Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial

Jennifer M Kwon¹, Francina Munell², Laure Le Goff³, Kotaro Yuge⁴, Tamaki Kato⁵, Claude Cances⁶, Liesbeth De Waele^{7

8}, Ian R Woodcock^{9

10}, Eugenio M Mercuri^{11

12}, Crystal M Proud¹³, Basil T Darras¹⁴, Leslie H Hayes¹⁴, Maryam Oskoui^{15

16}, Jeannie Visootsak¹⁷, Gemma Williams¹⁸, Andreja Ilić¹⁹, Lina Yang¹⁷, W Ludo van der Pol²⁰

Affiliations

¹ American Family Children's Hospital, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. kwon@neurology.wisc.edu.
² Department of Pediatric Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
³ Department of Physical Medicine and Rehabilitation, Hôpital Femme Mère Enfant - Hospices Civils de Lyon, Lyon, France.
⁴ Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
⁵ Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
⁶ Department of Paediatric Neurology, Reference Centre for Neuromuscular Disorders AOC, and Paediatric Clinical Research Unit Children's Hospital, Toulouse University Hospital Center, Toulouse, France.
⁷ Department of Paediatric Neurology, Neuromuscular Reference Centre for Children, University Hospitals Leuven, Leuven, Belgium.
⁸ Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
⁹ Department of Neurology, The Royal Children's Hospital, Melbourne, Victoria, Australia.
¹⁰ The Murdoch Children's Research Institute, Parkville, Victoria, Australia.
¹¹ Paediatric Neurology, Catholic University, Rome, Italy.
¹² Nemo Clinical Centre, Fondazione Policlinico Gemelli, IRCCS, Rome, Italy.
¹³ Children's Hospital of The King's Daughters, Norfolk, VA, USA.
¹⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Departments of Neurology and Neurosurgery and Pediatric, McGill University, Montreal, Quebec, Canada.
¹⁶ Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
¹⁷ Novartis Pharmaceuticals, East Hanover, NJ, USA.
¹⁸ Novartis Pharmaceuticals, London, UK.
¹⁹ Novartis Pharmaceuticals, Basel, Switzerland.
²⁰ UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands.

PMID: 41360995
DOI: 10.1038/s41591-025-04119-2

Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial

Jennifer M Kwon et al. Nat Med. 2025.

. 2025 Dec 8.

doi: 10.1038/s41591-025-04119-2. Online ahead of print.

Authors

Affiliations

¹ American Family Children's Hospital, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. kwon@neurology.wisc.edu.
² Department of Pediatric Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
³ Department of Physical Medicine and Rehabilitation, Hôpital Femme Mère Enfant - Hospices Civils de Lyon, Lyon, France.
⁴ Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
⁵ Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
⁶ Department of Paediatric Neurology, Reference Centre for Neuromuscular Disorders AOC, and Paediatric Clinical Research Unit Children's Hospital, Toulouse University Hospital Center, Toulouse, France.
⁷ Department of Paediatric Neurology, Neuromuscular Reference Centre for Children, University Hospitals Leuven, Leuven, Belgium.
⁸ Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
⁹ Department of Neurology, The Royal Children's Hospital, Melbourne, Victoria, Australia.
¹⁰ The Murdoch Children's Research Institute, Parkville, Victoria, Australia.
¹¹ Paediatric Neurology, Catholic University, Rome, Italy.
¹² Nemo Clinical Centre, Fondazione Policlinico Gemelli, IRCCS, Rome, Italy.
¹³ Children's Hospital of The King's Daughters, Norfolk, VA, USA.
¹⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Departments of Neurology and Neurosurgery and Pediatric, McGill University, Montreal, Quebec, Canada.
¹⁶ Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
¹⁷ Novartis Pharmaceuticals, East Hanover, NJ, USA.
¹⁸ Novartis Pharmaceuticals, London, UK.
¹⁹ Novartis Pharmaceuticals, Basel, Switzerland.
²⁰ UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands.

PMID: 41360995
DOI: 10.1038/s41591-025-04119-2

Erratum in

Author Correction: Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial.
Kwon JM, Munell F, Le Goff L, Yuge K, Kato T, Cances C, De Waele L, Woodcock IR, Mercuri EM, Proud CM, Darras BT, Hayes LH, Oskoui M, Visootsak J, Williams G, Ilić A, Yang L, van der Pol WL. Kwon JM, et al. Nat Med. 2026 Jan 28. doi: 10.1038/s41591-026-04233-9. Online ahead of print. Nat Med. 2026. PMID: 41606122 No abstract available.

