Ultragenyx Reports Positive Progress on GTX-102 Angelman Syndrome Program at FAST Summit

Ultragenyx Pharmaceutical Inc. has announced promising results from its Phase 1/2 study supporting the Phase 3 Aspire trial for GTX-102, an investigational antisense oligonucleotide intended to treat Angelman syndrome. These findings will be shared at the 2024 Foundation for Angelman Syndrome Therapeutics (FAST) Global Science Summit in Orlando, Florida.

According to Eric Crombez, M.D., Chief Medical Officer at Ultragenyx, the data from the Phase 1/2 study underscore the potential of the Aspire Phase 3 trial’s primary endpoint, cognition, which is measured using the Bayley-4 cognitive scale. The study appears well-powered to demonstrate significant differences between the GTX-102 treatment group and the placebo group. The recruitment for the Phase 3 Aspire study is expected to commence by the end of the year, benefitting from a robust global network of research sites poised for rapid study execution.

The Phase 3 Aspire study aims to enroll about 120 patients with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study will feature a 48-week primary efficacy analysis phase. The study’s main outcome will be the improvement in cognition, evaluated by the Bayley-4 cognitive raw score. The key secondary outcome will be the Multi-domain Responder Index (MDRI), which assesses cognition, receptive communication, behavior, gross motor function, and sleep.

As of the September data cut-off for the Phase 1/2 study, patients in the Dose Expansion Cohorts exhibited continued improvement across various domains at Week 48. For example, patients in the Dose-escalation and Expansion Cohorts demonstrated a mean change in the Bayley-4 Cognition Growth Scale Value (GSV) score from baseline of +6.7, which is above the minimally important difference of +5. The Phase 3 primary endpoint of the Bayley-4 Cognition Raw Score showed a mean change from baseline of +10.9. This indicates that the Phase 3 study has greater than 95% power to detect a treatment effect, even if the placebo arm's response is up to three times higher than observed in natural history data.

Moreover, data from 28 patients in Expansion Cohorts A&B evaluated with the Phase 3 key secondary endpoint of MDRI showed a total net response of +2.0, with a p-value of less than 0.0001. Approximately 80% of these patients achieved clinically meaningful net improvement in at least one domain.

These findings bolster the confidence that the Phase 3 Aspire study is well-powered to confirm the efficacy of GTX-102 in improving cognition and other key domains measured by MDRI at the 48-week mark. GTX-102 has demonstrated a consistent and acceptable safety profile up to the data cutoff.

GTX-102 is delivered via intrathecal administration and designed to inhibit the expression of UBE3A-AS. Preclinical studies have shown that GTX-102 reduces UBE3A-AS levels and reactivates the expression of the paternal UBE3A allele in central nervous system neurons, which is linked to improvements in neurological symptoms associated with Angelman syndrome. The FDA has granted GTX-102 Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation, while the EMA has awarded it Orphan Designation and PRIME designation.

Ultragenyx is committed to developing innovative treatments for serious rare and ultra-rare genetic diseases. With a diverse portfolio of approved therapies and product candidates, the company focuses on delivering effective treatments quickly to meet high unmet medical needs. The experienced management team at Ultragenyx prioritizes efficient drug development to provide safe and effective therapies to patients with urgency.