The FDA has issued accelerated approval of pariglasgene brecaparvovec-opnr (Genglycos, Ultragenyx Pharmaceutical Inc.), a novel, one-time gene therapy, as an adjunctive treatment to nutritional management of children aged 8 years and older and adults with the rare disorder glycogen storage disease type Ia (GSDIa).

“Genglycos offers these patients and their families a one-time therapy that targets the root cause of the disease,” said Megha Kaushal, MD, MSc, acting deputy director of the Center for Biologics Evaluation and Research Office of Therapeutic Products, in an FDA press statement.

“This accelerated approval reflects our confidence in the clinical evidence to date and our commitment to bringing innovative treatments to patients with rare genetic diseases while we continue to gather data to confirm long-term benefit,” Kaushal said.

GSDIa, affecting about 1500-2500 patients in the US, is an ultra-rare, potentially life-threatening genetic metabolic disorder caused by a deficiency in the enzyme glucose-6-phosphatase, which helps regulate fasting blood sugar levels by releasing glucose from the liver and kidneys into the bloodstream.

To compensate for the deficiency, patients must endure a burdensome regimen involving supplementation with raw cornstarch as an oral glucose replacement therapy, along with strict dietary management to prevent hypoglycemic episodes.

Consequently, patients often wind up being hyperglycemic much of the day, Ultragenyx reports in a press statement.

Pariglasgene brecaparvovec-opnr, the first treatment to receive FDA approval for the condition, delivers a functional G6PC gene to the liver as a one-time AAV8-vector-based gene therapy, addressing the deficiency.

The FDA approval was based on results from the phase 3, randomized, double-blind GlucoGene trial of patients with GSDIa who were followed for 48 weeks after dosing with pariglasgene brecaparvovec-opnr and, for the primary endpoint, showed a mean reduction in daily cornstarch intake from baseline of 31% compared with placebo.

For the secondary endpoint, patients treated with pariglasgene brecaparvovec-opnr had a mean reduction from baseline of one cornstarch dose per day compared with the placebo. 

Patients showed a mean 3% increase in the percentage of glucose values in the hypoglycemic range (< 70 mg/dL) compared with placebo.

The drug’s most common side effects included increased transaminases, nausea, headache, constipation, and hyperglycemia.

Serious side effects, observed in two clinical trials of pariglasgene brecaparvovec-opnr, included anaphylaxis, adrenal insufficiency, high lactate levels, and hypoglycemia.

Of note, compared with placebo-treated patients, pariglasgene brecaparvovec-treated patients had higher rates of hypertriglyceridemia, a metabolic marker of GSDIa (29% vs 8%), the FDA reports.

Overall, the drug’s accelerated approval is expected to help reduce the high burden that patients with GSDIa face in management of the disease.

“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,” explained David Weinstein, MD, MMSc, of the University of Connecticut Health Center in Farmington, Connecticut, and a leading GSDIa expert, in an Ultragenyx press statement.

“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,” he said.

“The approval of Genglycos represents a major step forward for the GSDIa community and reflects almost 30 years of work and scientific progress aimed at improving safety and the quality of life of people living with this disease,” Weinstein added.

The GlucoGene trial was sponsored by Ultragenyx Pharmaceutical Inc.