Ultragenyx Pharmaceutical Inc. has announced positive Phase 1/2 data supporting the Phase 3 Aspire study for GTX-102, an investigational antisense oligonucleotide for Angelman syndrome. The data, presented at the 2024 Foundation for Angelman Syndrome Therapeutics (FAST) Global Science Summit, reinforce the potential of GTX-102 to address the cognitive and functional impairments associated with this rare neurogenetic disorder.
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). Specifically, patients (n=40) in the Dose-escalation and Expansion Cohorts at Week 48 demonstrated 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. According to Ultragenyx, this suggests 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 with the Phase 3 key secondary endpoint of MDRI and showed a total net response of +2.0 (p-value < 0.0001). The data demonstrate that approximately 80% (22 of 28 patients) of patients have achieved clinically meaningful net improvement in at least one domain.
"Cognition is the building block for the development and ascertainment of many new skills across a range of the domains we have evaluated in the Phase 1/2 study. The data presented at FAST reinforce that the Aspire Phase 3 primary endpoint of cognition, as measured by Bayley-4, appears very well powered to show statistically significant separation between the GTX-102 and sham arms," said Eric Crombez, M.D., chief medical officer at Ultragenyx. "We are on track to begin enrolling the Phase 3 Aspire study by the end of this year and have a robust and experienced global network of sites that will enable accelerated study execution."
Aspire Phase 3 Study Design
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 will be improvement in cognition assessed by Bayley-4 cognitive raw score, and the key secondary endpoint will be the Multi-domain Responder Index (MDRI) across the five domains of cognition, receptive communication, behavior, gross motor function, and sleep.
About GTX-102
GTX-102 is an investigational antisense oligonucleotide administered intrathecally. It is designed to target and inhibit 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 and Orphan Designation and PRIME designation from the EMA.
Angelman Syndrome: An Unmet Need
Angelman syndrome is a rare, neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene. It is estimated to affect approximately 60,000 people in commercially accessible geographies. Individuals with Angelman syndrome face lifelong neurodevelopmental challenges, including cognitive and motor impairment, balance issues, and seizures. Currently, there are no approved therapies that address the underlying genetic cause of Angelman syndrome, highlighting the urgent need for effective treatments.
