If at first you don’t succeed in gene therapy, then try, try again. That's the lesson Ultragenyx likely took home this week as it pocketed its first FDA nod in the class just over a year after a separate program stalled on manufacturing grounds.
Late Wednesday, the FDA gave an accelerated go-ahead to pariglasgene brecaparvovec-opnr, Ultragenyx’s AAV gene therapy for the rare genetic disorder glycogen storage disease type Ia (GSDIa), which will now head to market with the brand name Genglycos.
The accelerated approval specifically covers the gene therapy—previously coded DTX401—in adults and kids over the age of 8 years with GSDIa, an ultrarare genetic disorder driven by a deficiency of the enzyme G6PC needed to release glucose from the liver to the bloodstream. The liver is less capable of controlling glucose levels in these patients, leading to potentially life-threatening hypoglycemia episodes and other complications.
By Ultragenyx’s reckoning, there are between 1,500 and 2,500 people living with GSDIa in the U.S. out of an estimated global patient population of 6,000 to 8,000 “within commercially accessible geographies,” the company said in an Aug. 19 release.
The green light marks Ultragenyx’s fifth from the FDA and its first for a gene therapy. The company has also secured a valuable priority review voucher in tandem with its approval.
Just over a year ago, Ultragenyx came up short with another gene therapy contender at the FDA, receiving a rejection on its advanced therapy candidate UX1111 for Sanfilippo syndrome type A, which causes progressive damage to the central nervous system.
In a complete response letter, the FDA requested additional information and improvements tied to manufacturing-related issues and observations gleaned from production facility inspections, Ultragenyx explained at the time.
While Ultragenyx stressed that the core data behind its filing was not in question, the setback came as the FDA’s stance on cell and gene therapies for rare diseases was being tested under controversial leadership installed with the Trump administration’s return to the White House.
Nevertheless, the company pressed forward with its filing and is presently awaiting a Sept. 19 target decision date on UX111 by an FDA whose upper ranks look very different now than they did this time last year.
As for Genglycos, the newly christened therapy proved its merit in Ultragenyx’s late-stage GlucoGene study, which pitted the treatment against placebo over 48-weeks and found that it helped patients reduce daily cornstarch intake when coupled with an appropriate diet.
As a one-time AAV8 gene therapy, Genglycos is designed to deliver a functional G6PC gene to the liver, with the aim of restoring the deficient enzyme needed to release stored glucose and ensure stable blood sugar levels when a person is fasting.
Treating GSDIa calls for “rigorous nutritional management,” requiring an “around-the-clock regimen of raw cornstarch” as an oral glucose replacement therapy, Ultragenyx explained in its approval announcement.
Moreover, glucose control with cornstarch is a “crude” tool at best, per the company, which noted that patients often experience large swings in glucose and spend much of their day with high blood sugar levels to avoid low blood sugar episodes.
“The reduced reliance on cornstarch, experienced by patients in our clinical studies, demonstrates this gene therapy’s ability to establish the normal breakdown of glycogen to produce glucose during fasting or episodes of metabolic stress,” Eric Crombez, M.D., Ultragenyx’s chief medical officer, said in a statement. “This ability to regulate glucose has alleviated the disease burden and has the potential to mitigate the risk of severe or life-threatening hypoglycemia for these patients.”
In Ultragenyx’s phase 3 study, Genglycos helped patients chart a mean 31% reduction from baseline in daily cornstarch intake versus placebo, satisfying the trial’s primary endpoint. In a secondary endpoint, Genglycos was also tied to a mean reduction from baseline of one cornstarch dose per day compared to placebo.
As a follow-up on its accelerated green light, Ultragenyx says it has pledged to furnish the FDA with two years of safety and efficacy data from open-label commercial treatment of 50 patients and 20 control patients via modifications to its current GSDIa disease monitoring program. The company noted that the control arm will be comprised of “patients who sought commercial treatment but cannot be treated with Genglycos due to the presence of anti-AAV8 antibodies.”
Ultragenyx will now face the test of launching its first-ever gene therapy, with a second approval in the field potentially close behind.
That puts the Novato, California-based company on similar footing with Regeneron, which earlier this year ushered in the start of its own gene therapy era with the approval of Otarmeni, cleared under the FDA’s controversial Commissioner's National Priority Voucher program in a genetic form of hearing loss. Regeneron has pledged to give the groundbreaking therapy away for free.
For its part, Ultragenyx did not touch on the price of Genglycos in its initial announcement. The company did, however, note that it will provide access support via its UltraCare program, which now includes specially trained gene therapy guides to assist in navigating the route to treatment.
Ultragenyx added that it will produce the therapy entirely at its gene therapy production facility in Bedford, Massachusetts, which it expects to help further streamline access for U.S. patients.