FDA Grants Accelerated Approval to Ultragenyx for GSDIa Gene Therapy

Rare Daily Staff

The U.S. Food and Drug Administration has granted accelerated approval to Ultragenyx Pharmaceutical’s gene therapy Genglycos for adults and children aged 8 years and older with glycogen storage disease type Ia, or GSDIa.

The decision marks Ultragenyx’s first gene therapy approval and gives people with the ultra-rare metabolic disorder their first FDA-approved treatment designed to address its underlying cause.

The approval also earned Ultragenyx a Priority Review Voucher, which can be used to speed FDA review of a future drug application or sold to another company. Rocket Pharmaceuticals most recently sold a Priority Review Voucher in April for $180 million.

GSDIa is caused by disease-causing variants in the G6PCgene, which provides instructions for making the enzyme glucose-6-phosphatase alpha, also known as G6Pase-α. Without enough of this enzyme, the liver cannot release stored glucose into the bloodstream effectively. As a result, patients can develop dangerously low blood sugar during periods without food, along with excess glycogen buildup in the liver, metabolic abnormalities and other long-term complications.

People with GSDIa currently depend on frequent doses of raw cornstarch and strict dietary schedules—including overnight dosing—to prevent dangerous drops in blood glucose. Missing a dose can lead to severe hypoglycemia, seizures or death. Genglycos, previously known as DTX401, is approved alongside continued nutritional management to reduce patients’ daily cornstarch requirements.

Genglycos is an adeno-associated virus serotype 8, or AAV8, gene therapy designed to deliver a functional copy of the G6PCgene to liver cells. The therapy is intended to enable treated cells to make G6Pase-α and respond to normal hormonal signals, including insulin, glucagon and cortisol, that help regulate blood glucose.

“The approval of Genglycos fulfills our commitment to provide the first therapy that directly targets the root cause of GSDIa,” said Eric Crombez, Ultragenyx’s chief medical officer. He said the lower need for cornstarch seen in clinical studies suggests the treatment could ease the disease-management burden and potentially reduce the risk of serious hypoglycemic episodes.

The FDA based its decision on the randomized, double-blind, placebo-controlled phase 3GlucoGene trial. The study enrolled 46participants aged 8years and older. The modified intention-to-treat analysis included 44 participants: 20 who received DTX401 and 24 who received placebo.

At week 48, patients treated with Genglycos had a statistically significant reduction in cornstarch requirements compared with placebo, according to Ultragenyx. Following the 48-week primary analysis period, eligible participants crossed over to receive the alternate treatment and continued follow-up through weeks 96 and 144.

Because Genglycos received accelerated approval on the basis of reduced daily cornstarch use, its continued approval may depend on confirmation of clinical benefit in post-marketing studies. Ultragenyx has agreed to collect two years of safety and efficacy data from 50commercially treated patients and 20control patients through an expanded disease-monitoring program.

The control group will include patients who sought commercial treatment but cannot receive Genglycos because they have antibodies to the AAV8 viral vector. Ultragenyx plans to follow commercial patients and previous clinical-trial participants for a total of 10 years. The program will assess cornstarch burden, fasting tolerance and longer-term safety.

The therapy carries important safety warnings. Genglycos is contraindicated in patients with severe hepatic fibrosis or cirrhosis. Reported risks include hypersensitivity and infusion reactions, including anaphylaxis; immune-mediated liver toxicity; and adrenal insufficiency associated with corticosteroid treatment and tapering.

The label also notes a theoretical risk of tumor development because AAV vector DNA could potentially integrate into a patient’s genome. AAV vector DNA typically remains outside chromosomes, but random integration events have been reported with AAV-based gene therapies.

Photo: Eric Crombez, Ultragenyx’s chief medical officer