Long-Term Safety and Efficacy Evaluation of Pariglasgene Brecaparvovec Gene Transfer in Adults with Glycogen Storage Disease Type Ia

The primary objective of this study is to determine the long-term **safety** of DTX401 following a single intravenous dose in adults with **Glycogen Storage Disease Type Ia (GSDIa)**. This is clinically relevant as it aims to assess the potential risks associated with the gene therapy, ensuring that the treatment does not pose significant adverse effects over an extended period, which is crucial for patient safety and treatment viability.

Secondary objectives include evaluating the long-term effect of DTX401 on symptom-free **euglycemia** in a setting of a controlled fasting challenge. This objective is important as it seeks to understand the efficacy of the treatment in maintaining normal blood glucose levels without symptoms, which is a critical aspect of managing GSDIa and improving patient quality of life.

The clinical trial involves a total of **9 participants** diagnosed with **Glycogen storage disease type Ia**. The study population includes both male and female adults, with an age range that encompasses young adults to middle-aged individuals. Participants were selected based on their prior receipt of DTX401 in a previous study, ensuring they meet specific inclusion criteria. The trial does not involve a vulnerable population. Participants are expected to maintain their usual lifestyle, with no specific dietary or physical activity requirements outlined. The selection process ensures that all participants are willing and able to comply with the study's requirements, including attending scheduled visits and procedures. The trial aims to assess the long-term safety of DTX401 following a single intravenous dose in this specific patient group.

The clinical trial is designed to evaluate the long-term safety and efficacy of **pariglasgene brecaparvovec**, a recombinant AAV8-mediated gene transfer therapy, in adults with **Glycogen Storage Disease Type Ia** (GSDIa). This study is a Phase 1/2 long-term follow-up trial, which is neither low-intervention nor involves a pediatric formulation. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial extends from October 18, 2023, to November 3, 2026, allowing for comprehensive data collection and analysis over an extended period.

Participants in this study are individuals who have previously received DTX401 in Study 401GSDIA01. The trial begins with an inclusion (screening) visit, where eligibility is confirmed based on specific criteria, including the ability to provide informed consent and comply with study requirements. Following the initial screening, participants will undergo a series of scheduled study visits to monitor the incidence of adverse events (AEs) and serious adverse events (SAEs), as well as to assess the primary and secondary endpoints. The primary endpoint focuses on the incidence of AEs and SAEs, while the secondary endpoint evaluates the change in time to the first hypoglycemic event during a controlled fasting challenge.

The expected length of participant involvement is aligned with the overall trial duration, with regular follow-up visits to ensure ongoing safety and efficacy assessments. The study will conclude with an end-of-study visit, where final evaluations are conducted, and data is collected for comprehensive analysis. Conditions that may lead to early termination from the study include the inability to comply with study procedures or the occurrence of significant adverse events that compromise participant safety. The trial's structured approach and rigorous methodology aim to provide valuable insights into the long-term effects of pariglasgene brecaparvovec in managing GSDIa.

The clinical trial involves the administration of **Pariglasgene brecaparvovec**, an experimental gene therapy product. This investigational medication is formulated as a **solution for infusion** and is administered via the **intravenous** route. The treatment is designed to deliver a single dose of the gene therapy to adult participants diagnosed with Glycogen Storage Disease Type Ia (GSDIa). The active substance, **pariglasgene brecaparvovec**, is a recombinant adeno-associated virus serotype 8 (AAV8) vector encoding the glucose-6-phosphatase (G6PC) transgene. This gene transfer product is intended to address the underlying genetic deficiency in GSDIa by facilitating the expression of the G6PC enzyme.

In this study, **Pariglasgene brecaparvovec** is the sole investigational treatment, and no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized. The investigational product is classified as an orphan drug, indicating its designation for a rare disease. The trial aims to evaluate the long-term safety and efficacy of this gene therapy following a single intravenous administration. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol and to assess the therapeutic outcomes effectively.

The efficacy of the investigational product, **Pariglasgene brecaparvovec**, will be assessed in a clinical trial involving adults with Glycogen Storage Disease Type Ia (GSDIa). The primary endpoint for evaluating efficacy is the incidence of adverse events (AEs) and serious adverse events (SAEs) for each cohort and overall, assessed by severity and relationship to the investigational product. A secondary endpoint involves measuring the change from Day 0 in the time to the first hypoglycemic event during a controlled fasting challenge over time by cohort and overall, following intravenous administration of DTX401. These endpoints will be systematically collected and analyzed to determine the efficacy of the gene transfer therapy mediated by Adeno-Associated Virus Serotype 8 (AAV8) in delivering the Glucose-6-Phosphatase (G6Pase) gene. The study is designed as a long-term follow-up to ensure comprehensive evaluation of the treatment's impact on the disease.