FDA Approves First Gene Therapy for GSDIa

The FDA has granted accelerated approval to pariglasgene brecaparvovec-opnr (Genglycos; Ultragenyx Pharmaceutical, Inc), the first-ever therapy for glycogen storage disease type Ia (GSDIa) and the first gene therapy to target the underlying cause of the ultra-rare metabolic disorder. Approved for adults and pediatric patients aged 8 years and older, the 1-time treatment is indicated to reduce daily cornstarch intake as an adjunct to nutritional management, offering a potential path away from the relentless, around-the-clock dietary regimen that has defined care for this population.^1,2

A First Therapy for a Disease Managed by the Clock

GSDIa is an autosomal recessive disorder caused by pathogenic variants in the G6PC gene, which encodes glucose-6-phosphatase (G6Pase), an enzyme critical to releasing free glucose from the liver during fasting and between meals. Without functional G6Pase, patients cannot maintain stable blood glucose, leaving them vulnerable to severe, potentially life-threatening hypoglycemia along with hepatomegaly, hyperlipidemia, and other long-term metabolic complications. The condition accounts for roughly 80% of type I glycogen storage disease and is estimated to affect 1500 to 2500 patients in the US.^1-3

Standard management centers on strict, around-the-clock supplementation with uncooked cornstarch—a slow-digesting complex carbohydrate that provides an exogenous glucose source—alternating with frequent meals to prevent hypoglycemia. The burden is substantial: Patients must adhere perfectly, and a single missed dose can trigger severe hypoglycemia, seizures, or death. Until this approval, no pharmacologic therapy addressed the root cause.^2,3

What Pariglasgene Brecaparvovec is and How it Works

Pariglasgene brecaparvovec is a 1-time, AAV8-based gene therapy administered as a single intravenous infusion, designed to deliver a functional G6PC gene to the liver and restore the enzyme activity needed to release stored glucose during fasting. It carries a rare pediatric disease priority review voucher and holds regenerative medicine advanced therapy and fast track designations.^1,2

For pharmacists, several elements of the label warrant attention. Pariglasgene brecaparvovec is contraindicated in patients with known severe hepatic fibrosis or cirrhosis, and the prescribing information carries warnings for anaphylaxis, hepatotoxicity, adrenal insufficiency, and a theoretical risk of tumorigenicity from AAV vector integration. A prophylactic corticosteroid regimen is administered to mitigate immune-mediated hepatic reactions, with transaminase monitoring recommended for the first 6 months; corticosteroid tapering must be gradual to avoid adrenal insufficiency. Vaccines should be avoided in the month prior to administration, and vector shedding precautions apply for 3 months after infusion. Pariglasgene brecaparvovec should not be used during pregnancy.²

The Evidence Behind Accelerated Approval

Approval rests on the 48-week randomized, double-blind, placebo-controlled phase 3 GlucoGene study (NCT05139316), which treated 46 participants aged 8 years and older. Patients receiving pariglasgene brecaparvovec showed a statistically significant mean reduction from baseline in daily cornstarch intake of 31% compared with placebo—the surrogate end point on which the accelerated approval is based. A secondary end point demonstrated a mean reduction of 1 cornstarch dose per day versus placebo. Pariglasgene brecaparvovec-treated patients experienced a numerical mean 3% increase in the percentage of glucose values in the hypoglycemic range (<70 mg/dL) compared with placebo.^1,2

Reduction in cornstarch intake is a surrogate endpoint reasonably likely to predict clinical benefit. Ultragenyx must confirm effectiveness in postmarketing studies, including 2 years of safety and efficacy data through an enhanced GSDIa Disease Monitoring Program. Across the clinical program, serious adverse events (AEs) included anaphylaxis, adrenal insufficiency, high lactate levels, and hypoglycemia. The most common AEs were increased transaminases, nausea, headache, constipation, and hyperglycemia. Hypertriglyceridemia occurred more often with pariglasgene brecaparvovec than placebo (29% vs 8%).¹

The therapy builds on earlier data: In the open-label phase 1/2 study of DTX401 in adults with GSDIa, published in the Journal of Inherited Metabolic Disease, liver-directed AAV8 gene transfer reduced cornstarch requirements while maintaining glycemic control, supporting the mechanism carried into the phase 3 program.⁴

REFERENCES

1. FDA approves first therapy for patients aged 8 years and older with glycogen storage disease type Ia. News release. FDA. August 19, 2026. Accessed August 20, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-patients-aged-8-years-and-older-glycogen-storage-disease-type-ia

2. Ultragenyx announces U.S. FDA approval of Genglycos gene therapy, the first-ever FDA-approved treatment designed to treat the underlying cause of glycogen storage disease type Ia (GSDIa). News release. Ultragenyx Pharmaceutical Inc. August 19, 2026. Accessed August 20, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-us-fda-approval-genglycostm-gene-therapy

3. Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014;16(11):e1. doi:10.1038/gim.2014.128

4. Weinstein DA, Derks TG, Rodriguez-Buritica DF, et al. Safety and efficacy of DTX401, an AAV8-mediated liver-directed gene therapy, in adults with glycogen storage disease type Ia (GSDIa). J Inherit Metab Dis. 2025;48(2):e70014. doi:10.1002/jimd.70014