The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial.

Angelman syndrome (AS) is a severe genetic neurodevelopmental disorder with no disease-modifying treatments. AS is caused by deletion or mutation of the neuronally imprinted gene encoding the ubiquitin-protein ligase E3A (UBE3A). Rugonersen (RO7248824) is an antisense oligonucleotide that reinstates UBE3A by derepressing the silenced paternal allele. TANGELO was a phase 1, multicenter, open-label, multiple-ascending-dose trial with a long-term extension to investigate the safety and tolerability (primary) and pharmacokinetics (secondary) of rugonersen in children aged 1-12 years with AS (n = 61, F/M: 28/33). Key exploratory endpoints assessing changes following rugonersen treatment were electroencephalogram δ-power (2-4 Hz) and domains of the Bayley Scales of Infant and Toddler Development-Third Edition and Vineland Adaptive Behavior Scales-Third Edition. The primary endpoint was met; rugonersen had an acceptable safety and tolerability profile. Analysis of exploratory endpoints showed that rugonersen led to a dose-dependent partial normalization of the AS-associated electroencephalogram abnormality and revealed signals of clinical improvement in core AS symptom domains beyond expectation from natural history data. The results of the primary study objective support continued development of rugonersen for AS. ClinicalTrials.gov registration: NCT04428281 .