Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in Adults With Glycogen Storage Disease Type Ia (GSDIa)

Phase 1

Completed

Brief Summary: The primary objective of the study is to determine the safety of single doses of DTX401, including the incidence of dose-limiting toxicities (DLTs) at each dose level.

Detailed Description: Participants enrolled in the 401GSDIA01 study will be monitored for 52 weeks following DTX401 administration. Participants in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible vector-induced hepatitis following treatment with DTX401. Participants in Cohort 4 will receive prophylactic oral steroid treatment to prevent possible vector-induced hepatitis. After completion of the Week 52 visit or early withdrawal, participants will be offered enrollment into a 4-year extension study.

Recruitment & Eligibility

Inclusion Criteria

Males and females ≥18 years of age
Documented GSDIa with confirmation by molecular testing
Documented history of ≥1 hypoglycemic event with blood glucose <60 mg/dL (<3.33 mmol/L)
Patient's GSDIa disease is stable as evidenced by no hospitalization for severe hypoglycemia during the 4-week period preceding the screening visit

Key

Exclusion Criteria

Anti-AAV8 neutralizing antibody titer ≥1:5
Screening or Baseline (Day 0) blood glucose level <60 mg/dL (<3.33 mmol/L)
Liver transplant, including hepatocyte cell therapy/transplant
Presence of liver adenoma >5 cm in size
Presence of liver adenoma >3 cm and ≤5 cm in size that has a documented annual growth rate of ≥0.5 cm per year
Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN), total bilirubin > 1.5 x ULN, or alkaline phosphatase > 2.5 x ULN

Note additional inclusion/exclusion criteria may apply, per protocol.

Arm && Interventions

Group	Intervention	Description
DTX401 Cohort 1	DTX401	Dose 1 (2.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after alanine aminotransferase \[ALT\] elevation)
DTX401 Cohort 1	steroid regimen	Dose 1 (2.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after alanine aminotransferase \[ALT\] elevation)
DTX401 Cohort 2	DTX401	Dose 2 (6.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)
DTX401 Cohort 2	steroid regimen	Dose 2 (6.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)
DTX401 Cohort 3	DTX401	Dose 2 (6.0 × 10\^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)
DTX401 Cohort 3	steroid regimen	Dose 2 (6.0 × 10\^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)
DTX401 Cohort 4	DTX401	Dose 2 (6.0 × 10\^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)
DTX401 Cohort 4	steroid regimen	Dose 2 (6.0 × 10\^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs)	AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug through the End of Study (EOS)/Early Withdrawal visit (up to Week 52) plus 30 days.	An AE is defined as any untoward medical occurrence, regardless of its causal relationship to study product. An SAE is defined as any event that: results in death; is immediately life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or an important medical event, in the opinion of the investigator. The relationship to study drug was categorized as unrelated, possible, probable or definite. A DLT is defined as any AE/SAE ≥ Grade 3 that is considered by the Investigator and/or Sponsor to be related to DTX401, based on the Nation Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 or later version. Per protocol, SAEs that occurred \> 30 days after EOS or Early withdrawal visit, did not need to be reported unless Investigator considered them related to study product.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Time to First Hypoglycemic Event Over Time	Baseline, Weeks 12, 24, 52	The change from baseline in time (in hours) to first hypoglycemic event (defined as glucose \< 54 mg/dL \[\< 3.0 mmol/L\]) during a controlled fasting challenge at 12, 24, and 52 weeks after IV administration of DTX401. A positive change from baseline is favorable.

Locations (6): Michigan Medicine University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
UCONN Health
🇺🇸
Farmington, Connecticut, United States
UT Health - McGovern Medical School
🇺🇸
Houston, Texas, United States
University Medical Center Groningen
🇳🇱
Groningen, Netherlands
Montreal Children Hospital, McGill University Health Centre
🇨🇦
Montréal, Quebec, Canada
Complejo Hospitalario Universitario de Santiago
🇪🇸
Santiago De Compostela, A Coruna, Spain