AAV8 gene therapy DTX401 reduces cornstarch intake by 41% at 48 weeks in patients with glycogen storage disease type Ia
Background
In a phase 3 trial in patients with glycogen storage disease type Ia (GSDIa), daily cornstarch intake in the DTX401 group fell by 41% from baseline at week 48. GSDIa is a genetic disorder caused by pathogenic variants in both alleles of the G6PC gene, resulting in a deficiency of glucose-6-phosphatase. This deficiency severely impairs glucose production through glycogen breakdown and gluconeogenesis. Prolonged fasting can cause severe hypoglycemia, and elevated lactate and triglycerides, as well as liver and kidney complications, may also occur.
Dietary management centers on taking uncooked cornstarch every few hours to provide a steady supply of glucose. This approach is life-sustaining, but overnight dosing and meal management constrain the daily lives and sleep of patients and their families. Incorrect dose adjustments can also lead to hypoglycemia or excessive carbohydrate intake. DTX401 is an adeno-associated virus serotype 8 (AAV8) vector carrying the human G6PC gene. It is designed to deliver the gene to liver cells and restore endogenous glucose production.
Key findings
The phase 3 DTX401-CL301 study was a double-blind, randomized, placebo-controlled trial in patients with GSDIa aged 8 years and older. Participants had no detectable AAV8 antibodies and no history of certain liver diseases or abnormal liver function. The safety analysis included 46 participants: 21 who received DTX401 and 25 who received placebo. The modified intention-to-treat efficacy analysis included 44 participants: 20 in the DTX401 group and 24 in the placebo group. The first 48 weeks were the primary efficacy analysis period. Eligible participants were then switched to the alternative treatment under blinded conditions and followed for another 48 weeks.
At week 48, the least-squares mean percentage reduction from baseline in daily cornstarch intake was 41% in the DTX401 group and 10% in the placebo group. The standard errors were 4.6 and 4.1, respectively, and the between-group difference in reduction was 31 percentage points (p<0.0001). The least-squares mean number of daily doses also fell by 1.1 in the DTX401 group and 0.2 in the placebo group (p=0.0011). Among 33 respondents to baseline interviews, the desired reduction considered meaningful averaged 45%, with a median of 41%. The investigators interpreted these findings as supporting the clinical relevance of reducing treatment burden.
Blood glucose measures should be considered separately. At week 48, the change from baseline in the proportion of continuous glucose monitoring readings below 70 mg/dL was an increase of 3.13 percentage points in the DTX401 group and 0.08 percentage points in the placebo group. The between-group difference was within the prespecified noninferiority margin of 10 percentage points. The change in the proportion of readings in the 70–120 mg/dL range also met the noninferiority criterion. However, superiority over placebo in glycemic control was not established. The between-group difference in time to hypoglycemia during a fasting challenge was also not significant (p=0.590). Among participants who had consumed cornstarch immediately before the challenge, time to hypoglycemia adjusted for the amount consumed was significantly longer in the DTX401 group (p=0.0269).
The group that switched from placebo to DTX401 had a faster and larger reduction in cornstarch intake from weeks 48 to 96 than the initial DTX401 group had from weeks 0 to 48. Because the crossover group used week 48 as its new baseline, this should not be interpreted as a comparison establishing superiority between the groups at the same 96-week time point. Intake continued to decline in the initial treatment group as well.
The investigators considered safety acceptable, but serious events were reported in addition to elevated liver enzymes. Serious adverse events judged by investigators to be related to DTX401 included one case of hyperlactatemia, two infusion reactions, and one case of hypertriglyceridemia. Both infusion reactions led to immediate discontinuation of the infusion and resolved after symptomatic treatment. Two serious cases of adrenal insufficiency, among other events, were also associated with prophylactic prednisolone use. After enhanced monitoring and a slower steroid taper were introduced, no further serious adrenal insufficiency was reported.
Meaning and outlook
These results suggest that DTX401 may reduce the recurring dietary management burden of GSDIa by lowering both the amount and frequency of cornstarch intake. However, the similarity between participants’ desired reductions and the observed effect does not confirm an improvement in quality of life. At week 48, the between-group difference in patient global impression of change was not statistically significant.
A 41% reduction in cornstarch intake does not mean that dietary therapy can be stopped or that GSDIa has been cured. This was a small trial that enrolled participants selected according to specific antibody and liver-disease criteria. After week 48, eligible participants in the placebo group also received DTX401, making long-term placebo-controlled comparisons difficult. The durability of the effect and its impact on liver and kidney complications remain subjects for further follow-up. Ultragenyx funded the study and was responsible for its design, conduct, analysis, and reporting.
The study design and results are described in the full article in the Journal of Inherited Metabolic Disease.
Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening inherited carbohydrate metabolism disorder caused by biallelic pathogenic G6PC gene variants resulting in deficiency of glucose-6-phosphatase. DTX401 is an investigational AAV8 vector containing the human G6PC gene. DTX401-CL301 is a pivotal, phase 3, double-blind, randomized, placebo-controlled trial of DTX401 in patients ≥ 8 years with GSDIa. The primary endpoint was percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 versus placebo group. Participants were randomly assigned (1:1) to blinded DTX401 or placebo. After the 48-week Primary Efficacy Analysis Period (PEAP), participants crossed over in a blinded manner for an additional 48-week blinded Crossover Period. Following randomization: 21 participants received DTX401; 25 received placebo. At Week 48, DTX401 treatment resulted in a statistically significant least squares (LS) mean (SE) daily cornstarch intake reduction of 41% (4.6) versus 10% (4.1) for Placebo (p < 0.0001). Clinical meaningfulness was evidenced by a mean desired percent reduction in daily cornstarch intake among those reporting in Baseline interviews (n = 33) of 45% (median = 41%). Greater and faster reductions in cornstarch were observed at Week 96 for the Crossover DTX401 group compared with the DTX401 group in the PEAP. The DTX401 safety profile was acceptable, and expected hepatic reactions consisting of transaminase elevations were managed with prophylactic corticosteroids. Treatment with DTX401 resulted in both a statistically significant and clinically meaningful reduction in cornstarch intake in the 48-week PEAP versus placebo, with greater cornstarch reductions in both groups at Week 96.
DTX401’s practical value depends both on how much it reduces cornstarch intake and on whether it can lessen dosing burden while blood glucose and metabolic status are managed. Among participants who took cornstarch overnight at baseline and had week 48 assessment data, at least one overnight dose was eliminated in 7 of 14 participants in the DTX401 group and 1 of 14 in the placebo group. This suggests that the burden of waking during the night to take cornstarch may lessen, but it does not mean that all patients stopped overnight dosing. In the trial, clinicians reviewed self-monitored blood glucose and continuous glucose monitoring data when adjusting cornstarch prescriptions, and participants were blinded to their continuous glucose monitoring results through week 96. In clinical practice, these findings call for a multidisciplinary approach that monitors nutrition, blood glucose, triglycerides, liver enzymes, and steroid-related risks together; they should not be interpreted as a basis for patients to reduce cornstarch on their own.