[en] Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA.
Disciplines :
Pediatrics
Author, co-author :
Kirschner, Janbernd ; Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. Electronic address: Janbernd.kirschner@uniklinik-freiburg.de
Bernert, Günther; Neuromuscular Centre, Department of Pediatrics and Adolescent Medicine, Clinic Favoriten, Vienna, Austria
Butoianu, Nina; Pediatric Neurology Clinic, "Prof. Dr. Al. Obregia" Hospital, Bucharest, Faculty of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
De Waele, Liesbeth ; Department of Pediatric Neurology, University Hospitals Leuven, and Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Fattal-Valevski, Aviva ; Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Israel
Haberlova, Jana; Dept of Pediatric Neurology, Motol University Hospital, Prague, Czech Republic
Moreno, Teresa; Pediatric Neurology Unit, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
Klein, Andrea ; Division of Neuropaediatrics, Development and Rehabilitation, Department of Paediatrics, Inselspital, Bern University Hospital, Bern, Switzerland
Kostera-Pruszczyk, Anna ; Department of Neurology, Medical University of Warsaw, Poland
Mercuri, Eugenio; Pediatric Neurology, Università Cattolica del Sacro Cuore, and Centro Clinico Nemo, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Quijano-Roy, Susana; Neuromuscular Unit, Child Neurology and ICU Department, Raymond Poincaré University Hospital (UVSQ), APHP Paris Saclay, Garches, France
Sejersen, Thomas ; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden, Department Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, New Territories, Hong Kong, China
Tizzano, Eduardo F; Department of Clinical and Molecular Genetics, Medicine Genetics Group, University Hospital Vall d'Hebron, Barcelona, Spain
van der Pol, W Ludo; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, the Netherlands
Wallace, Sean; Department of Clinical Neurosciences for Children and Unit for Congenital and Hereditary Neuromuscular Disorders, Department of Neurology, Oslo University Hospital, Oslo, Norway
Zafeiriou, Dimitrios; 1st Department of Pediatrics, «Hippokratio» General Hospital, Aristotle University, Thessaloniki, Greece
Ziegler, Andreas ; Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Germany
Muntoni, Francesco; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, and NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children, London, UK
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques
Several authors of this manuscript are members of the European Reference Network for Rare Neuromuscular Diseases EURO-NMD (www.euro-nmd.eu). We would like to thank Adrian Tassoni from the Clinical Trials Unit of the Medical Center \u2013 University of Freiburg for setting up the anonymous online voting.
Annoussamy, M., Seferian, A.M., Daron, A., et al. Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study. Ann Clin Transl Neurol 8:2 (2021), 359–373.
Calucho, M., Bernal, S., Alias, L., et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul. Disord. 28:3 (2018), 208–215.
Wijngaarde, C.A., Stam, M., Otto, L.A.M., et al. Population-based analysis of survival in spinal muscular atrophy. Neurology 94:15 (2020), e1634–e1644.
Aragon-Gawinska, K., Mouraux, C., Dangouloff, T., Servais, L., Spinal muscular atrophy treatment in patients identified by newborn screening-A systematic review. Genes, 14(7), 2023.
Gowda, V., Atherton, M., Murugan, A., et al. 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. Lancet Reg Health Eur, 37, 2024, 100817.
Schwartz, O., Vill, K., Pfaffenlehner, M., et al. Clinical effectiveness of newborn screening for spinal muscular atrophy: a nonrandomized controlled trial. JAMA Pediatr. 178 (2024), 540–547.
Kirschner, J., Butoianu, N., Goemans, N., et al. European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy. Eur. J. Paediatr. Neurol. 28 (2020), 38–43.
Gusset, N., Erbas, Y., Germanenko, O., Rucinski, K., Stumpe, E., de Lemus, M., A Decision for Life - treatment decisions in newly diagnosed families with spinal muscular atrophy (SMA). Eur. J. Paediatr. Neurol. 30 (2021), 105–107.
Novartis. Novartis presents new data on safety and efficacy of Zolgensma, including maintained and improved motor milestones in older and heavier children with SMA. https://www.novartis.com/news, 2024.
Weiss, C., Ziegler, A., Becker, L.L., et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. Lancet Child Adolesc Health 6:1 (2022), 17–27.
Pane, M., Berti, B., Capasso, A., et al. Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naive patients with spinal muscular atrophy and following switch from other therapies. EClinicalMedicine, 59, 2023, 101997.
Bitetti, I., Lanzara, V., Margiotta, G., Varone, A., Onasemnogene abeparvovec gene replacement therapy for the treatment of spinal muscular atrophy: a real-world observational study. Gene Ther. 30:7–8 (2023), 592–597.
Finkel, R.S., Darras, B.T., Mendell, J.R., et al. Intrathecal onasemnogene abeparvovec for sitting, nonambulatory patients with spinal muscular atrophy: phase I ascending-dose study (STRONG). J. Neuromuscul. Dis. 10:3 (2023), 389–404.
Baranello, G., Darras, B.T., Day, J.W., et al. Risdiplam in type 1 spinal muscular atrophy. N. Engl. J. Med. 384:10 (2021), 915–923.
Mercuri, E., Deconinck, N., Mazzone, E.S., et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 21:1 (2022), 42–52.
Proud, C.M., Mercuri, E., Finkel, R.S., et al. Combination disease-modifying treatment in spinal muscular atrophy: a proposed classification. Ann Clin Transl Neurol, 2023.
Chiriboga, C.A., Bruno, C., Duong, T., et al. Risdiplam in patients previously treated with other therapies for spinal muscular atrophy: an interim analysis from the JEWELFISH study. Neurol Ther, 2023, 1–15.
Harada, Y., Rao, V.K., Arya, K., et al. Combination molecular therapies for type 1 spinal muscular atrophy. Muscle Nerve 62:4 (2020), 550–554.
Dangouloff, T., Hiligsmann, M., Deconinck, N., et al. Financial cost and quality of life of patients with spinal muscular atrophy identified by symptoms or newborn screening. Dev. Med. Child Neurol. 65:1 (2023), 67–77.
Friese, J., Geitmann, S., Holzwarth, D., et al. Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec -A single centre experience. J. Neuromuscul. Dis. 8:2 (2021), 209–216.
Servais, L., Day, J.W., De Vivo, D.C., et al. Real-world outcomes in patients with spinal muscular atrophy treated with onasemnogene abeparvovec monotherapy: findings from the RESTORE registry. J. Neuromuscul. Dis. 11:2 (2024), 425–442.
Shih, S.T.F., Keller, E., Wiley, V., Farrar, M.A., Wong, M., Chambers, G.M., Modelling the cost-effectiveness and budget impact of a newborn screening program for spinal muscular atrophy and severe combined immunodeficiency. Int J Neonatal Screen, 8(3), 2022.
Weidlich, D., Servais, L., Kausar, I., Howells, R., Bischof, M., Cost-effectiveness of newborn screening for spinal muscular atrophy in england. Neurol Ther 12:4 (2023), 1205–1220.
Dangouloff, T., Vrscaj, E., Servais, L., Osredkar, D., Group, S.N.W.S., Newborn screening programs for spinal muscular atrophy worldwide: where we stand and where to go. Neuromuscul. Disord. 31:6 (2021), 574–582.
Oskoui, M., Dangouloff, T., Servais, L., Universal newborn screening for spinal muscular atrophy. JAMA Pediatr., 178, 2024, 520.
