A Comprehensive Report on GTX-102: An Investigational Antisense Oligonucleotide for the Treatment of Angelman Syndrome

1.0 Executive Summary

GTX-102 is an investigational antisense oligonucleotide (ASO) therapy being developed by Ultragenyx Pharmaceutical for the treatment of Angelman Syndrome (AS), a rare and severe neurogenetic disorder with no approved disease-modifying treatments. The therapeutic rationale for GTX-102 is to address the root genetic cause of the disease. AS is caused by the loss of function of the maternally inherited UBE3A gene. In neurons, the paternal copy of UBE3A is epigenetically silenced by a long non-coding RNA, the UBE3A antisense transcript (UBE3A-AS). GTX-102 is designed to bind to and promote the degradation of UBE3A-AS, thereby "unsilencing" the paternal allele and restoring the production of functional UBE3A protein in the central nervous system.

The clinical development of GTX-102, initiated by GeneTx Biotherapeutics (a company founded by the patient advocacy group FAST) and now led by Ultragenyx, has shown promising results. The Phase 1/2 KIK-AS study (NCT04259281) demonstrated rapid, multi-domain, and clinically meaningful improvements in cognition, communication, motor function, and behavior in pediatric patients. At Week 48, treated patients (n=40) showed a mean improvement of +6.7 points on the Bayley-4 Cognition Growth Scale Value (GSV), exceeding the minimally important difference threshold. The program successfully navigated a clinical hold initiated due to a serious adverse event (SAE) of transient lower extremity weakness observed at high doses; this was resolved by amending the dosing protocol, and the safety profile has since been deemed acceptable.