Ultragenyx Pharmaceutical Inc. Presents Positive Update on GTX-102 Angelman Syndrome Program at FAST?s 17th Annual Global Science Summit

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Ultragenyx Pharmaceutical Inc. announced Phase 1/2 data in support of the Phase 3 Aspire study for GTX-102, its investigational antisense oligonucleotide for Angelman syndrome, that will be presented at the 2024 Foundation for Angelman Syndrome Therapeutics (FAST) Global Science Summit in Orlando, Florida. The global Phase 3 Aspire study will enroll approximately 120 patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion and will include 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.

As of the September Phase 1/2 data cut-off, patients in the Dose Expansion Cohorts demonstrated continued improvement across multiple domains at Week 48 (Day 338). 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. 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. GTX-102 demonstrated a consistent and acceptable safety profile as of the data cutoff. GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and designed to target and inhibit expression of UBE3A-AS.

Nonclinical studies have shown 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.

The Phase 1/2, open-label, multiple-dose, dose-escalating study is evaluating the safety and tolerability of GTX-102 administered by intrathecal (IT) injection to pediatric patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study is also assessing clinical response as measured by a panel of efficacy assessments for the functional domains impacted in Angelman syndrome. The study has enrolled and treated 74 patients in both Dose-escalation and Expansion Cohorts.

Patients in Dose-escalation Cohorts 4-7 are receiving long-term maintenance dosing. Data from the Expansion Cohorts will be used to verify the GTX-102 dose and treatment regimen for the pivotal Phase 3 study.