A Phase 2, Open-label, Basket Study Investigating the Safety and Efficacy of GTX-102 in Adult and Pediatric Subjects with Deletion- or Nondeletion-type Angelman Syndrome

The primary objective of this study is twofold: to evaluate the safety of GTX-102 in patients with Angelman syndrome and to assess its efficacy in this population. Angelman syndrome is a rare neurodevelopmental disorder characterized by severe intellectual disability, developmental delay, speech impairment, and movement disorders. The evaluation of safety is essential to determine the tolerability profile and identify potential adverse events associated with intrathecal administration of this antisense oligonucleotide therapy. The efficacy assessment aims to determine whether GTX-102 produces clinically meaningful improvements in patients with either deletion-type or nondeletion-type Angelman syndrome, addressing an unmet medical need in this patient population.

The secondary objective is to evaluate the effect of GTX-102 on key domains that define Angelman syndrome. This includes assessment of core clinical manifestations and functional outcomes that are characteristic of the disorder, providing a comprehensive understanding of the therapeutic impact across multiple disease-relevant parameters.

This clinical trial enrolled a total of **44 participants** diagnosed with **Angelman Syndrome**. The study population included both **males** and **females** across a broad age range from **1 year to under 65 years of age**. Participants were stratified into four subprotocols based on age and genetic subtype: children aged 1 to under 4 years with deletion-type Angelman Syndrome, individuals aged 4 to under 18 years with UPD/ICD-type Angelman Syndrome, adults aged 18 to under 65 years with any genotype of Angelman Syndrome, and individuals aged 4 to under 18 years with mutation-type Angelman Syndrome. All participants required a genetically confirmed diagnosis of Angelman Syndrome and a minimum body weight of 8 kg at screening. Selection criteria included normal coagulation parameters, with prothrombin time/international normalized ratio and partial thromboplastin time below 1.5 times the upper limit of normal and platelet counts above 75,000 cells/mm³. Participants were required to tolerate study procedures including lumbar puncture, MRI, and anesthesia without intubation. The trial involved a vulnerable population and required informed consent from parents or legal guardians for minors.

This is a Phase 2, open-label, basket study designed to investigate the safety and efficacy of GTX-102 (apazunersen) administered via intrathecal route in subjects with Angelman Syndrome. The study employs a basket design comprising four subprotocols that stratify participants based on age and genotype. Subprotocol A enrolls subjects aged 1 to less than 4 years with deletion-type Angelman Syndrome. Subprotocol B includes subjects aged 4 to less than 18 years with UPD/ICD Angelman Syndrome. Subprotocol C involves adults aged 18 to less than 65 years with any genotype of Angelman Syndrome. Subprotocol D enrolls subjects aged 4 to less than 18 years with mutation-type Angelman Syndrome. The investigational product GTX-102 is formulated as a solution for injection and is classified as an antisense oligonucleotide with orphan drug designation. An auxiliary product, GTX/UX Diluent and Flush Solution, is also utilized during the study procedures. The maximum daily dose of GTX-102 is 14.0 mg, and the maximum treatment period is 48 weeks.

The primary safety objective is to evaluate the safety of GTX-102 by monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including their frequency, severity, and relationship to the investigational product, procedure, and premedication throughout the study. The primary efficacy objectives vary by subprotocol. For Subprotocol A, the primary efficacy endpoint is the change from baseline at Day 338 in Bayley-4 Cognitive raw score without caregiver input. For Subprotocols B and D, the primary efficacy endpoint is the Multidomain Responder Index (MDRI) Net response at Day 338, incorporating assessments of cognition, communication, behavior, sleep, and motor function. For Subprotocol C, the MDRI Net response at Day 338 evaluates expressive and receptive communication, behavior, and motor function. Secondary endpoints include changes from baseline in various developmental, behavioral, and functional assessments specific to each subprotocol, such as Bayley-4 scores, Vineland-3 scores, Aberrant Behavior Checklist-Community (ABC-C) subscale scores, and Angelman Syndrome Assessment (ASA) ratings.

Principal inclusion criteria require signed informed consent from parent(s) or legal guardian(s), males and females meeting specific age and genotype criteria as defined by each subprotocol, and a minimum weight of 8 kg at the screening visit. Subjects must have prothrombin time/international normalized ratio and partial thromboplastin time less than 1.5 times the upper limit of normal, and platelet counts greater than 75,000 cells/mm³ at screening. Participants must be willing and able to comply with scheduled visits, drug administration plan, laboratory tests, and all study procedures, including lumbar puncture procedure, magnetic resonance imaging (MRI), and tolerating anesthesia without intubation. Females of childbearing potential who are sexually active must use highly effective contraception or abstinence from informed consent through at least 6 months after the final dose of GTX-102. Males must agree to remain abstinent or use acceptable contraceptive methods during the study and for at least 3 months after the final dose.

