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<p>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 <i>UBE3A</i> 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 (<i>n</i> = 61, F/M: 28/33). Key exploratory endpoints assessing changes following rugonersen treatment were electroencephalogram <i>δ</i>-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: <a href="https://clinicaltrials.gov/search?cond=NCT04428281">NCT04428281</a>.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月11日

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  • Jörg F. Hipp,
  • Carlos A. Bacino,
  • Lynne M. Bird,
  • Ina Bruenig-Traebert,
  • Daniel Chan,
  • Marie Claire de Wit,
  • Paulo Fontoura,
  • Gregory Hooper,
  • Ravi Jagasia,
  • Michelle L. Krishnan,
  • Lorraine Murtagh,
  • Alessandro Noci,
  • Ana Roche Martínez,
  • Dietmar Schwab,
  • Mercedes Serrano,
  • Mark D. Shen,
  • Julian Tillmann,
  • Jorrit Tjeertes,
  • Brenda Vincenzi,
  • Elizabeth Berry-Kravis,
  • Azad Bonni,
  • Muhamed Barakovic,
  • Charlotte Bon,
  • Ponghatai Boonsimma,
  • Mariana Bustamante,
  • Katalin Buzasi,
  • Stormy Chamberlain,
  • Susanne Clinch,
  • Siobhan Connor-Ahmad,
  • Philipp Daetwyler,
  • Oana Danila,
  • Sebastian Holst,
  • Thomas Kremer,
  • Florian Lipsmeier,
  • Stefano Magon,
  • Amanda Messer,
  • David Nobbs,
  • Giuseppe Palermo,
  • Lisa Squassante,
  • Thomas Wiese,
  • Jennifer M. Bain,
  • Jamie Capal,
  • Ralitza Gavrilova,
  • María Muñoz Cabeza,
  • Nicola Pietrafusa,
  • Rajsekar Rajamaran,
  • Shafali Jeste,
  • Federico Vigevano

摘要

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.