Ornithine Transcarbamylase (OTC) Deficiency
Conditions
Keywords
Gene Transfer, OTC Deficiency, Urea Cycle Disorder
Brief summary
This is a Phase 1/2, open-label, single arm, multicenter, safety and dose finding study of DTX301 in adults with late-onset OTC deficiency. The primary objective of the study is to determine the safety of single intravenous (IV) doses of DTX301.
Detailed description
Eligible participants will receive a single IV infusion of DTX301. Dose escalation will be conducted according to a model that uses the collected data to predict the safety profile of the dose in order to determine the optimal biological dose (OBD). The decision to proceed to the next dose cohort will be made after the data monitoring committee (DMC) has evaluated the safety data for all participants in a dosing cohort. Participants will be followed for 52 weeks after dosing. After completion of this study, participants will be asked to enroll in a 4-year extension study to evaluate the long term (a total of 5 years) safety and efficacy of DTX301. This study was previously posted by Dimension Therapeutics, which has been acquired by Ultragenyx.
Interventions
GENETICscAAV8OTC
non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)
DRUGReactive Corticosteroid Taper Regimen
Oral prednisone \[or oral prednisolone\] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels. Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.
DRUGProphylactic Corticosteroid Taper Regimen
Oral prednisone \[or oral prednisolone\] 60 mg/day at least 5 days prior to DTX301 administration, tapered over 9 weeks. A prophylactic corticosteroid taper regimen will be administered to prevent or minimize transient vector-induced hepatic effects.
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: 1. Males and females ≥18 years of age with documented diagnosis of late onset (defined as first manifestation of signs and symptoms at ≥1 month of age) OTC deficiency, confirmed via enzymatic, biochemical, or molecular testing 2. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L. 3. Subject's OTC deficiency is stable as evidenced by either a) no clinical symptoms of hyperammonemia OR b) an ammonia level \<100 µmol/L within the 4 week period preceding the Screening visit. 4. On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks. 5. Males and all females of childbearing potential must be willing to use effective contraception at the time of administration of gene transfer and for the 52 weeks following administration of DTX301 Key
Exclusion criteria
1. At Screening or Baseline (Day 0), plasma ammonia level ≥ 100 μmol/L for patients who historically maintain normal ammonia levels; OR plasma ammonia level ≥ 200 μmol/L for patients who historically are not able to fully control ammonia levels with baseline management; OR signs and symptoms of hyperammonemia. 2. Liver transplant, including hepatocyte cell therapy/transplant. 3. History of liver disease 4. Significant hepatic inflammation or cirrhosis 5. Serum creatinine \>2.0 mg/dL. 6. Participation in another investigational medicine study (including another gene transfer trial) within 3 months of Screening 7. Pregnant or nursing Note additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug up to End of Study (Week 52). | AE: any untoward medical occurrence regardless of its causal relationship to study product. TEAE: any event not present before exposure to study product or any event already present that worsens in either intensity or frequency after exposure to study product. SAE: 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; is an important medical event, according to the investigator. AE intensity was rated as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life threatening), or 5 (death) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The relationship or association of the study product in causing or contributing to the AE was characterized as: unrelated; possible; probably; definite. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Over Time in Rate of Ureagenesis | Baseline (Day 0), Weeks 6, 12, 20, 24, End of Study (Week 52). AUC was derived based on the following time points: 0.5, 1, 1.5, 2, 3, and 4 hours postdose. | The change from baseline in the rate of ureagenesis (as measured by the generation of \[13C\]urea over 4 hours) as determined by gas chromatography mass spectrometry over time to 52 weeks after the IV administration of DTX301. Sodium acetate was used as a tracer to measure the rate of ureagenesis. Rate of ureagenesis was derived in the following manner: 1. Derive area under the curve from time zero to 240 minutes (AUC0-240min) of absolute 13C-urea (µmol/l/min) estimated by the linear trapezoidal rule 2. Derive percent of normal AUC0-240min of absolute 13C-urea by dividing AUC0-240min of absolute 13C-urea (µmol\*min/L) by 669.56 µmol\*min/L (i.e. the AUC0-240min of absolute 13C-urea for an adult control) 3. Derive rate of ureagenesis by multiplying % of normal AUC0-240min of absolute 13C-urea by 300 µmol\*h/kg (i.e. the approximate rate of ureagenesis in healthy adults). |
| Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Baseline (Day 0), Weeks 6, 12, 24, End of Study (Week 52). AUC was derived based on predose (time 0) and approximately 2, 4, 8, 12, 16, 20, 24 hours (±5 minutes) postdose. | — |
Countries
Canada, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 27 subjects were screened for the study, 16 of whom were enrolled. Of the 16 participants enrolled, 5 participants discontinued the study before receiving DTX301, and were not assigned to a treatment arm.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: DTX301 2.0 × 10^12 GC/kg DTX301 (scAAV8OTC) 2.0 × 10\^12 GC/kg administered as a single peripheral IV infusion. | 3 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg DTX301 (scAAV8OTC) 6.0 × 10\^12 GC/kg administered as a single peripheral IV infusion. | 3 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg DTX301 (scAAV8OTC) 1.0 × 10\^13 GC/kg administered as a single peripheral IV infusion. | 3 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids Oral prednisone (or prednisolone), 60 mg tapered over 9 weeks, initiated before dosing with DTX301 (scAAV8OTC) and administered through Week 4. DTX301 (scAAV8OTC) 1.0x10\^13 GC/kg administered as a single peripheral IV infusion. | 2 |
