Wilson Disease
Conditions
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.
Interventions
GENETICUX701
Nonreplicating, recombinant gene transfer vector
DRUGStandard of Care (SOC)
SOC treatment (i.e., copper chelators and/or zinc) administered according to standard regimens.
Sponsors
Ultragenyx Pharmaceutical Inc
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Those responsible for reviewing MRI assessments, ophthalmology assessments, and analyzing liver biopsy samples will be double-blinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * 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
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. * 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/
Design outcomes
Primary
| 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-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 |
| 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
| 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 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 |
Countries
Portugal, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Ultragenyx Pharmaceutical Inc
Outcome results
None listed