Innovative gene therapy offers new option for children and adults with rare disease
The U.S. Food and Drug Administration today issued an accelerated approval for Genglycos (pariglasgene brecaparvovec-opnr) to reduce daily cornstarch intake as an adjunct to nutritional management in adults and pediatric patients 8 years of age and older with glycogen storage disease type Ia (GSDIa), a rare, inherited genetic disorder caused by a deficiency of the enzyme glucose-6-phosphatase, which prevents the body from properly breaking down stored glycogen into glucose. Genglycos is the first approved treatment for this condition.
The accelerated approval pathway allows the FDA to approve certain drugs or biologics intended to treat a serious or life-threatening disease or condition if the agency determines the treatment has an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit.
“Patients with GSDIa face possible life-threatening complications and have limited treatment options that include primarily life-long, strict dietary management,” said Karim Mikhail, B. Pharm., M.S., acting director of the Center for Biologics Evaluation and Research (CBER). “Today’s approval is a great milestone in using a gene therapy to treat this disease and improve the quality of life for people with this condition.”
The agency based this accelerated approval on clinical trial data showing Genglycos helps reduce daily cornstarch intake, when taken with an appropriate diet. Reducing cornstarch intake is the surrogate endpoint, and the manufacturer must complete additional clinical trials to confirm Genglycos’s effectiveness.
GSDIa is caused by a genetic mutation that results in a missing enzyme called glucose-6-phosphatase (G6PC). This enzyme normally releases free glucose (a simple sugar and main source of energy for the body) from the liver and kidneys into the bloodstream, helping to maintain stable blood sugar levels during fasting and between meals. This enzyme deficiency causes the blood sugar to drop dangerously low whenever a person goes too long without eating. The condition can lead to long-term metabolic complications that can impair normal function in certain organs and tissues. GSDIa is typically managed through careful medical monitoring, frequent meals, avoidance of certain foods containing simple sugars, and daily, strict, around-the-clock dietary supplementation of uncooked or specially formulated cornstarch (slow-digesting complex carbohydrate) to prevent hypoglycemia (abnormally low blood sugar levels).
Genglycos is a one-time AAV8 based gene therapy designed to deliver a functional G6PC gene to the liver, aiming to restore the deficient enzyme required to release stored glucose and ensure stable blood sugar levels when a person is fasting.
“Genglycos offers these patients and their families a one-time therapy that targets the root cause of the disease,” said Megha Kaushal, M.D., MSc., acting deputy director of the CBER Office of Therapeutic Products. “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.”
The effectiveness of Genglycos was evaluated in a randomized, double-blind, placebo-controlled study in patients with GSDIa followed over 48 weeks after dosing. Patients treated with Genglycos demonstrated a statistically significant mean reduction from baseline in daily cornstarch intake of 31% compared to placebo, the study’s primary endpoint. A mean reduction from baseline of one cornstarch dose per day was seen in the Genglycos group compared to placebo, the study’s secondary endpoint. Genglycos-treated patients experienced a numerical (mean 3%) increase in the percentage of glucose values in the hypoglycemic range (< 70 mg/dL) compared to placebo.
Across two clinical studies of Genglycos including the randomized clinical study, serious adverse reactions reported in Genglycos-treated patients included anaphylaxis, adrenal insufficiency (a condition where the adrenal glands do not produce enough stress hormones), high lactate levels, and hypoglycemia. The most commonly reported adverse reactions included increased transaminases (elevation of liver enzymes), nausea, headache, constipation, and hyperglycemia. Genglycos-treated patients had a higher rate of hypertriglyceridemia (high blood triglyceride levels), a metabolic marker of GSDIa, compared to placebo-treated patients (29% vs 8%). The prescribing information contains warnings about the risks of anaphylaxis, liver toxicity, adrenal insufficiency, and risk of tumorigenicity (development of tumors). Genglycos should not be used during pregnancy.
The application for Genglycos received a Rare Pediatric Disease Priority Review Voucher. The FDA granted Genglycos regenerative medicine advanced therapy (RMAT) and Fast Track designations.
The FDA granted accelerated approval of Genglycos to Ultragenyx Pharmaceutical, Inc.
|
