A Phase 1/2/3 Study of UX701 Gene Therapy in Adults With Wilson Disease
- Conditions
- Wilson Disease
- Interventions
- Genetic: UX701Other: PlaceboDrug: Standard of Care (SOC)
- Registration Number
- NCT04884815
- Lead Sponsor
- Ultragenyx Pharmaceutical Inc
- Brief Summary
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.
- Detailed Description
Stage 1 (Phase 1/2) is an open-label safety and dose-finding stage designed to evaluate the safety and efficacy of 4 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, open-label, active-controlled stage to evaluate the safety and efficacy of UX701 using the dose selected in Stage 1. Stage 3 is a long-term follow-up stage designed to evaluate the safety, efficacy, and clinical benefit of UX701 for at least 5 years from the time of UX701 administration.
Participants who receive UX701 will receive premedication, prophylactic oral corticosteroids and immunomodulation therapy.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 82
- Confirmed diagnosis of Wilson disease based on genetic confirmation of heterozygous or homozygous biallelic ATP7B mutation.
- Stable Wilson disease as evidenced by ongoing copper chelator (ie, penicillamine, trientine) and/or zinc therapy for at least 2 months at screening, with no medication or dose changes for at least 2 months at screening.
- Ongoing restriction of high copper containing foods for at least 2 months at Screening and 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
- 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.
- Active decompensated hepatic cirrhosis or history of 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.
- Known hypersensitivity to UX701 or its excipients, copper chelators, zinc, rituximab, tacrolimus, corticosteroids, or eculizumab that, in the Investigator's judgement, places the participant at increased risk for adverse events.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Stage 2: UX701 or Placebo 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). Stage 1: UX701 Dose Level 2 UX701 Participants receive a single, peripheral IV infusion of UX701 at dose level 2. Stage 1: UX701 Dose Level 1 UX701 Participants receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1. Stage 3: Placebo or UX701 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. Stage 1: UX701 Dose Level 3 UX701 Participants receive a single, peripheral IV infusion of UX701 at dose level 3. Stage 2: UX701 or Placebo UX701 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). Stage 3: Placebo or UX701 Placebo 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. Stage 1: UX701 Dose Level 1 UX701 Participants receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1. Stage 1: UX701 Dose Level 2 UX701 Participants receive a single, peripheral IV infusion of UX701 at dose level 2. Stage 1: UX701 Dose Level 3 UX701 Participants receive a single, peripheral IV infusion of UX701 at dose level 3. Stage 1: UX701 Dose Level 4 UX701 Participants receive a single, peripheral IV infusion of UX701 at dose level 4. Stage 2: UX701 at Selected Dose UX701 Participants randomized to UX701 receive a single, peripheral IV infusion of UX701 at the selected dose. Stage 2: Standard of Care (SOC) to UX701 UX701 Participants randomized to SOC will continue their baseline SOC medications for 52 weeks, followed by a single, peripheral IV infusion of UX701 at the selected dose. Following UX701 administration, participants will be evaluated for modification of their SOC medications. Stage 2: Standard of Care (SOC) to UX701 Standard of Care (SOC) Participants randomized to SOC will continue their baseline SOC medications for 52 weeks, followed by a single, peripheral IV infusion of UX701 at the selected dose. Following UX701 administration, participants will be evaluated for modification of their SOC medications.
- Primary Outcome Measures
Name Time Method 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 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-bound 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
- Secondary Outcome Measures
Name Time Method Stage 2: Change in Ceruloplasmin Activity Levels from Baseline at Week 52, Evaluated for Superiority Baseline, Week 52 Stage 2: Change in FACIT-Fatigue Scale Score from Baseline at Week 52 Baseline, Week 52 Stage 2: Change in Liver Copper Concentration Assessed by Liver Biopsy from Baseline at Week 52 Baseline, Week 52 Stage 2: Number of Participants who Discontinue SOC Medication by Week 52 Week 52
Trial Locations
- Locations (17)
University of California Los Angeles
🇺🇸Los Angeles, California, United States
University of California Davis
🇺🇸Sacramento, California, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Stanford University
🇺🇸Redwood City, California, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Gordon and Leslie Diamond Health Care Centre
🇨🇦Vancouver, British Columbia, Canada
Centro Hospitalar Universitário Lisboa Norte
🇵🇹Lisboa, Lisbon, Portugal
Centro Hospitalar Universitário de São João
🇵🇹Porto, Portugal
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸Barcelona, Spain
Kings College NHS Foundation
🇬🇧London, Surrey, United Kingdom