| Total | 11 |
Baseline characteristics
| Characteristic | Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Total | Cohort 1: DTX301 2.0 × 10^12 GC/kg | Cohort 2: DTX301 6.0 × 10^12 GC/kg | Cohort 3: DTX301 1.0 × 10^13 GC/kg |
|---|---|---|---|---|---|
| Age, Continuous | 30.5 years STANDARD_DEVIATION 13.44 | 29.2 years STANDARD_DEVIATION 7.67 | 32.3 years STANDARD_DEVIATION 11.06 | 27.7 years STANDARD_DEVIATION 1.15 | 26.7 years STANDARD_DEVIATION 7.09 |
| Area Under the Curve From Time Zero to 24 Hours (AUC0 24) of Plasma Ammonia | 1834.39 μmol*h/L STANDARD_DEVIATION 1091.019 | 2230.01 μmol*h/L STANDARD_DEVIATION 1370.847 | 1831.78 μmol*h/L STANDARD_DEVIATION 1445.24 | 2153.74 μmol*h/L STANDARD_DEVIATION 1406.173 | 4444.76 μmol*h/L |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 10 Participants | 3 Participants | 2 Participants | 3 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 | 1 Participants | 1 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 | 2 Participants | 10 Participants | 2 Participants | 3 Participants | 3 Participants |
| Rate of Ureagenesis | 174.678 μmol*h/kg STANDARD_DEVIATION 210.914 | 136.791 μmol*h/kg STANDARD_DEVIATION 88.4373 | 166.293 μmol*h/kg STANDARD_DEVIATION 28.0167 | 103.329 μmol*h/kg STANDARD_DEVIATION 76.9798 | 115.492 μmol*h/kg STANDARD_DEVIATION 71.0753 |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 1 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 1 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 / 2 | 2 / 16 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 2 / 2 | 11 / 11 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 2 | 1 / 11 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation
AE: any untoward medical occurrence regardless of its causal relationship to study product. TEAE: any event not present before exposure to study product or any event already present that worsens in either intensity or frequency after exposure to study product. SAE: 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; is an important medical event, according to the investigator. AE intensity was rated as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life threatening), or 5 (death) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The relationship or association of the study product in causing or contributing to the AE was characterized as: unrelated; possible; probably; definite.
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 up to End of Study (Week 52).
Population: Safety Set: all participants who received DTX301.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE | 2 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related serious TEAE | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE related to corticosteroid regimen | 1 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any hyperammonemic crisis-related TEAE | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE with grade >=3 | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE | 3 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any serious TEAE | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any adverse event leading to death | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE leading to study discontinuation | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE with grade >=3 | 0 Participants |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any AE prior to dosing | 1 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any AE prior to dosing | 1 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE | 1 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE | 3 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any adverse event leading to death | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE related to corticosteroid regimen | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related serious TEAE | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any hyperammonemic crisis-related TEAE | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE leading to study discontinuation | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE with grade >=3 | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE with grade >=3 | 0 Participants |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any serious TEAE | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related serious TEAE | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE with grade >=3 | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE with grade >=3 | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any AE prior to dosing | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE | 3 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any serious TEAE | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE | 3 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE related to corticosteroid regimen | 1 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any hyperammonemic crisis-related TEAE | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE leading to study discontinuation | 0 Participants |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any adverse event leading to death | 0 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE with grade >=3 | 1 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related serious TEAE | 0 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE with grade >=3 | 0 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any serious TEAE | 1 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE | 2 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any adverse event leading to death | 0 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE leading to study discontinuation | 0 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any study drug-related TEAE | 2 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any TEAE related to corticosteroid regimen | 1 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any AE prior to dosing | 1 Participants |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation | Any hyperammonemic crisis-related TEAE | 1 Participants |
Secondary
Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia
Time frame: Baseline (Day 0), Weeks 6, 12, 24, End of Study (Week 52). AUC was derived based on predose (time 0) and approximately 2, 4, 8, 12, 16, 20, 24 hours (±5 minutes) postdose.
