Gene Therapy Improves Quality of Life in Patients With Glycogen Storage Disease Type 1a


All evaluable patients had significant reductions in daily cornstarch intake at 1 year and at last visit during long-term follow-up.

DTX401, an investigational adeno-associated virus serotype 8 (AAV8) vector gene therapy expressing the human G6PC gene, showed a positive efficacy and safety profile in all patients with glycogen storage disease type 1a (GSD1a) treated in a phase 1/2 clinical trial (NCT03517085) at 1 year.

Data from the trial were presented in a clinical trial symposium at the the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, by investigator Andrew Grimm, MD, PhD, vice president, global clinical development for metabolic diseases, Ultragenyx.

“GSD1a is a life-threatening metabolic disease caused by deficiency in gluco-6-phosphatase. This is the enzyme that catalyzes thelast step in gluconeogenesis and glycogenolysis. Sopatients are not able to produce glucose endogenously to maintain normal blood sugar levels when they're in a catabolic state,” Grimm said. “To keep these patients alive, they need a continuous source of exogenous glucose 24/7... Despite very strict rigorous nutritional management, they continue to have glycogen accumulationin their liver and kidneys, and this can lead to liver damage. They are at high risk of developing hepatocellular adenoma, which can progress to carcinoma; renal injury; proteinuria... Obesity is a problem, and metabolic micronutrient deficiencies is an issue.”

The open-label, dose-escalation trial evaluated 12 adults (age range, 18-57; mean, 30) with GSD1a treated with a single intravenous infusion of DTX401 for 52 weeks. Cornstarch regimens consisted of around 5 to 7 doses per day and around 300 g per day.

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Patients received either 2.0 x 1012 gc/kg (n = 3; cohort 1) or 6.0 x 1012 GC/kg (n = 9; 3 patients each in cohorts 2, 3, and 4). Cohorts 1 through 3 received reactive steroids whereas cohort 4 received prophylactic steroids. All participants are now enrolled in a long-term follow-up study (NCT03970278) and data reported had a cutoff date of March 10, 2023.

The study primarily assessed time to hypoglycemia (TTH) via a controlled fasting challenge, average cornstarch dose and frequency, percentage of time in euglycemia via continuous glucose monitoring (CGM) in cohorts 3 and 4, and corticosteroid therapy.

Investigators found that 11 evaluable patients had a mean 70.0% reduction (standard deviation [SD], 23.1; range, 28-100; P <.0001) in total daily cornstarch intake from baseline to week 52. At the last available timepoint in the follow-up study, which represents around 4 years posttreatment for cohort 1, all 12 patients had a mean total daily cornstarch intake reduction of 66.3% (SD, 22.0; P <.0001) from baseline. As of the last visit, 5 participants had reduced dose frequency by half and received less than 3 doses a day. CGM analysis in cohorts 3 and 4 revealed that time in euglycemia remained stable or improved while reducing cornstarch dose frequency. TTH tests showed a mean 1.5-hour (SD, 3.3) change in TTH from baseline at week 52 (n = 11) and a 4.7-hour (SD, 3.3) change at the last visit (n = 12).

All patients experienced a treatment-emergent adverse event (AE) and a related TEAE, which included 3 patients each experiencing hypertriglyceridemia, hyperglycemia and headache. There were 4 casesof related proteinuria (2 resolved, 2 ongoing). All patients had related transaminase elevations which resolved with prednisone. There were no infusion-related or treatment-related serious AEs. Of the 29 reported, unrelated serious AEs, all have resolved excepting one continuing case of grade 4 gastroenteritis that started on day 847.

“We have not completely restored G6P activity to normal levels, and patients still need some degree of metabolic support, but our hope is that with the activity that we’re providing these patients, they will have a buffer that puts them at lower risk for severe hypoglycemia in the settings of acute illness when they're unable to take oral intake,” Grimm said.

Quality of life tests saw improvements with total calories from cornstarch decreasing as diets were able to become more balanced and a 4.1% reduction (range, -11.8 to 2.8) in body weight at week 52 and a 2.5% reduction (range, -13.2 to 10.8) at last visit. Two-thirds of patients (n = 9) felt that their disease was moderately or much improved since study start on Patient Global Impression of Change (PGIC) assessments. PGIC scores were found to be highly correlated to cornstarch reductions (R2, 0.55; Spearman rank correlation coefficient, -0.77), showing that cornstarch reduction is a clinically meaningful benefit in these patients. Positive reports from exit interviews included having more energy and stamina, better mental clarity, improved glycemic control independent from cornstarch, imrpoved sleep quality, and quality of life improvements.

Grimm quoted a patient treated with DTX401 that said “the other day I went to the gym for the first time and I didn’t... bring a snack. I cried because that was my first time I was able to go do something without having to snack before.”

Grimm concluded his presentation by noting that the phase 3, double-blind, randomized, placebo-controlled trial of DTX401 (NCT05139316) is now fully enrolled and results from the trial are expected in the first half of 2024.

Riba-Wolman R, Rodriguez-Buritica DF, Ahmad A, et al. Efficacy and safety at week 52 and up to four years in adults with glycogen storage disease type IA (GSDIa): Results from a phase 1/2 clinical trial and long-term follow-up study of DTX401, an AAV8-mediated, liver-directed gene therapy. Presented at: ASGCT 2023 Annual Meeting; May 16-20; Los Angeles, California. Abstract #4
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