A Long-Term Follow-up Study to Evaluate the Safety and Efficacy of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Adults with Late-Onset OTC Deficiency

The primary objective of this study is to determine the long-term **safety** of DTX301 following a single intravenous dose in adults with late-onset **ornithine transcarbamylase deficiency**. This is clinically relevant as it addresses the potential risks associated with the use of gene therapy in this patient population, ensuring that the treatment does not pose significant adverse effects over an extended period.

Secondary objectives include:

• Evaluating the long-term efficacy of DTX301 on AUC0-24 for plasma ammonia following a single IV dose in adults with late-onset ornithine transcarbamylase deficiency. This is important for understanding the sustained impact of the treatment on ammonia levels, which are critical in managing the metabolic disorder.
• Assessing the long-term effects of DTX301 on the rate of ureagenesis in adults with late-onset ornithine transcarbamylase deficiency. This objective is significant as it evaluates the treatment's influence on the body's ability to convert ammonia into urea, a key process in detoxifying ammonia.

The clinical trial involves a total of **seven participants** diagnosed with **ornithine transcarbamylase deficiency**, specifically targeting adults with late-onset manifestations of the condition. The study population includes both male and female subjects, with an age range that encompasses adults. Participants were selected based on their completion of the Week 52 visit in a prior study, indicating a commitment to the trial's requirements. The trial population is characterized by a vulnerable group, necessitating careful consideration of their health status. Lifestyle factors such as diet and physical activity are not specified, but participants are expected to comply with scheduled study visits and procedures. The trial aims to assess the long-term safety of a single intravenous dose of DTX301 in this specific patient group.

The clinical trial is designed to evaluate the long-term safety and efficacy of **avalotcagene ontaparvovec**, a recombinant adeno-associated viral vector, in adults with late-onset **ornithine transcarbamylase deficiency**. This study is a Phase I/II long-term follow-up trial, characterized by a randomized, double-blind, and controlled design. The trial is expected to span from August 15, 2022, to December 24, 2029, with participants involved for a duration of up to 416 weeks. The primary objective is to assess the incidence of adverse events (AEs) and serious adverse events (SAEs) related to the study product, while secondary endpoints include changes in plasma ammonia levels and ureagenesis rates over time.

Participants eligible for this study must have completed the Week 52 visit in a prior study (Study 301OTC01) and be willing to provide informed consent and comply with study requirements. The study involves a series of visits, beginning with an inclusion (screening) visit to confirm eligibility. Subsequent follow-up visits are scheduled to monitor safety and efficacy parameters, with the end-of-study visit marking the conclusion of participant involvement. The study protocol allows for early termination if participants experience significant adverse effects or fail to adhere to study procedures.

The clinical trial involves the administration of **avalotcagene ontaparvovec**, an experimental gene therapy product. This investigational medication is formulated as a **solution for infusion** and is administered via **intravenous use**. The active substance, **avalotcagene ontaparvovec**, is a recombinant adeno-associated viral vector designed to deliver the human **Ornithine Transcarbamylase (OTC)** gene. The therapy is intended for adults with late-onset OTC deficiency. The product is identified by the sponsor product code **DTX301, SCAAV8OTC** and is developed by Ultragenyx Pharmaceutical Inc. The trial aims to evaluate the long-term safety of a single intravenous dose of this gene therapy.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental gene therapy. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial does not include a pediatric formulation, and the product has been designated as an orphan drug, indicating its use for a rare condition. The study is designed to assess the safety and efficacy of the gene transfer product over an extended follow-up period.

The efficacy of the clinical trial will be assessed through several key endpoints. The primary endpoint focuses on the incidence of adverse events (AEs) and serious adverse events (SAEs) for each dosing cohort, evaluated by severity and their relationship to the study product, **Avalotcagene ontaparvovec**. Secondary endpoints include the change from baseline in the area under the curve (AUC0-24) for plasma ammonia over time, up to 208 weeks following intravenous administration of DTX301. Additionally, the change from baseline in the rate of ureagenesis, measured by the generation of [13 C]urea over 4 hours, will be assessed using gas chromatography mass spectrometry over a period extending to 416 weeks post-administration. These parameters will be collected and analyzed to determine the efficacy of the gene transfer therapy in adults with late-onset ornithine transcarbamylase (OTC) deficiency. The study is designed as a long-term follow-up to evaluate both safety and efficacy, with data collection scheduled at various timepoints throughout the trial duration.