Ultragenyx Reports Positive Longer-Term Data for MPS IIIA Gene Therapy as It Resubmits BLA to FDA

Rare Daily Staff

Ultragenyx Pharmaceutical said new long-term data from clinical studies of its experimental gene therapy UX111 for Sanfilippo syndrome show substantial and durable biomarker improvements and meaningful functional benefits compared with natural history.

The company said the benefits were seen across age and disease severity, and that UX111 was well-tolerated and continues to show a favorable safety profile.

In July, the U.S. Food and Drug Administration told Ultragenyx it would not approve its application to market UX111 without additional information and improvements related to aspects of its chemistry, manufacturing, and controls, following an inspection of its manufacturing facility. The resubmitted application includes comprehensive responses to chemistry, manufacturing, and controls-related observations outlined in the FDA’s complete response letter, as well as additional long-term clinical data from current patients, as requested by the agency.

“These data continue to demonstrate a remarkable and unprecedented separation from the natural history of Sanfilippo syndrome through more than eight years of follow-up, with children in their teens retaining skills at an age when many of their untreated peers have sadly lost their most basic abilities and succumbed to this disease,” said Emil Kakkis, CEO and president of Ultragenyx. “Our studies consistently show that reductions in heparan sulfate are associated with meaningful clinical benefits across multiple domains, underscoring the urgency to bring forward a treatment for families who currently have no options to stop or delay the heartbreaking and inevitable progression and loss of function associated with this disease.”

​Sanfilippo syndrome type A, or MPS IIIA, is a rare lysosomal storage disorder with no approved treatment that primarily affects the brain and is characterized by rapid neurodegeneration beginning in early childhood. It is caused by pathogenic variants in the SGSH gene that lead to a deficiency in the sulfamidase enzyme responsible for breaking down heparan sulfate, a sulfated glycosaminoglycan that accumulates in cells throughout the body. Children with MPS IIIA present with global developmental delay that progresses to cognitive, language, and motor decline, behavioral abnormalities, and premature death, with median survival reported in the mid- to late-teen years in the most rapidly progressive forms of the disease.

UX111 is a one-time in vivo AAV9 gene therapy in phase 1/2/3 development for MPS IIIA. The therapy uses a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to cells, leading transduced cells to secrete functional sulfamidase into surrounding tissue, where it is taken up and trafficked to lysosomes to reduce toxic heparan sulfate accumulation and downstream neurodegeneration.

The product, originally developed as ABO-102 by Abeona Therapeutics, was licensed to Ultragenyx to complete development. UX111 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.

“There is an unmet clinical need for a therapy for this devastating disease,” said Kevin Flanigan, director of the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio, and a principal investigator on the study. “These results provide evidence of benefit from this gene transfer therapy, especially when delivered early.”

Photo: Emil Kakkis, CEO and president of Ultragenyx