Ultragenyx Begins Dosing in Phase 3 Aspire Trial for GTX-102 in Angelman Syndrome

On December 19, 2024, Ultragenyx Pharmaceutical Inc. announced that the first patient has been treated in the pivotal Phase 3 Aspire study. This clinical trial is designed to evaluate the efficacy and safety of GTX-102, an investigational antisense oligonucleotide (ASO) therapy for Angelman syndrome, a rare neurogenetic disorder.

Dr. Eric Crombez, the Chief Medical Officer at Ultragenyx, emphasized the significance of this milestone, stating that the initiation of patient dosing marks a crucial advancement in developing a much-needed treatment for those affected by Angelman syndrome. The Aspire study aims to confirm the safety and clinical efficacy of GTX-102 in a comprehensive, randomized trial that represents the majority of Angelman syndrome patients. Additionally, the Aurora study will further explore safety and verify efficacy across different patient genotypes and age groups.

The Phase 3 Aspire study is a global initiative that will involve approximately 120 children aged 4 to 17, all with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. Participants will be randomized in a 1:1 ratio to receive GTX-102 via intrathecal injection or to a sham comparator group for a 48-week primary efficacy analysis period. Those in the active treatment group will receive three monthly loading doses of GTX-102, starting at 8 mg, followed by a maintenance period with a maximum dose of 14 mg quarterly. Patients in the sham group will have the option to transition to the active treatment after the 48-week period concludes. The study's primary endpoint is the improvement in cognition, measured by the Bayley-4 cognitive raw score. A key secondary endpoint is the Multi-domain Responder Index (MDRI), which evaluates cognition, communication, behavior, motor function, and sleep.

Angelman syndrome presents significant challenges, including cognitive and motor impairments that affect daily activities such as walking and communicating. The Angelman Syndrome Foundation (ASF) and the Foundation for Angelman Syndrome Therapeutics (FAST) have expressed enthusiasm about the Aspire study, recognizing it as a significant achievement for the community.

At the 2024 FAST Global Science Summit, Ultragenyx presented data from earlier Phase 1/2 studies, which supported the dosing strategy for the Phase 3 study and confirmed that it is sufficiently powered to demonstrate GTX-102's efficacy on cognitive improvement and other key measures at the 48-week marker.

GTX-102 works by targeting and inhibiting the UBE3A antisense transcript, which plays a role in silencing the paternally inherited allele of the UBE3A gene. The aim is to reactivate the expression of the deficient protein. GTX-102 has received several designations from the FDA and EMA, including Orphan Drug and Fast Track Designations, highlighting its potential significance.

Angelman syndrome is caused by a loss-of-function mutation in the maternally inherited allele of the UBE3A gene due to genomic imprinting. This disorder leads to various neurological symptoms including cognitive and motor impairment, balance issues, and seizures, although individuals can have a normal lifespan with continuous care. There is currently no approved therapy for Angelman syndrome, but research indicates that symptoms could potentially be improved at any age.

Ultragenyx is a biopharmaceutical company dedicated to developing novel therapies for rare and ultra-rare genetic diseases. The company focuses on addressing diseases with unmet medical needs, aiming to provide effective treatments where none currently exist. With an experienced leadership team, Ultragenyx strives for efficient drug development to deliver therapies to patients swiftly.