Clinical trial NCT04884815: A Phase 1/2/3 Study of UX701 Gene Therapy in Adults With Wilson Disease
Official title: An Operationally Seamless Phase 1/2/3 Study Consisting of a Safety and Dose-finding Phase 1/2 and Randomized, Open-label, Active-controlled Phase 3 to Evaluate UX701 AAV Gene Therapy in Adults With Wilson Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Wilson Disease
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2021-05-13
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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/ Exclusion criteria may apply

Primary outcomes:
measure: 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
timeFrame: Up to Week 52
measure: Stage 1: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Change in Total Copper from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Change in Ceruloplasmin-bound Copper from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Change in Ceruloplasmin from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Change in Non-Ceruloplasmin-bound Copper (NCC) from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Change in Free Copper from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Change in Ceruloplasmin Activity from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 1: Percent Reduction in Standard of Care (SOC) Medication by Week 52
timeFrame: Week 52
measure: Stage 1: Number of Participants Who Discontinue SOC Medication by Week 52
timeFrame: Week 52
measure: Stage 1: Number of Consecutive Weeks off SOC Medication at Week 52
timeFrame: Week 52
measure: Stage 2: Change in 24-hour Urinary Copper Concentration from Baseline at Week 52, Evaluated for Superiority
timeFrame: Baseline, Week 52
measure: Stage 2: Percent Reduction in SOC Medication by Week 52, Evaluated for Superiority
timeFrame: Week 52
Secondary outcomes:
measure: Stage 2: Change in Ceruloplasmin Activity Levels from Baseline at Week 52, Evaluated for Superiority
timeFrame: Baseline, Week 52
measure: Stage 2: Number of Participants who Discontinue SOC Medication by Week 52
timeFrame: Week 52
measure: Stage 2: Change in FACIT-Fatigue Scale Score from Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Stage 2: Change in Liver Copper Concentration Assessed by Liver Biopsy from Baseline at Week 52
timeFrame: Baseline, Week 52
Other outcomes:
measure: Stage 2: Development of Anti-ATP7B Antibodies
timeFrame: Up to Week 104
measure: Stage 2: Incidence of TEAEs, TESAEs, AESIs, Treatment-Related TEAEs, and Treatment-Related TESAEs
timeFrame: Up to Week 312
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Redwood City
country: United States
facility: Stanford University
state: California
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Vancouver
country: Canada
facility: Gordon and Leslie Diamond Health Care Centre
state: British Columbia
city: Lisboa
country: Portugal
facility: Centro Hospitalar Universitário Lisboa Norte
state: Lisbon
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário de São João
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: London
country: United Kingdom
facility: Kings College NHS Foundation
state: Surrey
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References: