Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom.
Efficacy; Follow-up; Gene therapy; Longitudinal; Motor neuron disorder; Onasemnogene abeparvovec; Real-world experience; SMA; Safety; Spinal muscular atrophy; United Kingdom; Zolgensma; Internal Medicine; Oncology; Health Policy
Abstract :
[en] [en] BACKGROUND: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg.
METHODS: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements.
FINDINGS: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported.
INTERPRETATION: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients.
FUNDING: Novartis Innovative Therapies AG provided a grant for independent medical writing services.
Disciplines :
Pediatrics
Author, co-author :
Gowda, Vasantha ; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Atherton, Mark; Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom
Murugan, Archana; Department of Paediatric Neurology, University Hospital Bristol, Bristol, United Kingdom
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; MDUK Oxford Neuromuscular Centre and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
Sheehan, Jennie; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Standing, Emma; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Manzur, Adnan; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom
Scoto, Mariacristina; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom
Baranello, Giovanni ; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom ; NIHR Great Ormond Street Hospital Biomedical Research Centre and Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
Munot, Pinki; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom
McCullagh, Gary; Royal Manchester Children's Hospital, Manchester, United Kingdom
Willis, Tracey ; Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, United Kingdom
Tirupathi, Sandya; Royal Belfast Hospital for Sick Children, Belfast, United Kingdom
Horrocks, Iain; Royal Hospital for Children, Glasgow, United Kingdom
Dhawan, Anil; Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital, London, United Kingdom
Eyre, Michael; School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom
Vanegas, Maria ; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Fernandez-Garcia, Miguel A; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Wolfe, Amy; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Pinches, Laura; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Illingworth, Marjorie; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
Main, Marion; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom
Abbott, Lianne; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom
Smith, Hayley; Department of Paediatric Neurology, University Hospital Bristol, Bristol, United Kingdom
Milton, Emily; Department of Paediatric Neurology, University Hospital Bristol, Bristol, United Kingdom
D'Urso, Sarah; Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom
Vijayakumar, Kayal; Chelsea and Westminster Hospital, London, United Kingdom
Marco, Silvia Sanchez ; Paediatric Neurology Department, University Hospital of Wales, Cardiff, United Kingdom
Warner, Sinead; Royal Manchester Children's Hospital, Manchester, United Kingdom
Reading, Emily; Royal Manchester Children's Hospital, Manchester, United Kingdom
Douglas, Isobel; Royal Belfast Hospital for Sick Children, Belfast, United Kingdom
Muntoni, Francesco; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, United Kingdom ; NIHR Great Ormond Street Hospital Biomedical Research Centre and Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
Ong, Min ; Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom
Majumdar, Anirban; Department of Paediatric Neurology, University Hospital Bristol, Bristol, United Kingdom
Hughes, Imelda; Royal Manchester Children's Hospital, Manchester, United Kingdom
Jungbluth, Heinz; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom ; Randall Centre for Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine (FoLSM), London, King's College London, London, United Kingdom ; King's College London, London, United Kingdom
Wraige, Elizabeth; Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom.
Novartis Innovative Therapies AG provided a grant for independent medical writing services.Proof-reading, editing and formatting assistance for some sections of the manuscript was provided by Oxford PharmaGenesis, independent medical writer, funded by Evelina London Children's Hospital. Novartis Innovative Therapies AG provided a grant to Evelina London Children's Hospital for independent medical writing services. We acknowledge our non-author collaborators the SMAREACH consortium (a list of members and affiliations for the SMAREACH consortium appears in Supplement 2) and Prof Ming Lim, Evelina London Children's Hospital for critical review of the manuscript.
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