Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset Ornithine Transcarbamylase (OTC) Deficiency

Phase 1

Completed

Conditions: Ornithine Transcarbamylase (OTC) Deficiency

Interventions: Genetic: scAAV8OTC
Drug: Reactive Corticosteroid Taper Regimen
Drug: Prophylactic Corticosteroid Taper Regimen

Registration Number: NCT02991144

Lead Sponsor: Ultragenyx Pharmaceutical Inc

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

Inclusion Criteria

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
Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L.
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.
On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks.
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

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.
Liver transplant, including hepatocyte cell therapy/transplant.
History of liver disease
Significant hepatic inflammation or cirrhosis
Serum creatinine >2.0 mg/dL.
Participation in another investigational medicine study (including another gene transfer trial) within 3 months of Screening
Pregnant or nursing

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1: DTX301 2.0 × 10^12 GC/kg	Reactive Corticosteroid Taper Regimen	DTX301 (scAAV8OTC) 2.0 × 10\^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 2: DTX301 6.0 × 10^12 GC/kg	Reactive Corticosteroid Taper Regimen	DTX301 (scAAV8OTC) 6.0 × 10\^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 2: DTX301 6.0 × 10^12 GC/kg	scAAV8OTC	DTX301 (scAAV8OTC) 6.0 × 10\^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 1: DTX301 2.0 × 10^12 GC/kg	scAAV8OTC	DTX301 (scAAV8OTC) 2.0 × 10\^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 3: DTX301 1.0 × 10^13 GC/kg	Reactive Corticosteroid Taper Regimen	DTX301 (scAAV8OTC) 1.0 × 10\^13 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 3: DTX301 1.0 × 10^13 GC/kg	scAAV8OTC	DTX301 (scAAV8OTC) 1.0 × 10\^13 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids	scAAV8OTC	A prophylactic corticosteroid taper regimen (oral prednisone \[or prednisolone\], 60 mg tapered over 9 weeks) will be administered before dosing with DTX301 (scAAV8OTC) to prevent or minimize transient vector-induced hepatic effects. DTX301 (scAAV8OTC) 1.0x10\^13 GC/kg administered as a single peripheral IV infusion. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.
Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids	Prophylactic Corticosteroid Taper Regimen	A prophylactic corticosteroid taper regimen (oral prednisone \[or prednisolone\], 60 mg tapered over 9 weeks) will be administered before dosing with DTX301 (scAAV8OTC) to prevent or minimize transient vector-induced hepatic effects. DTX301 (scAAV8OTC) 1.0x10\^13 GC/kg administered as a single peripheral IV infusion. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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).

Trial Locations

Locations (9): Alberta's Children's Hospital
🇨🇦
Calgary, Alberta, Canada
Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
The Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Boston Children's Hospital
🇺🇸
Boston, Massachusetts, United States
University Hospital Cleveland Medical Center/Case Western Reserve University
🇺🇸
Cleveland, Ohio, United States
Hospital Clinico Universitario de Santiago
🇪🇸
Santiago de Compostela, A Coruna, Spain
National Hospital for Neurology & Neurosurgery
🇬🇧
London, London City, United Kingdom
Hospital Universitario de Cruzes
🇪🇸
Barakaldo, Vizcaya, Spain
Queen Elizabeth Hospital
🇬🇧
Birmingham, United Kingdom