The study is estimated to begin recruitment in December 2025 and is projected to conclude in January 2030. The expected duration of participant involvement extends through the treatment period and follow-up assessments, with the primary efficacy evaluation occurring at Day 338. Conditions that may lead to early termination from the study include safety concerns, withdrawal of consent, protocol non-compliance, or investigator discretion based on the participant's best interest. The study design incorporates multiple visits including a screening visit to assess eligibility, baseline assessments, treatment administration visits involving intrathecal injections, follow-up visits for safety and efficacy evaluations, and an end-of-study visit. Throughout the study, comprehensive monitoring of developmental outcomes, behavioral assessments, and safety parameters is conducted to evaluate the therapeutic potential of GTX-102 in the treatment of Angelman Syndrome across different age groups and genetic subtypes.

The experimental medication **GTX-102** is an **antisense oligonucleotide** formulated as a solution for injection containing the active substance **apazunersen**. This product has been designated as an **orphan drug** under the designation number EU/3/23/2869 and is available as a paediatric formulation. GTX-102 is administered via **intrathecal use** with a maximum daily dose of 14.0 mg. The treatment period extends up to 48 weeks. The active substance apazunersen is a nucleic acid-based therapeutic agent specifically designed as a chimeric locked nucleic acid and ribonucleic-deoxyribonucleic antisense oligonucleotide targeting the human UBE3A-antisense transcript for the treatment of **Angelman Syndrome** in both adult and pediatric subjects with deletion-type or nondeletion-type presentations.

The auxiliary medicinal product **GTX/UX Diluent and Flush Solution** is a solution for injection containing multiple chemical active substances including **sodium dihydrogen phosphate dihydrate**, **disodium phosphate**, **potassium chloride**, **sodium chloride**, **calcium chloride dihydrate**, and **magnesium sulfate heptahydrate**. This product is classified as a standard chemical entity and is administered via intrathecal use. The treatment period for this auxiliary product is up to 48 weeks. This diluent and flush solution serves a supportive role in the administration of the investigational medicinal product during the clinical trial procedures.

Efficacy will be assessed using multiple domain-specific endpoints tailored to the age and genotype of participants across different subprotocols. The primary efficacy endpoint for Subprotocol A evaluates change from baseline at Day 338 in Bayley-4 Cognitive raw score without caregiver input. For Subprotocol B, the primary efficacy endpoint is the Multi-Domain Responder Index (MDRI) Net response at Day 338, incorporating assessments across five domains: Cognition measured by Bayley-4 Cognitive raw score, Communication assessed through Bayley-4 Receptive Communication raw score, Behavior evaluated using the Aberrant Behavior Checklist-Community (ABC-C) Hyperactivity/Noncompliance subscale, Sleep measured by the Angelman Syndrome Assessment (ASA) Sleep rating, and Motor Function assessed via ASA Gross Motor rating. Subprotocol C utilizes MDRI Net response at Day 338 with four domains: Expressive Communication measured by Vineland-3 Expressive Communication raw score, Receptive Communication assessed through Vineland-3 Receptive Communication raw score, Behavior evaluated using ABC-C Irritability subscale score, and Motor Function measured by ASA Gross Motor rating. Subprotocol D employs MDRI Net response at Day 338 with the same five-domain assessment structure as Subprotocol B.

Secondary efficacy endpoints provide additional evaluations of treatment effect. For Subprotocol A, change from baseline at Day 338 is assessed in Bayley-4 Receptive Communication raw score and Bayley-4 Gross Motor raw score. Subprotocol B includes change from baseline at Day 338 across multiple parameters: Bayley-4 Cognitive raw score, Bayley-4 Receptive Communication raw score, Vineland-3 Receptive Communication raw score, Vineland-3 Expressive Communication raw score, ABC-C Hyperactivity/Noncompliance subscale score, ASA Sleep rating, ASA Gross Motor rating, and Bayley-4 Gross Motor raw score. For Subprotocol C, secondary endpoints evaluate change from baseline at Day 338 in Vineland-3 Receptive Communication raw score, Vineland-3 Expressive Communication raw score, ABC-C Irritability subscale score, and ASA Gross Motor rating. Subprotocol D assesses change from baseline at Day 338 using the same parameters as Subprotocol B.