Monday, July 15, 2024

Glycogen Storage Disease: Ultragenyx Announces Positive Phase 3 Results for DTX401 Gene Therapy

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Ultragenyx Pharmaceutical Inc. announced positive topline results from the Phase 3 GlucoGene study (NCT05139316) evaluating DTX401, an investigational gene therapy for patients aged eight years and older with glycogen storage disease type Ia (GSDIa). The study achieved its primary endpoint, demonstrating that treatment with DTX401 resulted in a statistically significant and clinically meaningful reduction in daily cornstarch intake compared to placebo at Week 48.

The mean percent reduction was 41.3% in the DTX401 group (n=20) compared to 10.3% in the placebo group (n=24) at Week 48 (p<0.0001). All patients in the treatment group achieved a reduction in cornstarch intake, with 68% achieving a ≥30% reduction and 37% achieving a ≥50% reduction. In comparison, the placebo group achieved these reductions in 13% and 4% of patients, respectively, at Week 48.

“This is an incredible milestone for the glycogen storage disease gene therapy DTX401 program. These clinically important and statistically significant results are consistent with our Phase 1/2 findings and reflect the acquired ability to break down glycogen as a source of endogenous glucose from treated livers,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “We thank the patients, families, and treating community for their participation in this study and their support for the GSDIa community.”

DTX401 Gene Therapy Shows Significant Benefits in Glycogen Storage Disease Phase 3 Study

The study also met key secondary endpoints, including a reduction in the number of cornstarch doses per day and maintenance of glucose control at Week 48. The mean reduction in cornstarch doses per day was 1.1 in the DTX401 group compared to 0.2 in the placebo group (p=0.0011). Patients in the DTX401 group also showed significant improvement in nighttime cornstarch dosing frequency and quantity compared to the placebo group. The study established non-inferiority (p<0.0001) of glucose control between the groups while significantly reducing daily cornstarch intake in the treatment group.

The Patient Global Impression of Change (PGIC) at Week 48 showed a median score of 2.0 (moderately improved) for the glycogen storage disease gene therapy DTX401 group and 1.0 (minimally improved) for the placebo group (p=0.132). A ≥30% reduction in total daily cornstarch intake correlated with moderately or higher improved PGIC scores, indicating this as a clinically meaningful threshold for patients.

“With these Phase 3 results, the significant reduction in cornstarch intake while maintaining glucose control offers meaningful benefits to patients, improving their quality of life,” stated Rebecca Riba-Wolman, M.D., director of the Glycogen Storage Disease Program & Disorders of Hypoglycemia at Connecticut Children’s Medical Center/University of Connecticut Medical School and study investigator. “GSDIa is a relentless disease, requiring constant vigilance to avoid severe low blood sugar and acidosis. A treatment that alleviates these daily concerns without significant risks is essential.”

Glycogen Storage Disease

Ultragenyx Reports Positive Safety and Efficacy for DTX401 in Glycogen Storage Disease

The study demonstrated an acceptable safety profile for DTX401, consistent with Phase 1/2 results. Anticipated vector-induced hepatic effects were manageable with a prophylactic corticosteroid regimen, and no AAV8 class effects of dorsal root ganglion toxicity or thrombotic microangiopathy were observed through Week 48. Full 48-week data from the Phase 3 study will be presented at a scientific conference later this year. These results will be discussed with regulatory authorities to support a marketing application in 2025.

Ultragenyx recently presented long-term Phase 1/2 data for glycogen storage disease gene therapy DTX401 at the American Society of Gene and Cell Therapy 2024, demonstrating durable response and sustained reductions in cornstarch intake lasting up to five years. All 12 patients in the study have been followed for an average of four years, showing a mean total daily reduction of 72% (p<0.0001) from baseline to the last available time point.

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Ultragenyx’s DTX401 Gene Therapy for Glycogen Storage Disease Shows Promising Results in 48-Week Study

The 48-week randomized, double-blind, placebo-controlled study treated 46 patients aged eight years and older with DTX401 (1.0 x 10^13 GC/kg dose measured by ddPCR) or placebo. There were 44 patients in the modified intention-to-treat (mITT) population with efficacy data within the Week 48 analysis period following treatment with glycogen storage disease gene therapy DTX401 (n=20) or placebo (n=24). At Week 48, eligible patients crossed over and received the alternate treatment. After crossover, patients will be followed for an additional 96 weeks. Post-study completion, patients will be offered enrollment into a Disease Monitoring Program (DMP) for at least 10 years post-DTX401 infusion.

DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-α under the control of the native promoter, allowing treated liver cells to manage glucose. Administered as a single intravenous infusion, glycogen storage disease gene therapy DTX401 has shown improved G6Pase-α activity and reduced hepatic glycogen levels in preclinical studies. DTX401 has received orphan drug designation, regenerative medicine advanced therapy (RMAT) designation, and Fast Track designation from the U.S. FDA, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency.


Resource: Ultragenyx Pharmaceutical, May 30, 2024

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