Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency

A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients With Late-onset OTC Deficiency

The primary objective is to evaluate the efficacy of DTX301 on the improvement of ornithine transcarbamylase (OTC) function by maintaining safe plasma ammonia levels.

Study Overview

• Status: Active, not recruiting
• Conditions: OTC Deficiency
• Intervention / Treatment: Genetic: DTX301; Other: Placebo; Drug: Oral Corticosteroids; Drug: Placebo for oral corticosteroids; Drug: Sodium Acetate

Detailed Description

This study is a Phase 3, randomized, double-blind, placebo-controlled study of DTX301 in patients with late-onset OTC deficiency 12 years of age and older.

Participants will be randomized 1:1 to DTX301 or placebo and followed closely for 36-64 weeks. Between Week 36 and Week 64, eligible participants will cross over and receive DTX301 if they had previously received placebo, and some who received DTX301 may receive placebo.

The planned study duration is up to 324 weeks. Upon completion of this study or early withdrawal, all participants who received DTX301 are invited to enroll in the Disease Monitoring Program (DMP) for follow-up for up to an additional 5 years.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1199
    • Hospital Italiano de Buenos Aires
  • Córdoba, Argentina, X5004
    • Clinica Universitaria Reina Fabiola
• Brazil
  • Porto Alegre, Brazil, 90035-903
    • Hospital De Clinicas De Porto Alegre
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• France
  • Bron, France, 69500
    • Hôpital Femme Mère Enfant
  • Paris, France, 75015
    • Necker-Enfants Maladas Hospital
• Germany
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg
• Japan
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Toyoake, Japan, 470-1192
    • Fujita Health University Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015
    • Erasmus Universitair Medisch Centrum Rotterrdam
• Portugal
  • Porto, Portugal, 4200-319
    • Centro Hospitalar Universitario de Sao Joao
• Spain
  • Barcelona, Spain, 08035
    • Fundacio Hospital Universitari Vall D'Hebron-Institute de Recerca
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation by enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis)
• Free from symptomatic hyperammonemia and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline
• If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening
• If on a protein-restricted diet, must be on a stable total daily protein intake that does not vary more than 20% for ≥ 4 weeks prior to screening
• From the time written informed consent through Visit 28, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not father a child or donate sperm

Key Exclusion Criteria:

• Significant hepatic inflammation or cirrhosis
• Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the 2021 CKD-EPI creatinine-based formula (Inker et al., 2021) for patients ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients < 18 years of age
• Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity
• Active infection (viral or bacterial)
• Detectable pre-existing antibodies to the AAV8 capsid
• Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
• Participation (current or previous) in another gene transfer study

Note: Additional inclusion/exclusion criteria may apply, per protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DTX301; Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may receive single peripheral IV infusion of placebo.	Genetic: DTX301; non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector; Other Names: avalotcagene ontaparvovec; Other: Placebo; normal saline infusion; Drug: Oral Corticosteroids; Participants who receive DTX301 solution will receive oral corticosteroids.; Other Names: Prednisolone; Drug: Placebo for oral corticosteroids; Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind; Drug: Sodium Acetate; A tracer for the Ureagenesis Rate Test (URT)
Experimental: Placebo, Then DTX301; Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.	Genetic: DTX301; non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector; Other Names: avalotcagene ontaparvovec; Other: Placebo; normal saline infusion; Drug: Oral Corticosteroids; Participants who receive DTX301 solution will receive oral corticosteroids.; Other Names: Prednisolone; Drug: Placebo for oral corticosteroids; Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind; Drug: Sodium Acetate; A tracer for the Ureagenesis Rate Test (URT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Plasma Ammonia as Measured by 24-Hour Ammonia (AUC0-24)	Week 36
Complete Responder Rate at the Final Study Visit After DTX301 Exposure	Up to 64 Weeks Post DTX301 Infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Anti-OTC Antibodies		Up to Week 324
Percentage of Complete Responders or Responders After DTX301 Exposure		Up to 64 Weeks Post DTX301 Infusion
Annualized Event Rate of Hyperammonemic Crises (HACs) Pre-DTX301 Exposure vs Post-DTX301 Exposure		Pre-enrollment, Baseline, Up to 64 Weeks Post DTX301 Infusion
Annualized Event Rate of Interim Clinical Events (ICEs) Pre-DTX301 Exposure vs Post-DTX301 Exposure		Pre-enrollment, Baseline, Up to 64 Weeks Post DTX301 Infusion
Change from Baseline in Plasma Ammonia (AUC0-24)		Baseline, Up to Week 36
Change in Plasma Ammonia (AUC0-24) After DTX301 Exposure		Up to 64 Weeks Post DTX301 Infusion
Percentage of Participants Who Have Achieved Complete Management Response (CMR) or Management Response (MR) After DTX301 Exposure		Up to 64 Weeks Post DTX301 Infusion
Change in Baseline Disease Management (Dietary Protein and Total Scavenger Medication Use) With Plasma Ammonia (AUC0-24)		Up to 64 Weeks Post DTX301 Infusion
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs, Related Serious TEAEs and Adverse Events of Special Interest (AESIs)		Up to Week 324
Long-Term Durability of Response	Based Upon Number of Complete Responders or Responders That Have ≥ 2 Consecutive Visits as a Complete Responder or Responder and Do Not Return to a Lower Responder Status for > 1 Consecutive Visit	Up to 64 Weeks Post DTX301 Infusion
Change in Plasma Ammonia (AUC0-24) for Participants Who Have an Elevated Ammonia AUC0-24 at Baseline		Baseline, Up to 64 Weeks Post DTX301 Infusion

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc
• Investigators: Study Director: Medical Director, Ultragenyx Pharmaceutical Inc

Publications and helpful links

General Publications

• Baruteau J, Brunetti-Pierri N, Gissen P. Liver-directed gene therapy for inherited metabolic diseases. J Inherit Metab Dis. 2024 Jan;47(1):9-21. doi: 10.1002/jimd.12709. Epub 2024 Jan 3.

Helpful Links

• Ultragenyx Patient Advocacy/OTC Disease Information
• Ultragenyx Transparency Commitment

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2022
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: April 18, 2022
• First Submitted That Met QC Criteria: April 22, 2022
• First Posted (Actual): April 25, 2022

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Genetic Diseases, X-Linked; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Ornithine Carbamoyltransferase Deficiency Disease; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Acids, Acyclic; Carboxylic Acids; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienetriols; Acetates; Acetic Acid; Prednisolone; Adrenal Cortex Hormones; Sodium Acetate
• Other Study ID Numbers: DTX301-CL301; 2020-003384-25 (EudraCT Number); 2024-514337-38-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No