Ultragenyx's approach to MPS IIIA

MPS IIIA is caused by biallelic variants in the SGSH gene, which encodes the lysosomal enzyme sulfamidase. Loss of enzyme function leads to progressive accumulation of heparan sulfate in the central nervous system, producing neurodegeneration that begins in early childhood and follows an irreversible course. Children present with global developmental delay, followed by cognitive, language, and motor deterioration, behavioral disturbance, and early death, with a median life expectancy of approximately 15 years. The disease is estimated to affect 3,000 to 5,000 patients in commercially accessible geographies, the company said.

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The central biological challenge that has frustrated earlier therapeutic attempts — including intrathecal enzyme replacement with recombinant human heparan-N-sulfatase — is the blood-brain barrier, which prevents systemically administered proteins from reaching the sites of pathology. UX111 uses a self-complementary AAV9 vector delivered intravenously to transduce cells and restore functional SGSH enzyme production, with the AAV9 capsid providing capacity for central nervous system penetration. Transduced cells secrete enzyme into tissue fluid, where it is taken up by surrounding neurons and routed to the lysosome. The therapy was originally developed by Abeona Therapeutics before being exclusively licensed to Ultragenyx in 2022.

The filing adds to a growing field of AAV-based gene therapies targeting lysosomal storage diseases, a class in which single-administration approaches have attracted sustained research interest given the chronic and progressive nature of the underlying enzyme deficiencies. Within MPS specifically, no subtype of MPS III — which has four variants (A, B, C, D) — has an approved disease-modifying therapy, reflecting the particular difficulty of achieving CNS delivery at scale. The UX111 program carries Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations in the United States, and PRIME and Orphan Medicinal Product designations in the European Union. If approved, the company said manufacturing would be conducted entirely within the United States, at Andelyn Biosciences in Columbus, Ohio and Ultragenyx's gene therapy facility in Bedford, Massachusetts. The US FDA's decision is expected by September 19, 2026.

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