Long-Term Safety and Efficacy Evaluation of GTX-102 in Angelman Syndrome Patients

The primary objective of this study is to evaluate the long-term **safety** profile of GTX-102 in subjects with **Angelman Syndrome**. This is clinically relevant as it aims to ensure that the therapeutic intervention does not pose significant risks to patients over extended periods, which is crucial for chronic conditions like Angelman Syndrome.

Secondary objectives include assessing the long-term efficacy of GTX-102 in improving cognitive function, communication, and motor skills and function. These evaluations are important as they address the potential benefits of GTX-102 in enhancing the quality of life and functional abilities of patients with Angelman Syndrome, beyond its safety profile.

The clinical trial involves a total of **60 participants** diagnosed with **Angelman Syndrome**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on prior involvement in a clinical trial with GTX-102, having completed the loading phase, and with approval from the Ultragenyx Medical Monitor. The trial population is considered vulnerable, and informed consent was obtained from parents or legal guardians. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the requirement for females of childbearing potential to use highly effective contraception or abstain from sexual activity, while males must agree to remain abstinent or use acceptable contraceptive methods during the study and for a specified period after the final dose of GTX-102.

The clinical trial is designed to evaluate the long-term safety profile of **GTX-102** in patients diagnosed with **Angelman Syndrome**. This study is a Phase III long-term extension trial, which is not classified as low intervention. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is set to conclude by October 2, 2029, with recruitment anticipated to commence on October 2, 2024. Participants are expected to be involved for a maximum treatment period of 260 weeks, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with the study protocol.

The sequence of study visits begins with an inclusion (screening) visit, which must occur within six months of the participant's last visit in a prior GTX-102 study. This visit is crucial for confirming eligibility based on the principal inclusion criteria, which include prior participation in a GTX-102 trial and obtaining informed consent from the participant's parent or legal guardian. Following the screening, participants will undergo regular follow-up visits to monitor treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as to assess changes in cognitive and motor function using the Bayley-4 scales. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term safety and efficacy of GTX-102.

Throughout the study, participants will receive intrathecal administration of GTX-102, a chemically synthesized antisense oligonucleotide targeting the human UBE3A-AS transcript. The trial will also utilize auxiliary products such as the GTX/UX Diluent and Flush Solution and ELLIOTTS B Solution to support the administration process. The primary endpoint focuses on the frequency, severity, and relationship of treatment-emergent AEs and SAEs to the investigational product. Secondary endpoints include changes in cognitive and motor function scores from baseline to various points throughout the study. Participants are required to adhere to specific contraceptive measures during the study and for a designated period after the final dose to ensure safety and compliance with the study protocol.

The clinical trial involves the administration of **GTX-102**, a chemically synthesized human UBE3A-AS transcript-targeted antisense oligonucleotide (ASO). GTX-102 is formulated as a **solution for injection** and is intended for **intrathecal use**. The active substance is a complex nucleic acid sequence, specifically designed to target the UBE3A-antisense transcript. The trial aims to evaluate the long-term safety profile of GTX-102 in patients with Angelman Syndrome. The dosing schedule and frequency of administration are determined by the study protocol, with a maximum treatment period of 260 days. Participant compliance is monitored through regular assessments and documentation of administration.

In addition to GTX-102, the trial utilizes **GTX/UX Diluent and Flush Solution** as an auxiliary treatment. This solution is also a **solution for injection** and is used for **intrathecal administration**. It contains a combination of chemical substances, including sodium dihydrogen phosphate dihydrate, disodium phosphate, potassium chloride, sodium chloride, calcium chloride dihydrate, and magnesium sulfate heptahydrate. The solution serves as a diluent and flushing agent to ensure proper delivery and distribution of the primary investigational product.

Another auxiliary treatment used in the study is **ELLIOTTS B SOLUTION**, a buffered intrathecal electrolyte/dextrose injection. This **solution for solution for injection** is administered via the **intrathecal route**. It comprises a mixture of chemical substances such as calcium chloride, glucose anhydrous, sodium hydrogen carbonate, potassium chloride, sodium chloride, sodium phosphate, and magnesium sulfate. ELLIOTTS B SOLUTION is a sterile, nonpyrogenic, isotonic solution that supports the administration of the investigational product by maintaining the appropriate physiological environment.

The efficacy of GTX-102 in patients with **Angelman Syndrome** will be assessed through a series of secondary endpoints. These endpoints include changes from Long-Term Extension (LTE) Month 0 and pretreatment, when available, in several developmental domains. Specifically, the Bayley-4 scales will be utilized to measure raw scores in cognition, receptive communication, expressive communication, gross motor skills, and fine motor skills. These assessments will provide a comprehensive evaluation of the impact of GTX-102 on various aspects of patient development over the course of the study.