First Therapy Approved for Dangerous Metabolic Disorder

The FDA on Wednesday granted accelerated approval to pariglasgene brecaparvovec (Genglycos) as the first treatment for glycogen storage disease type Ia (GSDIa), an inherited metabolic disorder that requires frequent consumption of cornstarch to prevent severe or life-threatening hypoglycemia.

People with GSDIa cannot properly break down stored glycogen into glucose due to a deficiency of glucose-6-phosphatase (G6PC), an enzyme that helps maintain stable blood sugar levels between meals. As a result, every few hours patients need to eat raw or specially formulated cornstarch, a slow-digesting carbohydrate.

The one-time adeno-associated virus vector (AAV)-based gene therapy delivers a functional G6PC gene to the liver to target the root cause of the disease. Approval stipulates use in adults and children ages 8 years and up in combination with nutritional management as a means of reducing cornstarch intake.

An estimated 1,500 to 2,500 Americans have GSDIa, also known as von Gierke disease.

“The approval of Genglycos represents a major step forward for the GSDIa community,” David Weinstein, MD, a leading expert on the ultra-rare disease, said in a press release from drugmaker Ultragenyx.

“Day-to-day management of GSDIa requires a relentless regimen of raw cornstarch and strict dietary management that can be extraordinarily demanding for patients and families,” said Weinstein. “Even with meticulous adherence to this regimen, patients must be perfect. Any missed cornstarch puts patients at risk of severe hypoglycemia, seizures, and even death.”

Phase III trial data supporting the approval showed that pariglasgene brecaparvovec as an adjunct to nutritional management reduced cornstarch intake by 41.1% at week 48, as compared with a 10.2% reduction in the placebo group (P<0.001). On average, patients in the gene therapy group needed one fewer dose of cornstarch per day compared with the placebo group.

Under the accelerated approval pathway, further data will be required to confirm the therapy’s clinical benefit.

Adverse events occurring in at least 10% of pariglasgene brecaparvovec-treated patients, and at a higher frequency than in the placebo arm, included liver enzyme elevations (71%), nausea (38%), headache (24%), hypertriglyceridemia (29%), adrenal insufficiency (24%), constipation (19%), hyperglycemia (14%), acne/dermatitis acneiform (19%), Cushingoid features (14%), and anaphylaxis (10%).

Warnings and precautions in the drug’s labeling include risks for hypersensitivity and infusion reactions, hepatotoxicity, adrenal insufficiency, and AAV tumorigenicity. The FDA said the drug should not be used in pregnancy, and contraindications include patients with severe hepatic fibrosis or cirrhosis.