Ultragenyx Pharmaceutical Inc. has announced that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for UX111 (ABO-102), an AAV gene therapy intended for patients with Sanfilippo syndrome type A (MPS IIIA). The FDA has granted Priority Review to the BLA, setting the Prescription Drug User Fee Act (PDUFA) action date for August 18, 2025. The agency also indicated that it does not currently plan to hold an advisory committee meeting to discuss the application. This decision brings hope to the Sanfilippo community, as UX111 aims to be the first approved treatment for this devastating condition.
Clinical Data Supporting UX111
The BLA submission is supported by data from the ongoing pivotal Transpher A study and long-term follow-up studies. These data, presented at WORLDSymposium™ 2025, demonstrate that UX111 treatment resulted in rapid and sustained reduction of heparan sulfate (HS) levels in cerebrospinal fluid (CSF) in patients with Sanfilippo syndrome type A, irrespective of age or disease stage at the time of treatment. The data also revealed a statistically significant improvement in Bayley-III raw scores for cognitive, receptive communication, and expressive communication subdomains in the modified intent-to-treat (mITT) group compared to natural history data from untreated patients. These clinical improvements correlated with substantial and sustained reductions in CSF-HS levels. The most frequently reported treatment-related adverse events were elevations in liver enzymes, the majority of which were mild (Grade 1) or moderate (Grade 2) in severity and resolved.
UX111: A Novel Gene Therapy Approach
UX111 is an in vivo gene therapy in Phase 1/2/3 development for Sanfilippo syndrome type A, a rare and fatal lysosomal storage disease that primarily affects the brain. The therapy is designed to address the underlying deficiency in the SGSH enzyme, which leads to abnormal accumulation of heparan sulfate in the brain, resulting in progressive cell damage and neurodegeneration. UX111 is administered as a one-time intravenous infusion using a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to cells. These transduced cells then produce the enzyme and secrete it for uptake by other brain cells, correcting the enzyme deficiency. The UX111 program has been granted Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations in the U.S., as well as PRIME and Orphan medicinal product designations in the EU.
Sanfilippo Syndrome Type A: A Devastating Condition
Sanfilippo syndrome type A (MPS IIIA) is a rare, fatal lysosomal storage disease characterized by rapid neurodegeneration, with onset in early childhood. Children with MPS IIIA experience global developmental delay, leading to progressive cognitive, language, and motor decline, behavioral abnormalities, and early death. It is estimated to affect approximately 3,000 to 5,000 patients in commercially accessible geographies, with a median life expectancy of 15 years. The disease is caused by biallelic pathogenic variants in the SGSH gene, resulting in a deficiency in the sulfamidase (SGSH) enzyme responsible for breaking down heparan sulfate, a glycosaminoglycan that accumulates in cells throughout the body.
Potential Impact and Future Directions
Emil D. Kakkis, M.D., Ph.D., chief executive officer and president of Ultragenyx, stated that the acceptance of the UX111 BLA brings the company closer to providing a first-ever treatment for Sanfilippo syndrome type A. He also noted that alignment with the FDA on an accelerated approval path for neuronopathic MPS diseases could serve as a step towards advancing drug development across multiple metabolic diseases of the brain. The FDA's acceptance of CSF HS as a disease-cause biomarker has enabled the BLA filing and may unlock future accelerated approvals of new therapies for other MPS diseases affecting the brain.
