Rare disease drugmaker Ultragenyx builds case for its gene therapy franchise with fresh trial updates
Focused on combating a smattering of rare diseases with an arsenal of biologics, small molecules, and gene therapies, Ultragenyx Pharmaceutical this week issued some updates on two of its experimental gene therapies as it works on building a franchise for one-time cures.
On Friday, the company unveiled early data on the effect of DTX401, its gene therapy under investigation, in patients with glycogen storage disease type Ia (GSDIa), a disease that affects roughly 6,000 people globally and is characterized by the inability to regulate blood sugar.
Nine patients are enrolled in the open-label Phase I/II trial, which has three cohorts encompassing three patients each. In the first cohort, patients received a smaller dose of DTX401, the second group was given a higher dose, and the third, confirmatory cohort was given the same higher dose, but other amendments were made, including patients receiving a smaller cornstarch dose at the start of the controlled fasting challenge.
In 1984, uncooked cornstarch was found to be the most effective therapy for maintaining suitable blood glucose concentrations — although cornstarch has dramatically improved the quality of life for patients with GSD type I, it has a limited duration of action, according to the NIH.
The three patients in Ultragenyx’s Phase I/II confirmatory cohort showed more rapid reductions in cornstarch requirements compared to the first two cohorts, and across all groups, patients demonstrated meaningful and sustained cornstarch reductions over time and significant increases in time to hypoglycemia.
At week 12, patients in cohort 3 had reduced mean daily cornstarch intake by 57%, compared with 38% in the first cohort and 14% in the second cohort. Four of the six patients in the first two cohorts have now discontinued daytime cornstarch, and one patient has completely discontinued cornstarch.
The company will report longer-term data in the second half of this year, and pending discussions with the FDA, will kick off a late-stage study by the end of 2020 if Covid-19 does not disrupt timelines.
Earlier in the week, the company also provided an update on its other experimental gene therapy, DTX301, which is being primed for use in OTC deficiency, the most common urea cycle disorder caused by a genetic defect in a liver enzyme responsible for ammonia detoxification.
The update comes from another multi-cohort Phase I/II trial. On Wednesday, the company said a third patient in cohort three is a confirmed responder, and additional longer-term data in cohorts 1 and 2 show sustained efficacy of treatment, with responses up to 2 years and 1.5 years, respectively.
In both the OTC and GSD trial, the safety profile of the company’s respective gene therapies appeared to be tolerable. Patients in both trials experienced ALT elevations, but those were resolved with steroid therapy.
But one analyst, Baird’s Madhu Kumar — who drew a comparison with DTX301 and Arcturus Therapeutics’ OTC mRNA drug-in-development — preached caution, suggesting the use of steroids in OTC patients was not necessarily a risk-free proposition.
“While this tapering course of steroids was able to blunt the liver enzyme elevations commonly seen with AAV GT drugs like DTX301, we emphasize that in the context of OTC deficiency particularly, there are potential significant safety risks associated with steroid therapy, in particular, the potential for steroids themselves to trigger hyperammonemic crises,” he wrote in a note. “These crises are triggered by steroids through induction of catabolic metabolism by the drugs which, in the context of a dysfunctional urea cycle as is found in OTC deficient patients, can trigger the accumulation of ammonia.”
Social: Emil Kakkis, Ultragenyx CEO