Ultragenyx Pharmaceutical Inc. has announced positive data from its Phase 1/2 trial of GTX-102, an investigational antisense oligonucleotide for Angelman syndrome. The data, presented at the 2024 Foundation for Angelman Syndrome Therapeutics (FAST) Global Science Summit, supports the ongoing Phase 3 Aspire study. GTX-102 aims to address the underlying genetic cause of Angelman syndrome by targeting and inhibiting the expression of UBE3A-AS, leading to the reactivation of the paternal UBE3A allele. This approach has shown promise in preclinical studies, with improvements observed in neurological symptoms in animal models.
Phase 1/2 Trial Results
The Phase 1/2 open-label study evaluated the safety, tolerability, and clinical response of GTX-102 administered via intrathecal injection in pediatric patients with Angelman syndrome who have a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The trial enrolled and treated 74 patients in Dose-escalation and Expansion Cohorts.
As of the September data cutoff, patients in the Dose Expansion Cohorts (n=40) demonstrated continued improvement across multiple domains at Week 48 (Day 338). The mean change in Bayley-4 Cognition Growth Scale Value (GSV) score from baseline was +6.7, compared to the minimally important difference of +5. When assessed using the Phase 3 primary endpoint of Bayley-4 Cognition Raw score, the mean change from baseline was +10.9. This suggests a high probability of detecting a treatment effect in the Phase 3 study, even with a potential response in the sham arm.
Week 48 data from 28 patients in Expansion Cohorts A&B, evaluated using the Phase 3 key secondary endpoint of Multi-domain Responder Index (MDRI), showed a total net response of +2.0 (p-value < 0.0001). Approximately 80% (22 of 28 patients) achieved clinically meaningful net improvement in at least one domain. The safety profile of GTX-102 remained consistent and acceptable throughout the study period.
Phase 3 Aspire Study
The global Phase 3 Aspire study will enroll approximately 120 patients with Angelman syndrome, all with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study includes a 48-week primary efficacy analysis period. The primary endpoint is the improvement in cognition assessed by Bayley-4 cognitive raw score. The key secondary endpoint is the Multi-domain Responder Index (MDRI) across the five domains of cognition, receptive communication, behavior, gross motor function, and sleep.
Mechanism of Action
GTX-102 is designed to target and inhibit the expression of UBE3A-AS. Nonclinical studies have demonstrated that GTX-102 reduces levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the central nervous system (CNS). Reactivation of paternal UBE3A expression in animal models of Angelman syndrome has been associated with improvements in some of the neurological symptoms associated with the condition.
GTX-102 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the FDA, as well as Orphan Designation and PRIME designation from the EMA.
