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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Glucose-6- Phosphatase (G6Pase) in Adults With Glycogen Storage Disease Type Ia (GSDIa)

Conditions
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GSD1

Intervention / Treatment
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* Genetic: DTX401
* Drug: steroid regimen


Participation Criteria
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Eligibility Criteria
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Key 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DTX401 Cohort 1<br>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) | Genetic: DTX401<br>* DTX401 administered as a single peripheral intravenous (IV) infusion<br>* Other names: Pariglasgene brecaparvovec;Drug: steroid regimen<br>* prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation<br>|
| Experimental: DTX401 Cohort 2<br>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) | Genetic: DTX401<br>* DTX401 administered as a single peripheral intravenous (IV) infusion<br>* Other names: Pariglasgene brecaparvovec;Drug: steroid regimen<br>* prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation<br>|
| Experimental: DTX401 Cohort 3<br>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) | Genetic: DTX401<br>* DTX401 administered as a single peripheral intravenous (IV) infusion<br>* Other names: Pariglasgene brecaparvovec;Drug: steroid regimen<br>* prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation<br>|
| Experimental: DTX401 Cohort 4<br>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) | Genetic: DTX401<br>* DTX401 administered as a single peripheral intravenous (IV) infusion<br>* Other names: Pariglasgene brecaparvovec;Drug: steroid regimen<br>* prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Time to First Hypoglycemic Event Over Time | 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. | Baseline, Weeks 12, 24, 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AAV, glycogen storage disorder Ia, gene therapy, von Gierke disease, glucose metabolism disorder