Ultragenyx Pharmaceutical Inc. announced that the U.S. Food and Drug Administration has issued a Complete Response Letter (CRL) for its Biologics License Application for UX111 (ABO-102) AAV gene therapy as a treatment for patients with Sanfilippo syndrome type A (MPS IIIA). The regulatory action centers on chemistry, manufacturing and controls (CMC) observations that the company characterizes as readily addressable.
Manufacturing Issues Delay Approval Timeline
The CRL requested additional information and improvements related to specific aspects of CMC and observations from recently completed manufacturing facility inspections. According to Ultragenyx, these observations are related to facilities and processes rather than product quality itself. The company expects to work with the FDA over the next few months to resolve these issues before resubmitting the BLA.
"Our goal is to get UX111 to patients as quickly as possible knowing how critical this first therapy is to the Sanfilippo community," said Emil D. Kakkis, M.D., Ph.D., chief executive officer and president of Ultragenyx. "We believe the CMC observations are readily addressable and many have already been addressed. While the CRL will delay the potential approval of UX111 to 2026, we are working with urgency to respond and resubmit."
Clinical Data Receives FDA Acknowledgment
Despite the manufacturing concerns, the FDA's clinical review yielded positive feedback. The agency acknowledged that the neurodevelopmental outcome data provided to date are robust and the biomarker data provide additional supportive evidence. The CRL noted no review issues related to the clinical data package or clinical inspections, requesting only that updated clinical data from current patients be included in the resubmission.
Once the manufacturing observations are resolved, Ultragenyx anticipates up to a 6-month review period following BLA resubmission.
Novel Gene Therapy Mechanism
UX111 is designed to address the underlying SGSH enzyme deficiency responsible for abnormal accumulation of heparan sulfate in the brain, which results in progressive cell damage and neurodegeneration. The therapy 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 to be taken up by other brain cells, cross-correcting the enzyme deficiency.
The product was originally developed by Abeona Therapeutics and transferred to Ultragenyx to complete development. The UX111 program has received multiple regulatory designations including Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations in the U.S., and PRIME and Orphan medicinal product designations in the EU.
Addressing Critical Unmet Medical Need
Sanfilippo syndrome type A is a rare, fatal lysosomal storage disease with no approved treatment that primarily affects the brain and is characterized by rapid neurodegeneration with onset in early childhood. Children with MPS IIIA present with global developmental delay which eventually leads to progressive cognitive, language and motor decline, behavioral abnormalities and early death.
The disease is estimated to affect approximately 3,000 to 5,000 patients in commercially accessible geographies with a median life expectancy of 15 years. MPS IIIA is caused by biallelic pathogenic variants in the SGSH gene that lead to a deficiency in the sulfamidase (SGSH) enzyme responsible for breaking down heparan sulfate, which accumulates in cells throughout the body resulting in the observed rapid neurodegeneration.