Abstract

Intrathecal onasemnogene abeparvovec (OAV101 IT) may enable a one-time gene transfer therapy, addressing an unmet need across the broader spinal muscular atrophy (SMA) population. STRENGTH ( NCT05386680 ) was a 52-week, phase 3b, single-arm, open-label, multicenter study evaluating OAV101 IT in participants with SMA aged 2 to <18 years who discontinued nusinersen or risdiplam. The primary objective was safety/tolerability. Twenty-seven participants were enrolled (mean (s.d.) age at OAV101 IT, 7.4 (3.35) years; range, 2.4-17.7 years) with prior nusinersen or risdiplam (mean (s.d.) duration of 4.3 (1.07) years; range, 1.86-6.18 years or 3.0 (2.02); range, 0.39-6.28 years). All (n = 27) experienced at least one adverse event (AE), most frequently nasopharyngitis (n = 15, 55.6%), pyrexia (n = 14, 51.9%) and vomiting (n = 13, 48.1%). Thirteen participants (48.1%) experienced treatment-related AEs, most frequently vomiting (n = 6, 22.2%), headache (n = 4, 14.8%) and pyrexia (n = 3, 11.1%). Serious adverse events (SAEs) were reported for four participants (n = 4, 14.8%) (mostly respiratory infection related). No AEs leading to death or study discontinuation were reported. Adverse events of special interest (AESI) reported were in categories of transient thrombocytopenia (n = 8, 29.6%), hepatotoxicity (n = 4, 14.8%) and signs and symptoms that may be suggestive of dorsal root ganglia toxicity (n = 2, 7.4%). The OAV101 IT safety profile was consistent with findings in treatment-naïve patients. Trial registration: ClinicalTrials.gov identifier: NCT05386680 .

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Conflict of interest statement

Competing interests: Novartis Pharma sponsored this clinical trial. The authors declare the following competing interests. J.M.K. served as a site principal investigator for clinical trials sponsored by Novartis Gene Therapies/Novartis Pharma and Scholar Rock and has received honoraria for serving on an advisory board for Novartis. L.L.G. has received payments for consulting from Roche; served as a member of advisory boards for Novartis; received non-financial support from Roche, Novartis and Biogen; and served as a principal investigator in clinical trials for Novartis, Genethon and PTC. C.C. has received consultancy payments from Roche; has been a non-remunerated member of advisory boards for Novartis, Roche and Pfizer; and has been a principal investigator in clinical trials for Novartis, Sarepta, Biogen, Roche and Scholar Rock. L.D.W. has received speaker and consulting fees from Novartis Gene Therapies/Novartis Pharma, Biogen and Roche; has worked as a principal investigator of SMA studies sponsored by Novartis Gene Therapies/Novartis Pharma, Roche, Scholar Rock and Biohaven; and has received research grants from Novartis Gene Therapies/Novartis Pharma and Roche. She is also a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). I.R.W. has received honoraria for work performed with Novartis, Biogen, Roche and Pfizer. E.M.M. has received honoraria for scientific advisory boards and educational speaker fees from Biogen, Novartis, F. Hoffmann-La Roche, Sarepta Therapeutics, Santhera Pharmaceuticals, PTC Therapeutics, Pfizer, Scholar Rock and Cytokinetics and has received research support grants from Biogen. His institution receives funding for clinical research from Biogen, Novartis, Roche and Scholar Rock. C.M.P. has served as a consultant for Novartis Gene Therapies/Novartis Pharma, Biogen and Sarepta; served on a speaker’s bureau for Novartis Gene Therapies/Novartis Pharma and Biogen; and received research support from Novartis Gene Therapies/Novartis Pharma, Biogen, Sarepta, PTC, CSL Behring, Scholar Rock and Catabasis. B.T.D. has served as an ad-hoc scientific advisory board member for Novartis Gene Therapies/Novartis Pharma, Merck, Sarepta, Scholar Rock and Roche/Genentech; as a steering committee chair/member for Roche FIREFISH and MANATEE studies; and as a Data and Safety Monitoring Board member for argenX BV and Lexeo Therapeutics. He has no financial interests in any of these companies. B.T.D. has also received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, Cure SMA and the Working on Walking Fund and grants from Biogen for CS11 and ASCEND studies and from Sarepta Pharmaceuticals, Novartis (Novartis Gene Therapies), PTC Therapeutics, Roche and Scholar Rock. L.H.H. is the site principal investigator for trials sponsored by Novartis, Biohaven, Vertex, Biogen and Astellas. She is also a consultant for Biohaven. F.M. has served as a consultant, scientific advisory board member and site principal investigator for trials sponsored by Novartis, Biogen and Roche. K.Y. and T.K. have no conflicts related to this work to disclose. M.O.’s institution has received research support as a clinical trial site for Novartis Pharmaceuticals, Roche/Genentech and Santhera Pharmaceuticals. W.L.v.d.P. is member of the scientific advisory board of SMA Europe and site principal investigator for trials sponsored by Biogen, Roche, Novartis, Scholar Rock, Biohaven and NMD Pharma. His employer received fees for consultancy service from these companies. J.V., G.W., A.I. and L.Y. are employees of Novartis and own stock/other equities.

References

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1. Aragon-Gawinska, K., Mouraux, C., Dangouloff, T. & Servais, L. Spinal muscular atrophy treatment in patients identified by newborn careening: a systematic review. Genes 14, 1377 (2023). - DOI - PubMed - PMC
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Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial

Affiliations

Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

Associated data

LinkOut - more resources

Full Text Sources

Medical