TY - JOUR
T1 - Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region
T2 - a population-based observational study
AU - SMArtCARE and Swiss-Reg-NMD study group
AU - Weiß, Claudia
AU - Becker, Lena Luise
AU - Friese, Johannes
AU - Blaschek, Astrid
AU - Hahn, Andreas
AU - Illsinger, Sabine
AU - Schwartz, Oliver
AU - Bernert, Günther
AU - Hagen, Maja von der
AU - Husain, Ralf A.
AU - Goldhahn, Klaus
AU - Kirschner, Janbernd
AU - Pechmann, Astrid
AU - Flotats-Bastardas, Marina
AU - Schreiber, Gudrun
AU - Schara, Ulrike
AU - Plecko, Barbara
AU - Trollmann, Regina
AU - Horber, Veronka
AU - Wilichowski, Ekkehard
AU - Baumann, Matthias
AU - Klein, Andrea
AU - Eisenkölbl, Astrid
AU - Köhler, Cornelia
AU - Stettner, Georg M.
AU - Cirak, Sebahattin
AU - Hasselmann, Oswald
AU - Kaindl, Angela M.
AU - Garbade, Sven F.
AU - Johannsen, Jessika
AU - Ziegler, Andreas
AU - Baum, Petra
AU - Baumgartner, Manuela
AU - Bertsche, Astrid
AU - Blankenburg, Markus
AU - Denecke, Jonas
AU - Deschauer, Marcus
AU - Eckenweiler, Matthias
AU - Geis, Tobias
AU - Groß, Martin
AU - Günther, René
AU - Hagenacker, Tim
AU - Hamelmann, Eckard
AU - Kamm, Christoph
AU - Kauffmann, Birgit
AU - Koch, Jan Christoph
AU - Löscher, Wolfgang
AU - Ludolph, Albert
AU - Martin, Pascal
AU - Lingor, Paul
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/12
Y1 - 2024/12
N2 - Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).
AB - Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).
KW - Gene addition therapy
KW - Gene therapy
KW - Onasemnogene abeparvovec
KW - SMA
KW - Spinal muscular atrophy
KW - Zolgensma
UR - http://www.scopus.com/inward/record.url?scp=85205675214&partnerID=8YFLogxK
U2 - 10.1016/j.lanepe.2024.101092
DO - 10.1016/j.lanepe.2024.101092
M3 - Article
AN - SCOPUS:85205675214
SN - 2666-7762
VL - 47
JO - The Lancet Regional Health - Europe
JF - The Lancet Regional Health - Europe
M1 - 101092
ER -