GSD1
Conditions
Keywords
glycogen storage disorder Ia, AAV, gene therapy, von Gierke disease, glucose metabolism disorder
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.
Interventions
GENETICDTX401
DTX401 administered as a single peripheral intravenous (IV) infusion
DRUGsteroid regimen
prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation
Sponsors
Ultragenyx Pharmaceutical Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Canada, Netherlands, Spain, United States
Participant flow
Pre-assignment details
Eligible participants were enrolled sequentially into 4 cohorts of 3 participants each and received a single intravenous (IV) infusion of DTX401, with steroids (prednisone/prednisolone) to manage alanine aminotransferase (ALT) elevation.
Participants by arm
| Arm | Count |
|---|---|
| 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 ALT elevation) | 3 |
| 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) | 3 |
| 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) | 3 |
| 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) | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | DTX401 Cohort 1 | DTX401 Cohort 2 | DTX401 Cohort 3 | DTX401 Cohort 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 15.3 | 29.7 years STANDARD_DEVIATION 10.1 | 26.0 years STANDARD_DEVIATION 13.9 | 25.0 years STANDARD_DEVIATION 5.2 | 31.5 years STANDARD_DEVIATION 13.2 |
| Controlled Fasting Challenge: Time to First Hypoglycemic Event | 4.4 hours STANDARD_DEVIATION 0.9 | 4.5 hours STANDARD_DEVIATION 1.4 | 2.3 hours STANDARD_DEVIATION 1.2 | 2.5 hours STANDARD_DEVIATION 0.9 | 3.4 hours STANDARD_DEVIATION 1.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 12 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 12 / 12 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 1 / 3 | 0 / 3 | 4 / 12 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Related TEAE | 3 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any TEAE | 3 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any AE prior to dosing | 1 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious related TEAE | 0 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious TEAE | 2 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to death | 0 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to study discontinuation | 0 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Grade 3 or 4 TEAE | 0 Participants |
| DTX401 Cohort 1 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Dose-limiting toxicity | 0 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any TEAE | 3 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to study discontinuation | 0 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to death | 0 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any AE prior to dosing | 1 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Related TEAE | 3 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious TEAE | 1 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious related TEAE | 0 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Grade 3 or 4 TEAE | 0 Participants |
| DTX401 Cohort 2 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Dose-limiting toxicity | 0 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious related TEAE | 0 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Related TEAE | 3 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to death | 0 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Dose-limiting toxicity | 0 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Grade 3 or 4 TEAE | 1 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any TEAE | 3 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious TEAE | 1 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any AE prior to dosing | 2 Participants |
| DTX401 Cohort 3 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to study discontinuation | 0 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to death | 0 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any AE prior to dosing | 2 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Any TEAE | 3 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Related TEAE | 3 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious related TEAE | 0 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Grade 3 or 4 TEAE | 0 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Dose-limiting toxicity | 0 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | TEAE leading to study discontinuation | 0 Participants |
| DTX401 Cohort 4 | Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) | Serious TEAE | 0 Participants |
Secondary
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.
Time frame: Baseline, Weeks 12, 24, 52
Population: Participants with an assessment at given time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTX401 Cohort 1 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 52 | 4.2 hours | Standard Deviation 2.2 |
| DTX401 Cohort 1 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 24 | 4.3 hours | Standard Deviation 4.2 |
| DTX401 Cohort 1 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 12 | 3.3 hours | Standard Deviation 2 |
| DTX401 Cohort 2 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 52 | -1.8 hours | Standard Deviation 1.7 |
| DTX401 Cohort 2 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 12 | 1.7 hours | Standard Deviation 0.6 |
| DTX401 Cohort 2 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 24 | 0.5 hours | Standard Deviation 0.6 |
| DTX401 Cohort 3 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 24 | 0.7 hours | Standard Deviation 1.7 |
| DTX401 Cohort 3 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 12 | 1.4 hours | Standard Deviation 0.8 |
| DTX401 Cohort 3 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 52 | -0.6 hours | Standard Deviation 0.1 |
| DTX401 Cohort 4 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 52 | 3.6 hours | Standard Deviation 2.7 |
| DTX401 Cohort 4 | Change From Baseline in Time to First Hypoglycemic Event Over Time | Change at Week 24 | 0.3 hours | — |