Study of UX701 Gene Transfer for the Treatment of Wilson Disease

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Seamless, Adaptive, Safety, Dose-Finding, and Phase 3 Clinical Study of UX701 AAV-Mediated Gene Transfer for the Treatment of Wilson Disease

The primary objectives of this study are to evaluate the safety of single IV doses of UX701 in patients with Wilson disease, to select the UX701 dose with the best benefit/risk profile based on the totality of safety and efficacy data and to evaluate the effect of UX701 on copper regulation.

Study Overview

• Status: Active, not recruiting
• Conditions: Wilson Disease
• Intervention / Treatment: Other: Placebo; Genetic: UX701

Detailed Description

This study is a randomized, double-blind, placebo-controlled, seamless, adaptive Phase 1/2/3 clinical study of UX701 in patients with Wilson disease.

Stage 1 (Phase 1/2) is a nonrandomized, open-label safety and dose-finding stage designed to evaluate the safety and efficacy of 3 dose levels of UX701 to establish initial safety of UX701 and select a safe and efficacious dose for further evaluation. Stage 2 (Phase 3) is a randomized, double-blind, placebo-controlled stage designed to evaluate the safety and efficacy of UX701 using the dose selected in Stage 1. Stage 3 is designed to evaluate the long-term safety, efficacy, and clinical benefit of UX701. All participants will be followed for at least 5 years from the time of UX701 administration.

Participants who receive UX701 will receive premedications and prophylactic oral corticosteroids. Participants who receive placebo will receive premedications and placebo oral corticosteroids to maintain the study blind.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Patients Contact: Trial Recruitment; Phone Number: 1-888-756-8657; Email: trialrecruitment@ultragenyx.com
• Study Contact Backup: Name: HCPs Contact: Medical Information; Phone Number: 1-888-756-8657; Email: medinfo@ultragenyx.com

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Gordon and Leslie Diamond Health Care Centre
• Portugal
  • Porto, Portugal, 4200-319
    • Centro Hospitalar Universitário de São João
  • Lisbon
    • Lisboa, Lisbon, Portugal, 1649-035
      • Centro Hospitalar Universitário Lisboa Norte
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron - PPDS
• United Kingdom
  • Surrey
    • London, Surrey, United Kingdom, SE5 9RS
      • Kings College NHS Foundation
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Redwood City, California, United States, 94063
      • Stanford University
    • Sacramento, California, United States, 95817-1348
      • University of California Davis
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37212-2700
      • Vanderbilt University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0001
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Confirmed diagnosis of Wilson disease
• Stable Wilson disease as evidenced by ongoing copper chelator (ie, penicillamine, trientine) and/or zinc therapy for at least 6 months at screening, with no medication or dose changes for at least 6 months at screening.
• Ongoing restriction of high copper containing foods for at least 6 months at Screening, continued through study participation.
• Willing and able to comply with all study procedures and requirements, including frequent blood collection, total urine collection over a 24-hour period, patient-reported outcome assessments, and long-term follow-up

Key Exclusion Criteria:

• Detectable pre-existing antibodies to the AAV9 capsid.
• Stage 1 only: History of copper chelator or zinc therapy noncompliance, in the Investigator's judgment, within 6 months prior to Screening.
• History of liver transplant.
• Decompensated hepatic cirrhosis or presence of advanced liver disease as evidenced by portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy.
• Significant hepatic inflammation as evidenced by laboratory abnormalities.
• Model for End-Stage Liver Disease (MELD) score > 13.
• Hemoglobin < 9 g/dL
• Presence of Stage 3 or higher chronic kidney disease based on estimated glomerular filtration rate < 60 mL/min/1.73 m2.
• Marked neurological deficit or compromise that, in the Investigator's opinion, would interfere with the subject's safety or ability to participate in the study.
• Moderate to severe depression, recent or active suicidal ideation with intent or suicidal behavior, psychosis, or unstable psychiatric illness.
• Participation in another gene transfer study or use of another gene transfer product before or during study participation.
• Subjects with known hypersensitivity to amide-containing local anesthetics are excluded from participating in the optional liver biopsy substudy.

