GTX-102 Advanced Drug Monograph

GTX-102 Report

Name: GTX-102 Name (English): GTX-102 DrugBank ID: DB16981 Type: Biotech Background: GTX-102 is an investigational antisense oligonucleotide developed by Ultragenyx Pharmaceutical. It is specifically designed to target and inhibit the expression of the UBE3A-antisense transcript (UBE3A-AS). In individuals with Angelman Syndrome, the maternal copy of the UBE3A gene is non-functional due to deletion or mutation. Normally, the paternal copy of the UBE3A gene is silenced in neurons by UBE3A-AS. GTX-102 aims to prevent this silencing, thereby reactivating the expression of the normally silent paternal UBE3A allele in the central nervous system. This reactivation is intended to restore the production of the UBE3A protein, which is crucial for neurodevelopment and is deficient in Angelman Syndrome. Current Status: GTX-102 is currently in Phase 3 clinical development. The global Phase 3 "Aspire" study (NCT06617429) is enrolling children and adolescents aged 4 to 17 with Angelman Syndrome due to a full maternal UBE3A gene deletion. This randomized, double-blind, sham-controlled study is evaluating the efficacy and safety of GTX-102 administered via intrathecal injection. Enrollment is expected to complete in the second half of 2025, with study completion anticipated around November 2027. Additionally, Ultragenyx plans to initiate the Phase 2/3 "Aurora" study in 2025 to evaluate GTX-102 in other Angelman Syndrome genotypes and age groups. Regulatory Designations: GTX-102 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation by the U.S. Food and Drug Administration (FDA), as well as Orphan Designation and PRIME designation by the European Medicines Agency (EMA). These designations are intended to expedite the development and review of therapies for rare and serious conditions. Mechanism of Action: Angelman Syndrome results from a deficiency of the UBE3A protein in neurons. The UBE3A gene is subject to genomic imprinting, meaning that in neurons, only the maternally inherited allele is typically expressed. In individuals with Angelman Syndrome, this maternal allele is non-functional. The paternal allele is normally silenced by the UBE3A antisense transcript (UBE3A-AS). GTX-102 is an antisense oligonucleotide that binds to UBE3A-AS, inhibiting its function. This inhibition prevents the silencing of the paternal UBE3A gene, leading to its expression and the production of the UBE3A protein. Clinical Trial Information:

• Phase 1/2 Study (KIK-AS, NCT04259281): This study evaluated the safety, tolerability, and preliminary efficacy of GTX-102 in pediatric patients with Angelman Syndrome. Interim data showed improvements across multiple domains, including cognition, behavior, communication, and sleep, with a generally acceptable safety profile.
• Phase 3 Study (Aspire, NCT06617429): A pivotal, randomized, double-blind, sham-controlled study assessing the efficacy and safety of GTX-102 in children and adolescents (4-17 years) with Angelman Syndrome due to maternal UBE3A deletion. The primary endpoint is improvement in cognition.
• Long-term Extension Study (NCT06415344): An ongoing study to evaluate the long-term safety and efficacy of GTX-102 in participants who have completed prior GTX-102 clinical studies.
• Phase 2/3 Study (Aurora): Planned to initiate in 2025, this study will evaluate the safety and efficacy of GTX-102 in a broader population of individuals with Angelman Syndrome, including different genotypes and age ranges.

GTX-102 represents a promising therapeutic approach for Angelman Syndrome by aiming to address the underlying genetic cause of the disorder. Clinical trial results are being closely monitored by the Angelman Syndrome community and researchers.