Claudia Weiß1, Andreas Ziegler2, Lena-Luise Becker3, Jessika Johannsen4, Heiko Brennenstuhl2, Gudrun Schreiber5, Marina Flotats-Bastardas6, Corinna Stoltenburg1, Hans Hartmann7, Sabine Illsinger7, Jonas Denecke4, Astrid Pechmann8, Wolfgang Müller-Felber9, Katharina Vill9, Astrid Blaschek9, Martin Smitka10, Lieske van der Stam1, Katja Weiss11, Benedikt Winter12, Klaus Goldhahn13, Barbara Plecko14, Veronka Horber15, Günther Bernert16, Ralf A Husain17, Christian Rauscher18, Regina Trollmann19, Sven F Garbade2, Andreas Hahn20, Maja von der Hagen10, Angela M Kaindl21. 1. Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany. 2. Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 3. Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. 4. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Department of Pediatric Neurology, Klinikum Kassel, Kassel, Germany. 6. Department of Pediatric Neurology, University Hospital Homburg, Homburg, Germany. 7. Hannover Medical School, Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover, Germany. 8. Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Freiburg, Germany. 9. Department of Paediatric Neurology and Developmental Medicine, Hauner Children's Hospital, Ludwig Maximilian University of Munich, Munich, Germany. 10. Department of Neuropediatrics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 11. Department of Pediatric Cardiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. 12. Department of Pediatrics, Ulm University, Ulm, Germany. 13. Department of Pediatrics and Neuropediatrics, DRK Klinikum Westend, Berlin, Germany. 14. Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University Graz, Graz, Austria. 15. Department of Paediatric Neurology, University Children's Hospital, Tübingen, Germany. 16. Department of Pediatrics, Klinik Favoriten, Vienna, Austria. 17. Department of Neuropediatrics, Jena University Hospital, Jena, Germany. 18. Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria. 19. Department of Pediatrics, Division of Pediatric Neurology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany. 20. Department of Child Neurology, University Hospital, Gießen, Germany. 21. Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address: angela.kaindl@charite.de.
Abstract
BACKGROUND: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. METHODS: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. FINDINGS: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings. INTERPRETATION: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. FUNDING: None. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.
BACKGROUND: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. METHODS: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. FINDINGS: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings. INTERPRETATION: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. FUNDING: None. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.
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