FDA Tells Ultragenyx It Won’t Approve Its Gene Therapy for Sanfilippo Syndrome Type A

Rare Daily Staff

The U.S. Food and Drug Administration notified Ultragenyx Pharmaceutical that it would not approve its application to market UX111, its experimental gene therapy for the rare lysosomal storage disorder Sanfilippo syndrome type A.

The agency, in issuing a complete response letter, told the company it would need to provide additional information and improvements related to aspects of its chemistry, manufacturing, and controls following an inspection of its manufacturing facility.

The company said it believes that these observations are readily addressable, relate to facilities and processes, and are not directly related to the quality of the product. The company will be working with the FDA over the next few months to resolve the observations. Once resolved, the company expects to resubmit its application and anticipates up to a six-month review period following the resubmission.

Ultragenyx said that clinical review had been ongoing and that the FDA has acknowledged the neurodevelopmental outcome data provided to date are robust and that the biomarker data provide additional supportive evidence. The complete response letter did not note any review issues related to the clinical data package or clinical inspections and asked that updated clinical data from current patients be included in the resubmission.

Sanfilippo syndrome type A (MPS IIIA) is a rare, fatal 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 that eventually leads to progressive cognitive, language, and motor decline, behavioral abnormalities, and early death.

MPS IIIA is caused by biallelic pathogenic variants in the SGSH gene that lead to a deficiency in the sulfamidase (SGSH) enzyme, which is responsible for breaking down heparan sulfate, a glycosaminoglycan. These glycosaminoglycans accumulate in cells throughout the body, resulting in the observed rapid neurodegeneration associated with the disorder.

UX111 is an experimental in vivo gene therapy for Sanfilippo syndrome type A. The therapy is designed to address the underlying SGSH enzyme deficiency responsible for the abnormal accumulation of heparan sulfate, a glycosaminoglycan, in the brain, which results 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 to be taken up by other brain cells, cross-correcting the enzyme deficiency.

The product was originally developed by Abeona Therapeutics and was transferred to Ultragenyx to complete development. The UX111 program has received Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations in the United States, as well as PRIME and Orphan medicinal product designations in the European Union.

If approved, the product will be commercialized by Ultragenyx’s existing metabolic disease team.

“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 Kakkis, CEO and president of Ultragenyx.

Photo: Emil Kakkis, CEO and president of Ultragenyx