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

The primary objective of this clinical study is to evaluate the **safety** of single intravenous doses of UX701 in patients with **Wilson disease** during Stage 1 (Phase 1/2). Additionally, the study aims to select the UX701 dose with the optimal benefit/risk profile based on comprehensive safety and efficacy data at Week 52. In Stage 2 (Phase 3), the primary focus is to assess the effect of UX701 on **copper regulation** by measuring the 24-hour urinary copper concentration and the percent reduction in standard of care (SOC) medication at Week 52. These objectives are clinically relevant as they address the critical aspects of safety and efficacy in managing Wilson disease, a genetic disorder affecting copper metabolism.

The secondary objectives in Stage 2 (Phase 3) include: - Evaluating the effect of UX701 on biomarkers of copper metabolism and regulation. - Assessing the impact of UX701 on the need for continued SOC medication to regulate copper. - Analyzing the effect of UX701 on patient-reported outcomes. - Investigating the influence of UX701 on liver function and overall health.

The clinical trial involves a total of **65 participants** diagnosed with **Wilson disease**, a genetic disorder affecting copper metabolism. The study population includes both male and female subjects, aged 18 years and older, who have a confirmed diagnosis of Wilson disease through genetic testing for the ATP7B mutation. Participants are required to have been on a stable regimen of copper chelation therapy, such as penicillamine or trientine, and/or zinc therapy for at least 12 months prior to screening, with no changes in medication or dosage for at least 6 months. Additionally, they must have maintained a diet restricting high-copper foods for at least 12 months. The trial population was selected based on these criteria to ensure a stable health status, as evidenced by consistent 24-hour urinary copper concentrations during the screening period. The study includes a vulnerable population, indicating that special considerations are in place to protect the participants' welfare throughout the trial. Participants are expected to comply with all study procedures, including frequent blood and urine collections and patient-reported outcome assessments.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety and efficacy of UX701, an **adeno-associated viral vector serotype 9 encoding human ATP7B**, for the treatment of **Wilson disease**. The trial is structured in two stages: Stage 1 (Phase 1/2) focuses on safety and dose-finding, while Stage 2 (Phase 3) assesses the therapeutic effect on copper regulation. The trial is expected to conclude by April 2031, with recruitment having commenced in July 2022.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, genetic confirmation of Wilson disease, and stable copper levels. The trial includes regular follow-up visits to monitor safety and efficacy endpoints, such as changes in 24-hour urinary copper concentration and ceruloplasmin activity levels. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.

The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including significant adverse events or non-compliance with study procedures. Participants must adhere to ongoing copper chelator or zinc therapy and dietary restrictions throughout the study. The trial aims to provide comprehensive data on the safety and potential benefits of UX701 in managing Wilson disease, contributing to the understanding of its impact on copper metabolism.

The clinical trial involves the administration of **UX701**, a gene therapy product, which is a **solution for infusion**. UX701 is an **adeno-associated viral vector serotype 9 encoding human ATP7B**, developed by Ultragenyx Pharmaceutical Inc. It is administered via **intravenous use**. The primary objective of the trial is to evaluate the safety and efficacy of UX701 in patients with Wilson disease, focusing on copper regulation and reduction in standard-of-care medication. The trial is designed to assess the safety of single IV doses and to determine the optimal dose based on safety and efficacy data at Week 52.

In addition to the experimental treatment, the trial includes the use of **Prednisolon STADA®** tablets as an auxiliary treatment. Two formulations are used: **5 mg** and **10 mg** tablets, both containing the active substance **prednisolone**. These tablets are manufactured by STADAPHARM GMBH and are administered orally. Prednisolone serves as a prophylactic corticosteroid to manage potential inflammatory responses associated with the gene therapy.

The trial also employs **Sodium Chloride 0.9%** as a placebo. This substance does not have a specified pharmaceutical form or route of administration in the trial documentation. It is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know who receives the active treatment or the placebo.

Efficacy in the clinical trial for the treatment of **Wilson Disease** will be assessed through a series of primary and secondary endpoints. The primary endpoints for Stage 1 (Phase 1/2) include the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), adverse events of special interest (AESIs), and treatment-related TEAEs and TESAEs. Additionally, changes in 24-hour urinary copper concentration, total copper, ceruloplasmin, non-ceruloplasmin copper (NCC), free copper, and ceruloplasmin activity levels from baseline at Week 52 will be evaluated. The percent reduction in standard of care (SOC) medication by Week 52, the number of subjects who discontinue SOC medication, and the number of consecutive weeks off SOC medication at Week 52 will also be assessed.

For Stage 2 (Phase 3), primary endpoints will compare UX701 with placebo, focusing on changes in 24-hour urinary copper concentration and percent reduction in SOC medication by Week 52, evaluated for superiority. Secondary endpoints in Stage 2 include changes in ceruloplasmin activity levels, Wilson Disease Functional Rating Scale (WDFRS) patient and clinician scores, and liver copper concentration assessed by liver biopsy from baseline at Week 52. These efficacy parameters will be measured and collected at specified time points, with Week 52 being a critical endpoint for both stages. The analysis will involve validated laboratory tests and patient-reported outcomes to ensure comprehensive evaluation of the treatment's efficacy.