An ultra-rare disease whose standard of care for decades has been consuming a kitchen pantry staple every few hours now has its first FDA-approved therapy, an Ultragenyx Pharmaceutical genetic medicine that offers a one-time treatment addressing the disorder’s root cause.
The regulatory decision announced after Wednesday’s market close covers the treatment of adults and children age 8 and older who have glycogen storage disease type Ia (GSDIa). Known in development by the code name DTX401, Novato, California-based Ultragenyx will commercialize this gene therapy, its first, under the brand name Genglycos.
GSDIa is an inherited deficiency of glucose-6-phosphatase, an enzyme found mainly in the liver and kidneys that plays a key role in maintaining healthy blood sugar levels. According to Ultragenyx, an estimated 1,500 to 2,500 patients in the U.S. have this disorder, which can lead to life-threatening hypoglycemia episodes. To avoid them, patients follow a strict dietary regimen that involves consuming raw cornstarch, typically mixed with water to make a drinkable slurry. Cornstarch is a complex carbohydrate that breaks down slowly, which helps maintain blood glucose levels in periods between meals. This regimen includes consuming cornstarch during the night, when blood sugar levels can drop. But uncooked cornstarch therapy does not address the underlying cause of GSDIa and can still lead to large swings in glucose levels.
“GSD1A is an urgent disease with round the clock demands on patients every day and night without holiday or break,” Ultragenyx President and CEO Emil Kakkis said during a Wednesday evening conference call. “A gene therapy designed to deliver the missing enzyme is [the] ideal way to address this severe ultra-rare disease.”
Genglycos uses an engineered virus to deliver a functioning version of the gene that codes for glucose-6-phosphatase, which is intended to restore stable expression of the enzyme. Ultragenyx evaluated this treatment in a placebo-controlled Phase 3 study that enrolled 46 participants age 8 and older.
At 48 weeks, results showed a reduction in the cornstarch requirements in the treatment cohort compared to the placebo arm. At that time point, those in the placebo group crossed over to receive the gene therapy and all participants continued to be followed. At week 96, the end of the crossover period, Ultragenyx reported that the Genglycos group showed an average 70% reduction in nighttime cornstarch consumption compared to baseline. For the crossover group, the average reduction was 75% compared to week 48. Serious adverse reactions reported in the study included anaphylaxis, adrenal insufficiency, high lactate levels, and hypoglycemia. The most common adverse reactions included elevated levels of liver enzymes, nausea, headache, constipation, and hyperglycemia.
The FDA decision for Genglycos is an accelerated approval based on data from the 48-week, placebo-controlled portion of the trial. The approval requires Ultragenyx to provide two years of safety and efficacy clinical data from 50 patients who receive the therapy commercially and 20 control patients. The control group will consist of patients who sought Genglycos but were deemed ineligible because they have antibodies against the engineered virus used to deliver the gene therapy.
Ultragenyx set a list price of $2.7 million for Genglycos, which the company manufactures at a wholly owned facility in Bedford, Massachusetts. Ultragenyx expects the therapy will become available in the next 30 to 60 days. Approval of Genglycos came with the award of a priority review voucher. While Ultragenyx may use this voucher to speed up the regulatory review of another eligible therapeutic candidate, most voucher recipients sell them to big pharma companies. Recent voucher sales have reached $200 million. Chief Financial Officer Howard Horn said the company plans to sell its voucher.
William Blair models $362 million in peak sales for Genglycos. In a Thursday research note, analyst Sami Corwin pointed to two other therapeutic candidates of interest to Ultragenyx investors. UX111, a gene therapy for mucopolysaccharidosis type III (MPS III), also called Sanfilippo syndrome type A, a rare enzyme deficiency that leads to cell and tissue damage in the central nervous system. Last year, the FDA turned down Ultragenyx’s application, citing manufacturing issues. Corwin said the resubmitted application could receive an FDA decision in September, and an approval could also come with a priority review voucher.
Corwin added that investors remain focused on GTX-102, an antisense oligonucleotide developed for Angelman syndrome, a rare inherited disorder that affects the nervous system and has no approved therapies. Corwin said a readout from a pivotal test of the Angelman therapy is expected in September or October.
Photo: Waldemarus, Getty Images
