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Clinical Trial
. 2025 Sep;31(9):2936-2945.
doi: 10.1038/s41591-025-03784-7. Epub 2025 Jul 11.

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

Jörg F Hipp  1 , Carlos A Bacino  2 , Lynne M Bird  3 , Ina Bruenig-Traebert  4 , Daniel Chan  5 , Marie Claire de Wit  6 , Paulo Fontoura  7 , Gregory Hooper  8 , Ravi Jagasia  4 , Michelle L Krishnan  4 , Lorraine Murtagh  4 , Alessandro Noci  9 , Ana Roche Martínez  10 , Dietmar Schwab  11 , Mercedes Serrano  12 , Mark D Shen  13 , Julian Tillmann  4 , Jorrit Tjeertes  9 , Brenda Vincenzi  9 , Elizabeth Berry-Kravis  14 , Azad Bonni  4 ; Rugonersen Study Group; all TANGELO investigators
Collaborators, Affiliations
Clinical Trial

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

Jörg F Hipp et al. Nat Med. 2025 Sep.

Abstract

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 .

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Conflict of interest statement

Competing interests: J.F.H., D.C., G.H., L.M., A.N., D.S., J. Tillmann and A.B. are employees of F. Hoffmann-La Roche. I.B.T., M.L.K., J. Tjeertes, B.V., P.F. and R.J. are former employees of F. Hoffmann-La Roche. M.L.K. is currently an employee of Biomedical Research, Translational Medicine, Novartis AG, Basel, Switzerland. J. Tjeertes is currently an employee of Bayer AG, Basel Switzerland. P.F. is Chief Scientific and Clinical Development Advisor, Stalicla SA, Geneva, Switzerland. L.M.B. has received funding from Aardvark Therapeutics, Acadia Pharmaceuticals, Biogen, Ionis Pharmaceuticals, F. Hoffman-La Roche, Gedeon Richter, Neuren Pharmaceuticals, Ovid Therapeutics, PTC Therapeutics, Radius Health, Soleno Therapeutics and Ultragenyx to conduct clinical trials or consult on trial design or results. E.B.-K. has received funding from Acadia, Alcobra, AMO, Asuragen, Avexis, Biogen, BioMarin, Cydan, Engrail, Erydel, Fulcrum, GeneTx, GW, Healx, Ionis, Jaguar, Kisbee, Lumos, Marinus, Mazhi, Moment Biosciences, Neuren, Neurogene, Neurotrope, Novartis, Orphazyme/Kempharm/Zevra, Ovid, PTC Therapeutics, Retrophin, Roche, Seaside Therapeutics, Taysha, Tetra, Ultragenyx, Yamo, Zynerba and Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, to consult on trial design or run clinical or lab validation trials in genetic neurodevelopmental or neurodegenerative disorders, all of which are directed to RUMC in support of rare disease programs. E.B.-K. receives no personal funds, and Rush University Medical Center has no relevant financial interest in any of the commercial entities listed. For M.C.d.W., Erasmus MC received compensation for participation in the Tangelo trial from Hoffmann-La Roche, and for consultation from Jazz Pharmaceuticals. M.D.S. has received research funding from Biogen, Ionis and Roche to conduct clinical trials or research studies. All funds were paid to the University of North Carolina; M.D.S. receives no personal funds and has no relevant financial interest in any of the commercial entities listed. The other authors declare no competing interests.

References

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