Population: Safety Set: all participants who received DTX301. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 6 | 97.69 μmol*h/L | Standard Deviation 104.381 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at End of Study (Week 52) | -381.54 μmol*h/L | Standard Deviation 1116.898 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 12 | -264.07 μmol*h/L | Standard Deviation 1471.172 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 24 | -252.54 μmol*h/L | Standard Deviation 586.131 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at End of Study (Week 52) | -387.02 μmol*h/L | Standard Deviation 277.086 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 12 | -1384.95 μmol*h/L | Standard Deviation 1279.839 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 24 | -1065.48 μmol*h/L | Standard Deviation 1024.167 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 6 | -1334.27 μmol*h/L | Standard Deviation 1271.205 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 12 | -3827.36 μmol*h/L | — |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at End of Study (Week 52) | -594.76 μmol*h/L | — |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 6 | -3790.83 μmol*h/L | — |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 24 | -3978.51 μmol*h/L | — |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at End of Study (Week 52) | -359.17 μmol*h/L | Standard Deviation 1641.519 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 12 | -1242.69 μmol*h/L | Standard Deviation 931.242 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 6 | -1095.20 μmol*h/L | Standard Deviation 785.719 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia | Change at Week 24 | -1276.25 μmol*h/L | Standard Deviation 943.999 |
Secondary
Change From Baseline Over Time in Rate of Ureagenesis
The change from baseline in the rate of ureagenesis (as measured by the generation of \[13C\]urea over 4 hours) as determined by gas chromatography mass spectrometry over time to 52 weeks after the IV administration of DTX301. Sodium acetate was used as a tracer to measure the rate of ureagenesis. Rate of ureagenesis was derived in the following manner: 1. Derive area under the curve from time zero to 240 minutes (AUC0-240min) of absolute 13C-urea (µmol/l/min) estimated by the linear trapezoidal rule 2. Derive percent of normal AUC0-240min of absolute 13C-urea by dividing AUC0-240min of absolute 13C-urea (µmol\*min/L) by 669.56 µmol\*min/L (i.e. the AUC0-240min of absolute 13C-urea for an adult control) 3. Derive rate of ureagenesis by multiplying % of normal AUC0-240min of absolute 13C-urea by 300 µmol\*h/kg (i.e. the approximate rate of ureagenesis in healthy adults).
Time frame: Baseline (Day 0), Weeks 6, 12, 20, 24, End of Study (Week 52). AUC was derived based on the following time points: 0.5, 1, 1.5, 2, 3, and 4 hours postdose.
Population: Safety Set: all participants who received DTX301.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 6 | 41.139 μmol*h/kg | Standard Deviation 83.3604 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 12 | 2.363 μmol*h/kg | Standard Deviation 51.2516 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 20 | 32.929 μmol*h/kg | Standard Deviation 71.05 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 24 | 42.540 μmol*h/kg | Standard Deviation 136.5861 |
| Cohort 1: DTX301 2.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at End of Study (Week 52) | 109.611 μmol*h/kg | Standard Deviation 171.0689 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at End of Study (Week 52) | 114.446 μmol*h/kg | Standard Deviation 98.8701 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 20 | 77.465 μmol*h/kg | Standard Deviation 67.1567 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 12 | 20.897 μmol*h/kg | Standard Deviation 56.9733 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 24 | 65.513 μmol*h/kg | Standard Deviation 50.5169 |
| Cohort 2: DTX301 6.0 × 10^12 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 6 | 46.857 μmol*h/kg | Standard Deviation 105.9147 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 20 | -0.194 μmol*h/kg | Standard Deviation 112.5922 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 6 | -29.017 μmol*h/kg | Standard Deviation 127.2471 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 12 | 7.544 μmol*h/kg | Standard Deviation 133.1715 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at End of Study (Week 52) | 10.016 μmol*h/kg | Standard Deviation 47.9128 |
| Cohort 3: DTX301 1.0 × 10^13 GC/kg | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 24 | 45.114 μmol*h/kg | Standard Deviation 147.576 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 24 | 63.854 μmol*h/kg | Standard Deviation 106.7694 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 12 | 65.781 μmol*h/kg | Standard Deviation 33.9137 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 6 | 14.586 μmol*h/kg | Standard Deviation 17.3499 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Rate of Ureagenesis | Change at End of Study (Week 52) | 128.023 μmol*h/kg | Standard Deviation 131.6469 |
| Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids | Change From Baseline Over Time in Rate of Ureagenesis | Change at Week 20 | 67.103 μmol*h/kg | Standard Deviation 102.5409 |