Ultragenyx Reports Positive Data from Phase 1/2 Study of Gene Therapy for Severe Glycogen Storage Disease

Rare Daily Staff

Ultragenyx Pharmaceutical reported positive initial data from the confirmatory third cohort and longer-term data from the first two cohorts of the ongoing phase 1/2 study of DTX401, an adeno-associated virus based gene therapy for the treatment of glycogen storage disease type Ia, with all three patients in Cohort 3 responding to therapy and demonstrating more rapid reductions in cornstarch requirements compared to the first two cohorts.

The news comes one day after the rare disease-focused biotech reported positive data from a phase 1/2 trial of another gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency.

Glycogen storage disease type Ia (GSDIa) is the most severe genetically inherited glycogen storage disease. It is caused by a defective gene for the enzyme G6Pase-α, resulting in the inability to regulate blood sugar. Hypoglycemia in patients with GSDIa can be life-threatening, while the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially death in infancy or childhood. There are no approved pharmacologic therapies. GSDIa affects about 6,000 people worldwide.

Ultragenyx’ open-label, multicenter phase 1/2 study is evaluating the safety, tolerability and therapeutic response of DTX401 in adults with GSDIa. DTX401 is an AAV8 gene therapy expressing the glucose-6-phosphatase gene (G6Pase-α) under control of the native promoter that has been shown in preclinical studies to improve G6Pase-α activity and reduce hepatic glycogen levels.

In the first cohort, three patients received a single 2.0 × 10^12 GC/kg dose of DTX401. In the second cohort, three patients each received a single 6.0 × 10^12 GC/kg dose of DTX401. In the confirmatory cohort, three patients received the same dose of DTX401 as in Cohort 2, but modifications were made to the protocol that included: reduction of cornstarch dose at the start of the controlled fasting challenge (decreased from 35 g to 5 g); use of continuous glucose monitoring; and implementation of an optimized reactive steroid regimen. Key efficacy assessments include time to hypoglycemia (defined as glucose <60 mg/dL or onset of clinical symptoms) during a controlled in-hospital fasting challenge, cornstarch reduction, impact on biomarkers such as lactic acid, and measurement of glycogen storage in liver by MRI.

“In the confirmatory third cohort, continuous glucose monitoring showed early transgene expression and enabled faster and more accurate reductions in cornstarch compared with prior cohorts,” said Eric Crombez, chief medical officer of the Ultragenyx Gene Therapy development unit.

All cohorts, comprising nine patients, demonstrated meaningful and sustained cornstarch reductions over time and significant increases in time to hypoglycemia. Data from the phase 1/2 study were presented at the American Society of Gene & Cell Therapy virtual meeting.

“The third cohort of patients is experiencing more rapid improvement with fasting and tolerating quicker reduction in their cornstarch therapy when compared with the prior cohorts,” said David Weinstein, professor and director of the glycogen storage disease program at Connecticut Children’s Medical Center and UConn Health. “Most importantly, the benefits seen for patients are being maintained, and the majority of treated patients are now off of cornstarch therapy during the day after one year of treatment. In 26 years of caring for people with GSD, I have never seen this before, and the community is excited for the phase 3 trial to commence.”

In Cohort 3, continuous glucose monitoring data showed early transgene expression within days of dosing with DTX401. This was demonstrated by prolonged periods of hyperglycemia, which is consistent with glucose being released from the liver and transgene expression. Continuous glucose monitoring also enabled more rapid reduction of cornstarch intake following observations of hyperglycemia at home, which minimized the insulin response and provided more metabolic stability for patients. At Week 12, patients in Cohort 3 had reduced mean daily cornstarch intake by 57 percent, compared with 38 percent in the first cohort and 14 percent in the second cohort.

Patients in Cohort 1 and 2 continue to decrease cornstarch with a mean 73 percent reduction as of the data cutoff of April 23, 2020, demonstrating durable responses over time. Four of the six patients in the first two cohorts have now discontinued daytime cornstarch, and one patient has completely discontinued cornstarch.

Patients in Cohort 3 received an optimized reactive steroid regimen as soon as alanine aminotransferase (ALT) levels began to rise above baseline, at approximately week 4 for all three patients in the cohort. This earlier steroid use was more effective at mitigating elevations in ALT, and could further enhance the level and consistency of expression that has been demonstrated.

By decreasing the cornstarch at the beginning of the controlled fasting challenge, the mean baseline time to hypoglycemia decreased from 4.5 hours in Cohorts 1 and 2, to 2.3 hours in Cohort 3, with two patients in Cohort 3 under 2 hours. At week 12, all patients in Cohort 3 demonstrated meaningful increases in time to hypoglycemia.

Due to the COVID-19 pandemic, only week 12 controlled fasting challenges have been conducted to date for Cohort 3, as patients were not able to complete the week 24 in-hospital fasting challenges.  It will be important to monitor these patients as they adapt to their lower cornstarch regimen to continue to assess their glucose metabolism.

As of the cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported.

Ultragenyx will continue to collect longer-term data from the phase 1/2 study, which is expected to be available in the second half of 2020, barring further significant delays related to COVID-19. The company also intends to hold an end-of-phase 2 meeting with the U.S. Food and Drug Administration in the second half of 2020. The phase 3 study could begin by the end of this year, depending on whether there are any COVID-19 related delays.

DTX401 has been granted Orphan Drug designation in both the United States and Europe, and Regenerative Medicine Advanced Therapy (RMAT) designation and Fast Track designation in the United States.

Photo: Eric Crombez, chief medical officer of the Ultragenyx Gene Therapy development unit