Ultragenyx Completes BLA Submission for First Gene Therapy Targeting Glycogen Storage Disease Type Ia
Key Insights
Ultragenyx Pharmaceutical has completed its rolling Biologics License Application submission to the FDA for DTX401, an AAV gene therapy designed to treat the underlying cause of Glycogen Storage Disease Type Ia (search).
The BLA is supported by data from 52 treated patients with up to six years of follow-up, including results from the Phase 3 GlucoGene study showing significant reductions in daily cornstarch intake while maintaining glucose control.
If approved, DTX401 would become the first therapy to directly target the underlying metabolic defect in GSDIa (search), a rare disease affecting approximately 6,000 people in commercially accessible regions.
Ultragenyx Pharmaceutical Inc. has completed the rolling submission of its Biologics License Application (BLA) to the U.S. Food and Drug Administration (search), seeking approval for DTX401 AAV gene therapy (pariglasgene brecaparvovec) as a treatment for Glycogen Storage Disease Type Ia (search) (GSDIa (search)). If approved, DTX401 would represent the first therapy to directly address the underlying metabolic cause of this rare, life-threatening genetic disorder.
Clinical Development Program Demonstrates Efficacy
The BLA submission is supported by data from a comprehensive clinical development program that includes 52 treated patients and up to six years of follow-up data. The pivotal evidence comes from the randomized, double-blind, placebo-controlled Phase 3 GlucoGene study, which demonstrated that patients treated with DTX401 experienced significant and clinically meaningful reductions in both the quantity and frequency of daily cornstarch intake while maintaining low levels of hypoglycemia (search), improved levels of euglycemia, and improved fasting tolerance.
These clinical benefits translated to meaningful improvements in patient-reported quality of life, as measured by the Patient Global Impression of Change (PGIC) scale. DTX401 was well tolerated throughout the study period, demonstrating an acceptable safety profile.
"The completion of our rolling submission of the BLA for DTX401 is a significant step toward our commitment to deliver the first therapy that directly targets the underlying cause of GSDIa (search)," said Eric Crombez, M.D., Chief Medical Officer at Ultragenyx. "Despite burdensome daily dietary and cornstarch management, patients continue to face life-threatening risks from acute hypoglycemia (search) and chronic complications impacting the liver, kidneys, gastrointestinal system, bones, and growth."
Gene Therapy Mechanism and Administration
DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase (search) under control of the native promoter. This approach allows treated liver cells to respond to normal hormonal signals intended to manage glucose, including insulin and cortisol. The therapy is administered as a single intravenous infusion and has demonstrated in preclinical studies the ability to improve G6Pase activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression.
Regulatory Pathway and Designations
The company previously received rolling review status and submitted the non-clinical and clinical modules to the FDA in August. The recent submission completes the regulatory package through the addition of the chemistry, manufacturing, and controls (CMC) module.
DTX401 has received multiple regulatory designations recognizing its potential therapeutic value, including Rare Pediatric Disease designation, orphan drug designation, Fast Track designation, and regenerative medicine advanced therapy (RMAT) designation from the U.S. FDA. The European Medicines Agency (search) has also granted orphan drug and PRIority MEdicines (PRIME) designations.
Addressing Significant Unmet Medical Need
GSDIa (search) is a rare, serious, and life-threatening disease caused by an inborn error of carbohydrate metabolism resulting from pathogenic variants of the G6PC gene (search), which encodes G6Pase (search). This enzyme is critical for the release of glucose from glycogen and other metabolic sources. Deficiency of G6Pase results in severe hypoglycemia (search) during periods of fasting between meals and during the night, along with excess hepatic glycogen storage, metabolic derangements and other disease-related complications.
Currently, cornstarch administration is critical in the management of GSDIa (search) throughout the day and night, providing an exogenous source of glucose to avoid sudden and severe drops in plasma glucose levels. However, current management strategies carry a significant burden to patients and families, and there are no approved pharmacologic therapies targeting the underlying disease mechanism. GSDIa is estimated to affect approximately 6,000 people in commercially accessible geographies.