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

NCT02991144 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 301OTC012016-001057-40
• Study Type: interventional
• Target: 16
• Locations: 4 countries
• Sites: 9

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.

Conditions

Ornithine Transcarbamylase (OTC) Deficiency

Keywords

Gene Transfer; OTC Deficiency; Urea Cycle Disorder

Outcome Measures

Primary Outcomes (1)

• 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.

  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).

Secondary Outcomes (2)

• 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.

• 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.

Study Arms (4)

Cohort 1: DTX301 2.0 × 10^12 GC/kg

EXPERIMENTAL

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.

Genetic: scAAV8OTC; Drug: Reactive Corticosteroid Taper Regimen

Cohort 2: DTX301 6.0 × 10^12 GC/kg

EXPERIMENTAL

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.

Genetic: scAAV8OTC; Drug: Reactive Corticosteroid Taper Regimen

Cohort 3: DTX301 1.0 × 10^13 GC/kg

EXPERIMENTAL

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.

Genetic: scAAV8OTC; Drug: Reactive Corticosteroid Taper Regimen

Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids

EXPERIMENTAL

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.

Genetic: scAAV8OTC; Drug: Prophylactic Corticosteroid Taper Regimen

Interventions

scAAV8OTC GENETIC

non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Also known as: DTX301

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; Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids

Reactive Corticosteroid Taper Regimen DRUG

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.

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

Prophylactic Corticosteroid Taper Regimen DRUG

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.

Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ultragenyx Pharmaceutical Inc: lead

Study Sites (9)

The Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029-6508, United States

Location

University Hospital Cleveland Medical Center/Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

Alberta's Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

Hospital Clinico Universitario de Santiago

Santiago de Compostela, A Coruna, 15706, Spain

Location

Hospital Universitario de Cruzes

Barakaldo, Vizcaya, 48903, Spain

Location

National Hospital for Neurology & Neurosurgery

London, London City, WC1N 3BG, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

MeSH Terms

Conditions

Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc

medinfo@ultragenyx.com

1-888-756-8657

Study Officials

• Medical Director

  Ultragenyx Pharmaceutical Inc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2016
• First Posted: December 13, 2016
• Study Start: July 31, 2017
• Primary Completion: December 16, 2021
• Study Completion: December 16, 2021
• Last Updated: January 26, 2023
• Results First Posted: December 23, 2022

Record last verified: 2023-01

Locations

CA (1); US (4); GB (2); ES (2)