Note: Other protocol defined Inclusion/ Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stage 1: UX701 Dose Level 1; Participants receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1.	Genetic: UX701; Nonreplicating, recombinant gene transfer vector
Experimental: Stage 1: UX701 Dose Level 2; Participants receive a single, peripheral IV infusion of UX701 at dose level 2.	Genetic: UX701; Nonreplicating, recombinant gene transfer vector
Experimental: Stage 1: UX701 Dose Level 3; Participants receive a single, peripheral IV infusion of UX701 at dose level 3.	Genetic: UX701; Nonreplicating, recombinant gene transfer vector
Experimental: Stage 2: UX701 or Placebo; Participants randomized 2:1 to receive UX701 or Placebo. Participants randomized to UX701 receive a single, peripheral IV infusion of UX701 at a dose selected in Stage 1. Participants randomized to placebo will receive a single, peripheral IV infusion of normal saline (placebo).	Other: Placebo; Normal saline; Genetic: UX701; Nonreplicating, recombinant gene transfer vector
Experimental: Stage 3: Placebo or UX701; Participants randomized in Stage 2 to UX701 will receive a single, peripheral IV infusion of normal saline (placebo). Participants randomized in Stage 2 to placebo will be eligible for a single, peripheral IV infusion of UX701 at the selected dose.	Other: Placebo; Normal saline; Genetic: UX701; Nonreplicating, recombinant gene transfer vector

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Stage 1: Incidence of Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Adverse Events of Special Interest (AESIs), Treatment-Related TEAEs, and Treatment-Related TESAEs	Up to Week 52
Stage 1: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52	Baseline, Week 52
Stage 1: Change in Total Copper from Baseline at Week 52	Baseline, Week 52
Stage 1: Change in Ceruloplasmin from Baseline at Week 52	Baseline, Week 52
Stage 1: Change in Non-Ceruloplasmin-bound Copper (NCC) from Baseline at Week 52	Baseline, Week 52
Stage 1: Change in Free Copper from Baseline at Week 52	Baseline, Week 52
Stage 1: Change in Ceruloplasmin Activity from Baseline at Week 52	Baseline, Week 52
Stage 1: Percent Reduction in Standard of Care (SOC) Medication by Week 52	Week 52
Stage 1: Number of Participants Who Discontinue SOC Medication by Week 52	Week 52
Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52	Week 52
Stage 2: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52, Evaluated for Superiority	Baseline, Week 52
Stage 2: Percent Reduction in SOC Medication by Week 52, Evaluated for Superiority	Week 52

Secondary Outcome Measures

Outcome Measure	Time Frame
Stage 2: Change in Ceruloplasmin Activity Levels from Baseline at Week 52, Evaluated for Superiority	Baseline, Week 52
Stage 2: Number of Participants who Discontinue SOC Medication by Week 52	Week 52
Stage 2: Change in Liver Copper Concentration Assessed by Liver Biopsy from Baseline at Week 52	Baseline, Week 52
Stage 2: Change in FACIT-Fatigue Scale Score from Baseline at Week 52	Baseline, Week 52

Other Outcome Measures

Outcome Measure	Time Frame
Stage 2: Development of Anti-ATP7B Antibodies	Up to Week 104
Stage 2: Incidence of TEAEs, TESAEs, AESIs, Treatment-Related TEAEs, and Treatment-Related TESAEs	Up to Week 312

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Ultragenyx Patient Advocacy/Wilson Disease Information
• Ultragenyx Wilson Disease (WD) Research Study Opportunities

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2021
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): November 1, 2031

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: May 7, 2021
• First Posted (Actual): May 13, 2021

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Metal Metabolism, Inborn Errors; Hepatolenticular Degeneration; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: UX701-CL301; 2020-005266-34 (EudraCT Number); 2022-502873-40-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Due to the rarity of Wilson Disease, individual patient data will not be shared in order to safeguard patient privacy. The study protocol and statistical analysis plan for this study will be available with the tabulated results once posted.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No