Study of UX701 Gene Transfer for the Treatment of Wilson Disease

• ClinicalTrials.gov Identifier: NCT04884815
• Recruitment Status: Active, not recruiting
• First Posted: May 13, 2021
• Last Update Posted: May 7, 2024
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Tracking Information

• First Submitted Date: May 7, 2021
• First Posted Date: May 13, 2021
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: September 27, 2021
• Estimated Primary Completion Date: August 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2022)

• 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 [ Time Frame: Up to Week 52 ]
• Stage 1: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Total Copper from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Ceruloplasmin from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Non-Ceruloplasmin-bound Copper (NCC) from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Free Copper from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Ceruloplasmin Activity from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Percent Reduction in Standard of Care (SOC) Medication by Week 52 [ Time Frame: Week 52 ]
• Stage 1: Number of Participants Who Discontinue SOC Medication by Week 52 [ Time Frame: Week 52 ]
• Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52 [ Time Frame: Week 52 ]
• Stage 2: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52, Evaluated for Superiority [ Time Frame: Baseline, Week 52 ]
• Stage 2: Percent Reduction in SOC Medication by Week 52, Evaluated for Superiority [ Time Frame: Week 52 ]

Original Primary Outcome Measures (submitted: May 7, 2021)

• Number of Participants with Adverse Events and Serious Adverse Events [ Time Frame: Up to Week 104 ]
• Stage 1: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Total Copper from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Total Ceruloplasmin from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Total Non-Ceruloplasmin-bound Copper (NCC) from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Total Free Copper from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Change in Total Ceruloplasmin Activity from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 1: Percent Reduction in Standard of Care (SOC) Medication by Week 52 [ Time Frame: Week 52 ]
• Stage 1: Number of Subjects Who Discontinue SOC Medication by Week 52 [ Time Frame: Week 52 ]
• Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52 [ Time Frame: Week 52 ]
• Stage 2: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52, evaluated for superiority [ Time Frame: Baseline, Week 52 ]
• Stage 2: Percent Reduction in SOC Medication by Week 52, Evaluated for Superiority [ Time Frame: Week 52 ]

Current Secondary Outcome Measures (submitted: June 12, 2023)

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

Original Secondary Outcome Measures (submitted: May 7, 2021)

• Stage 2: Change in Ceruloplasmin Activity Levels from Baseline at Week 52, Evaluated for Superiority [ Time Frame: Baseline, Week 52 ]
• Stage 2: Change in Wilson Disease Functional Rating Scale (WDFRS) Patient Scores from Baseline at Week 52, Evaluated for Superiority [ Time Frame: Baseline, Week 52 ]
• Stage 2: Number of Subjects who Discontinue SOC Medication by Week 52 [ Time Frame: Week 52 ]
• Stage 2: Change in WDFRS Clinician Scores from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]
• Stage 2: Change in Liver Copper Concentration Assessed by Liver Biopsy from Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]

Current Other Pre-specified Outcome Measures (submitted: November 2, 2022)

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

• Original Other Pre-specified Outcome Measures (submitted: May 7, 2021): Stage 2: Development of Anti-ATP7B Antibodies [ Time Frame: Up to Week 104 ]

Descriptive Information

• Brief Title: Study of UX701 Gene Transfer for the Treatment of Wilson Disease
• Official Title: 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
• 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

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Wilson Disease

Intervention

• Genetic: UX701
  Nonreplicating, recombinant gene transfer vector
• Other: Placebo
  Normal saline

Study Arms

• Experimental: Stage 1: UX701 Dose Level 1
  Participants receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1.
  Intervention: Genetic: UX701
• Experimental: Stage 1: UX701 Dose Level 2
  Participants receive a single, peripheral IV infusion of UX701 at dose level 2.
  Intervention: Genetic: UX701
• Experimental: Stage 1: UX701 Dose Level 3
  Participants receive a single, peripheral IV infusion of UX701 at dose level 3.
  Intervention: Genetic: UX701
• 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).
  Interventions:

  • Genetic: UX701
  • Other: Placebo
• 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.
  Interventions:

  • Genetic: UX701
  • Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: November 2, 2022): 78
• Original Estimated Enrollment (submitted: May 7, 2021): 90
• Estimated Study Completion Date: November 2031
• Estimated Primary Completion Date: August 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Portugal, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04884815
• Other Study ID Numbers: UX701-CL301; 2020-005266-34 ( EudraCT Number ); 2022-502873-40-00 ( Other Identifier: EU CT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• 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.

• Current Responsible Party: Ultragenyx Pharmaceutical Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Ultragenyx Pharmaceutical Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

• PRS Account: Ultragenyx Pharmaceutical Inc
• Verification Date: May 2024