Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) announced positive Phase 1/2 data for GTX-102, an investigational antisense oligonucleotide for Angelman syndrome, at the 2024 Foundation for Angelman Syndrome Therapeutics (FAST) Global Science Summit. The data supports the ongoing Phase 3 Aspire study, which is expected to begin enrollment by the end of 2024.
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 improvement in cognition assessed by Bayley-4 cognitive raw score, with a key secondary endpoint being the Multi-domain Responder Index (MDRI) across five domains: cognition, receptive communication, behavior, gross motor function, and sleep.
Phase 1/2 Data Highlights
As of the September data cut-off, patients in the Dose Expansion Cohorts demonstrated continued improvement across multiple domains at Week 48 (Day 338). Data from the Dose-escalation and Expansion Cohorts (n=40) at Week 48 showed a mean change in Bayley-4 Cognition Growth Scale Value (GSV) score from baseline of +6.7, compared to the minimally important difference of +5. Using the Phase 3 primary endpoint of Bayley-4 Cognition Raw score, the mean change from baseline was +10.9. Ultragenyx estimates that the Phase 3 study has greater than 95% power to detect a treatment effect, even if the response in the sham arm is up to three times higher than observed changes in available natural history data.
Week 48 (Day 338) data from 28 patients in Expansion Cohorts A&B were evaluated using the Phase 3 key secondary endpoint of MDRI, revealing a total net response of +2.0 (p < 0.0001). Approximately 80% (22 of 28 patients) achieved clinically meaningful net improvement in at least one domain.
GTX-102 Safety Profile
GTX-102 demonstrated a consistent and acceptable safety profile as of the data cutoff.
About GTX-102
GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration, designed to target and inhibit expression of UBE3A-AS. Nonclinical studies suggest 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 neurological symptoms. 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.
About Angelman Syndrome
Angelman syndrome is a rare, neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene. This condition affects an estimated 60,000 people in commercially accessible geographies. Individuals with Angelman syndrome experience cognitive impairment, motor impairment, balance issues, and seizures, often requiring continuous care.
