Ultragenyx Pharmaceuticals Gets CRL for UX111 AAV Gene Therapy for MPS IIIA

Ultragenyx Pharmaceuticals (NASDAQ: RARE) has announced that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for its Biologics License Application (BLA) for UX111, an AAV gene therapy targeting Sanfilippo syndrome type A (MPS IIIA).

The CRL primarily requests more information and enhancements regarding chemistry, manufacturing, and controls (CMC) elements and recent manufacturing facility inspection findings. Ultragenyx clarified that these issues are facility- and process-related, not impacting product quality, and anticipates a swift resolution. The company plans to collaborate closely with the FDA to address these observations, aiming for a BLA resubmission that would trigger a review period of up to six months. This regulatory setback is expected to delay potential approval of UX111 for MPS IIIA until 2026.

Notably, the FDA acknowledged the robustness of the submitted neurodevelopmental outcome data and the supportive nature of the biomarker findings, raising no concerns about the clinical data itself or prior inspections. However, updated clinical data from current patients will be required for inclusion in the resubmission.

Basis for BLA Submission & Pipeline Overview:

Ultragenyx’s UX111 BLA for MPS IIIA was submitted via accelerated approval, supported by pivotal Phase I/II/III Transpher A study data. This data showed UX111 led to a rapid, sustained reduction in CSF heparan sulfate (HS), correlating with improved long-term cognitive development compared to natural history, with overall good tolerability. MPS IIIA is a rare, fatal, untreated lysosomal storage disease affecting 3,000-5,000 patients with a median 15-year life expectancy. UX111, licensed from Abeona Therapeutics, holds multiple U.S. (RMAT, Fast Track, Rare Pediatric Disease, Orphan Drug) and EU (PRIME, Orphan) designations.

Ultragenyx’s pipeline also includes:

• UX143 (setrusumab): Late-stage monoclonal antibody for osteogenesis imperfecta (OI).
• UX701: Phase I/II/III AAV9 gene therapy for Wilson disease.
• DTX401: Phase III AAV8 gene therapy for GSD Ia, which met primary and key secondary endpoints in 2024, with marketing application discussions planned.
• GTX-102: Pivotal Phase III antisense oligonucleotide for Angelman syndrome, with dosing initiated last year.