Phase I/II Study of VTX-801 Gene Therapy in Adult Patients with Wilson's Disease: Safety and Tolerability Assessment

The primary objective of this study is to assess the **safety** and tolerability of single ascending doses of VTX-801, administered intravenously to adult patients with Wilson's Disease, both prior to and following the withdrawal of background therapy for Wilson's Disease. This is clinically relevant as it aims to establish the safety profile of VTX-801, a gene therapy product, which is crucial for determining its potential as a therapeutic option for managing Wilson's Disease.

Secondary objectives include:

• Exploring VTX-801 pharmacodynamics and efficacy, which will provide insights into the drug's mechanism of action and its potential therapeutic benefits.
• Assessing humoral and cellular immune responses to VTX-801, which is important for understanding the immunogenicity and potential immune-related effects of the therapy.
• Providing data to support VTX-801 dose level selection, which will aid in optimizing dosing strategies for future clinical use.

The clinical trial involves a total of **9 participants** diagnosed with **Wilson's Disease**, a rare genetic disorder affecting copper metabolism. The study population comprises both male and female adults aged between **18 and 65 years**. Participants were selected based on a confirmed diagnosis of Wilson's Disease and have been receiving treatment according to international guidelines, with no current evidence of inadequate treatment. All participants have demonstrated stable disease for at least one year, characterized by no significant changes in neurological examination, mood disorder status, and stable laboratory parameters related to copper metabolism. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study aims to assess the safety and tolerability of single ascending doses of VTX-801 administered intravenously, both prior to and following the withdrawal of background therapy for Wilson's Disease.

The clinical trial is a **Phase I/II**, multicenter, non-randomized, open-label, adaptive design study with a 5-year follow-up period. The primary objective is to assess the safety and tolerability of single ascending doses of VTX-801, a gene therapy product, administered intravenously to adult patients with **Wilson's Disease**. The trial involves a single dose-escalation approach, where participants will receive VTX-801 prior to and following the withdrawal of their background Wilson's Disease therapy. The study is expected to conclude by September 3, 2033, with recruitment having commenced on July 4, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-65 years), confirmed diagnosis of Wilson's Disease, and stable disease status for at least one year. Following the screening, participants will receive the investigational product, VTX-801, via intravenous infusion. Subsequent follow-up visits will be scheduled to monitor safety and efficacy, including assessments of treatment-emergent adverse events, clinical examinations, and changes in laboratory parameters. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last up to five years, aligning with the trial's follow-up duration.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The primary endpoints focus on the safety and tolerability profile, while secondary endpoints include measurements of free serum copper, total serum copper, 24-hour urinary copper, serum ceruloplasmin activity, VTX-801 responder status, and immune response to VTX-801. The investigational product, VTX-801, is a gene therapy medicinal product consisting of a non-replicating recombinant **adeno-associated viral vector serotype 3B** encoding a shortened form of the human ATP7B cDNA, designed to address the underlying genetic defect in Wilson's Disease.

The clinical trial involves the administration of **VTX-801**, an experimental gene therapy product. VTX-801 is a **solution for infusion** containing a non-replicating recombinant **adeno-associated viral vector serotype 3B**. This vector encodes a shortened form of the human **ATP7B** cDNA, known as the ATP7B-minigene, which produces a functional form of the ATP7B protein, referred to as miniATP7B. The product is administered via the **intravenous** route. The study is designed to assess the safety and tolerability of single ascending doses of VTX-801 in adult patients diagnosed with Wilson's Disease. The administration of VTX-801 is conducted prior to and following the withdrawal of background Wilson's Disease therapy. Participant compliance is monitored throughout the study to ensure adherence to the dosing schedule.

In addition to VTX-801, the trial utilizes **Copper (64Cu) Chloride** as an auxiliary treatment. Copper (64Cu) Chloride is also provided as a **solution for infusion** and is administered **intravenously**. This compound, a chemical substance, is used to support the study's objectives and is not the primary focus of the trial. The role of Copper (64Cu) Chloride in the study is to assist in the evaluation of the primary treatment's effects. The administration of this auxiliary treatment is carefully monitored to ensure participant safety and to maintain the integrity of the trial's outcomes.

Efficacy in this clinical trial will be assessed using several secondary endpoints related to **Wilson's Disease**. These include measurements of free serum copper, total serum copper, 24-hour urinary copper, and serum ceruloplasmin activity through enzymatic assays. Additionally, the VTX-801 responder status and immune response to VTX-801 will be evaluated. These parameters will be collected and analyzed at specified timepoints throughout the study duration, which includes a 5-year follow-up period. The trial employs a single dose-escalation design, and efficacy assessments will be conducted in conjunction with safety and tolerability evaluations. The data collection will involve laboratory tests and patient monitoring to ensure comprehensive analysis of the treatment's impact on the disease.