Study of UX701 Gene Transfer for the Treatment of Wilson Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Wilson Disease

Intervention / Treatment
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* Genetic: UX701
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: UX701 Dose Level 1<br>Participants receive a single, peripheral intravenous (IV) infusion of UX701 at dose level 1. | Genetic: UX701<br>* Nonreplicating, recombinant gene transfer vector<br>|
| Experimental: Stage 1: UX701 Dose Level 2<br>Participants receive a single, peripheral IV infusion of UX701 at dose level 2. | Genetic: UX701<br>* Nonreplicating, recombinant gene transfer vector<br>|
| Experimental: Stage 1: UX701 Dose Level 3<br>Participants receive a single, peripheral IV infusion of UX701 at dose level 3. | Genetic: UX701<br>* Nonreplicating, recombinant gene transfer vector<br>|
| Experimental: Stage 2: UX701 or Placebo<br>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). | Genetic: UX701<br>* Nonreplicating, recombinant gene transfer vector<br>Other: Placebo<br>* Normal saline<br>|
| Experimental: Stage 3: Placebo or UX701<br>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. | Genetic: UX701<br>* Nonreplicating, recombinant gene transfer vector<br>Other: Placebo<br>* Normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 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 |