Phase 3 Randomized Trial Results of DTX401 AAV Gene Therapy for the Treatment of GSDIa.

Glucose-6-phosphatase deficiency caused by biallelic pathogenic G6PC variants; DTX401 is an AAV8 vector carrying the human G6PC gene.

Glycogen storage disease type Ia is a rare, life-threatening inherited disorder of carbohydrate metabolism caused by biallelic pathogenic G6PC variants leading to glucose-6-phosphatase deficiency. DTX401-CL301 is a pivotal phase 3, double-blind, randomized, placebo-controlled trial in patients aged 8 years and older, with the percent change from baseline to Week 48 in daily cornstarch intake as the primary endpoint. Twenty-one participants received DTX401 and 25 received placebo after 1:1 randomization. At Week 48, the least squares mean reduction in daily cornstarch intake was 41% (SE 4.6) with DTX401 versus 10% (SE 4.1) with placebo (p < 0.0001), against a mean desired reduction of 45% (median 41%) reported by patients themselves at baseline interviews (n = 33). Reductions were greater and faster by Week 96 in the group that received DTX401 after crossover, and the expected hepatic reactions, transaminase elevations, were managed with prophylactic corticosteroids.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is the first positive randomized phase 3 trial of gene therapy in GSDIa, and the fact that the observed reduction (41%) matches what patients themselves said they wanted (45%) gives this surrogate endpoint a credibility it would not have on its own. Cornstarch intake nonetheless measures dietary burden rather than the complications that drive long-term prognosis — hepatic adenomas, renal involvement — and durability of transgene expression beyond 96 weeks is not settled here. Enrolment from age 8 also leaves aside the youngest patients, in whom the dietary treatment burden is heaviest.

Analysis by Dr Thibaut Benquey