Ultragenyx Pharmaceutical Inc. has announced the dosing of the first patient in its pivotal Phase 3 Aspire study (NCT06617429) evaluating GTX-102, an investigational antisense oligonucleotide (ASO), for the treatment of Angelman syndrome. This marks a significant step forward in the development of a potential therapy for this rare neurogenetic disorder.
The global Phase 3 Aspire study will enroll approximately 120 children aged 4 to 17 years with Angelman syndrome, all of whom have a genetically confirmed diagnosis of full maternal UBE3A gene deletion. Participants will be randomized in a 1:1 ratio to receive either GTX-102 via intrathecal injection (lumbar puncture) or a sham comparator during the 48-week primary efficacy analysis period.
Dosing and Endpoints
Patients in the active treatment group will receive three monthly 8 mg loading doses of GTX-102, followed by a maintenance period with quarterly doses increasing to a maximum of 14 mg. Patients in the sham comparator group will have the option to crossover to the treatment arm after Week 48. The primary endpoint of the study is the improvement in cognition, as measured by the Bayley-4 cognitive raw score. Key secondary endpoints include the Multi-domain Responder Index (MDRI) across five domains: cognition, receptive communication, behavior, gross motor function, and sleep.
GTX-102: Targeting the Root Cause of Angelman Syndrome
GTX-102 is designed to target and inhibit the expression of the UBE3A antisense transcript (UBE3A-AS). By doing so, it aims to prevent the silencing of the paternally inherited allele of the UBE3A gene and reactivate the expression of the deficient UBE3A protein. Angelman syndrome results from the loss-of-function of the maternally inherited UBE3A allele, leading to insufficient UBE3A protein in neurons.
Management Perspective
"Initiation of patient dosing in our Phase 3 Aspire study represents an important step forward in the development of an effective, and much needed, treatment for patients and families affected by Angelman syndrome," said Eric Crombez, M.D., chief medical officer at Ultragenyx. "Our goal with Aspire is to confirm the safety and clinical efficacy of GTX-102 in a large, randomized trial with a population that represents the majority of patients with Angelman syndrome. Additionally, the Aurora study will further assess safety and validate efficacy in patients with different genotypes and in younger and older patients."
Support from Angelman Syndrome Foundations
Amanda Moore, chief executive officer at the Angelman Syndrome Foundation (ASF) and Ryan Fischer, chief operating officer at Foundation for Angelman Syndrome Therapeutics (FAST), jointly stated, "The initiation of the Phase 3 Aspire study by Ultragenyx is a significant achievement and something the community should celebrate."
About Angelman Syndrome
Angelman syndrome is a rare neurodevelopmental disorder affecting an estimated 60,000 people in commercially accessible regions. It is characterized by cognitive and motor impairments, balance issues, seizures, and often the inability to walk or speak. There are currently no approved therapies for Angelman syndrome, highlighting the significant unmet medical need.
Future Plans: The Aurora Study
Ultragenyx is planning to initiate the Aurora study in 2025 to further evaluate GTX-102 in Angelman syndrome patients with different genotypes and across a broader age range. This study aims to validate the safety and efficacy of GTX-102 in a more diverse patient population.
