Phase 3 Randomized Double-Blind Sham-Controlled Trial of GTX-102 Efficacy and Safety in Pediatric Angelman Syndrome

The primary objective of this Phase 3, randomized, double-blind, sham-controlled study is to evaluate the effect of **GTX-102** on cognitive function in pediatric subjects with **Angelman Syndrome**. This objective is clinically relevant as cognitive impairment is a significant challenge in Angelman Syndrome, and improving cognitive function could substantially enhance the quality of life for affected individuals.

Secondary objectives include evaluating the effect of GTX-102 in the following domains: multi-domain responder index, behavior, communication, sleep, and the safety profile of GTX-102. These assessments are crucial for understanding the broader impact of GTX-102 on various aspects of daily living and overall well-being in patients with Angelman Syndrome, as well as ensuring the treatment's safety and tolerability.

The clinical trial involves a total of **80 participants** diagnosed with **Angelman Syndrome**, a neurogenetic disorder. The study population includes both male and female subjects, aged between 4 and less than 18 years, who have a confirmed genetic diagnosis of Angelman Syndrome due to a full maternal ubiquitin-protein ligase E3A (UBE3A) gene deletion. Participants are required to be able to ambulate independently or with assistance, as those whose primary means of mobility is by wheelchair are excluded. The trial population was selected based on specific inclusion criteria, including the ability to comply with study procedures and laboratory tests. Participants must have a platelet count, prothrombin time, and partial thromboplastin time within 1.5 times the normal limits. Lifestyle considerations such as the use of effective contraception or abstinence are required for sexually active females of childbearing potential and males during the study and for a specified period after the final dose of GTX-102. The study aims to evaluate the effect of GTX-102 on cognitive function in this vulnerable population.

The clinical trial is a **Phase 3**, randomized, double-blind, sham-controlled study designed to evaluate the efficacy and safety of GTX-102 in pediatric subjects diagnosed with **Angelman Syndrome**. The primary objective is to assess the effect of GTX-102 on cognitive function. The trial is expected to commence recruitment on February 20, 2025, and conclude by November 20, 2027, with a total duration of approximately 33 months. Participants will be randomly assigned to receive either GTX-102 or a sham treatment, with neither the participants nor the investigators aware of the group assignments to maintain the double-blind nature of the study.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit, or screening visit, will confirm eligibility based on criteria such as age, genetic confirmation of Angelman Syndrome, and the ability to comply with study procedures. Following the screening, participants will undergo regular follow-up visits to assess treatment effects and monitor safety. These visits will include evaluations of cognitive function, communication skills, and adverse events. The end-of-study visit will occur at Day 338, where final assessments will be conducted to determine changes from baseline in various endpoints, including the Bayley-4 Cognitive Raw Score and other secondary measures.

Participant involvement is expected to last for the entire duration of the study, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The study will utilize **intrathecal administration** of GTX-102, a solution for injection, alongside a sterile diluent and flush solution. The trial will adhere to rigorous ethical standards, ensuring informed consent is obtained from parents or legal guardians, and participants are monitored closely throughout the study period.

The clinical trial involves the administration of **GTX-102**, an experimental medication formulated as a **solution for injection**. GTX-102 is an antisense oligonucleotide designed to target the human UBE3A-antisense transcript. The active substance in GTX-102 is a complex nucleic acid sequence, specifically a chimeric locked nucleic acid and ribonucleic-deoxyribonucleic antisense oligonucleotide. The medication is administered via **intrathecal use**, which involves injection into the spinal canal. The dosing schedule and frequency of administration are determined based on the study protocol, with a maximum treatment period of 730 days. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to GTX-102, the study utilizes the **GTX/UX Diluent and Flush Solution**, which serves as a sterile diluent and flush solution. This solution is also provided as a **solution for injection** and is composed of several chemical substances, including **sodium dihydrogen phosphate dihydrate**, **disodium phosphate**, **potassium chloride**, **sodium chloride**, **calcium chloride dihydrate**, and **magnesium sulfate heptahydrate**. The GTX/UX Diluent and Flush Solution is administered via the same **intrathecal route** as GTX-102. The use of this solution is integral to the administration process, ensuring the proper delivery and efficacy of the experimental medication. The administration schedule and procedures for the diluent and flush solution are aligned with the study's protocol requirements.

The efficacy of GTX-102 in pediatric subjects with Angelman Syndrome will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the Bayley-4 Cognitive Raw Score without caregiver input at Day 338. This endpoint is designed to evaluate the cognitive function improvements attributable to the treatment.

Secondary endpoints include the net response in the Multidimensional Response Index (MDRI) at Day 338, changes from baseline in the Aberrant Behavior Checklist-Community (ABC-C) Hyperactivity/Noncompliance Subscale Score, Bayley-4 Receptive Communication raw score, and ORCA Total Mastery Communication T-Score, all measured at Day 338. Additionally, changes from baseline in the Angelman Syndrome Assessment (ASA) Sleep Rating Raw Score at Day 338 will be evaluated. The number of participants experiencing treatment-emergent adverse events (AEs) and serious adverse events (SAEs), along with the severity and relationship of these events to the investigational drug, procedure, and premedication, will also be recorded.

These efficacy parameters will be collected and analyzed at specified timepoints, with the primary and secondary endpoints being assessed at Day 338. The use of validated scales and patient-reported outcomes will ensure the reliability and accuracy of the efficacy assessments. The study is designed to provide comprehensive data on the impact of GTX-102 on cognitive and behavioral functions in children with Angelman Syndrome.