Tim Hagenacker1, Claudia D Wurster2, René Günther3, Olivia Schreiber-Katz4, Alma Osmanovic4, Susanne Petri4, Markus Weiler5, Andreas Ziegler6, Josua Kuttler7, Jan C Koch7, Ilka Schneider8, Gilbert Wunderlich9, Natalie Schloss10, Helmar C Lehmann10, Isabell Cordts11, Marcus Deschauer11, Paul Lingor11, Christoph Kamm12, Benjamin Stolte13, Lena Pietruck13, Andreas Totzeck13, Kathrin Kizina13, Christoph Mönninghoff14, Otgonzul von Velsen15, Claudia Ose15, Heinz Reichmann16, Michael Forsting14, Astrid Pechmann17, Janbernd Kirschner18, Albert C Ludolph19, Andreas Hermann20, Christoph Kleinschnitz13. 1. Department of Neurology, University Hospital Essen, Essen, Germany. Electronic address: tim.hagenacker@uk-essen.de. 2. Department of Neurology, Ulm University, Ulm, Germany. 3. Department of Neurology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Center for Neurodegenerative Diseases Dresden, Dresden, Germany. 4. Department of Neurology, Hanover Medical School, Hanover, Germany. 5. Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany. 6. Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany. 7. Department of Neurology, University Medicine Göttingen, Göttingen, Germany. 8. Department of Neurology, University Hospital Halle (Saale), Halle (Saale), Germany. 9. Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 10. Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 11. Department of Neurology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. 12. Department of Neurology, University of Rostock, Rostock, Germany. 13. Department of Neurology, University Hospital Essen, Essen, Germany. 14. Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany. 15. Institute of Medical Informatics, Biometrics, and Epidemiology, University Hospital Essen, Essen, Germany; Center for Clinical Trials, University Hospital Essen, Essen, Germany. 16. Department of Neurology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 17. Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany. 18. Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany; Department of Neuropediatrics, University Medical Center Bonn, Bonn, Germany. 19. Department of Neurology, Ulm University, Ulm, Germany; German Center for Neurodegenerative Diseases Ulm, Ulm, Germany. 20. Department of Neurology, University of Rostock, Rostock, Germany; Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; German Center for Neurodegenerative Diseases Rostock, Rostock, Germany.
Abstract
BACKGROUND: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.
BACKGROUND: Nusinersen is approved for the treatment of 5qspinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5qspinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5qspinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5qspinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.
Authors: Tina Duong; Connie Wolford; Michael P McDermott; Chelsea E Macpherson; Amy Pasternak; Allan M Glanzman; William B Martens; Elizabeth Kichula; Basil T Darras; Darryl C De Vivo; Zarazuela Zolkipli-Cunningham; Richard S Finkel; Michael Zeineh; Max Wintermark; Jacinda Sampson; Katharine A Hagerman; Sally Dunaway Young; John W Day Journal: Neurol Clin Pract Date: 2021-06
Authors: Er Chen; Stacy Dixon; Rupali Naik; Josh M Noone; J Daniel Buchenberger; Sarah M Whitmire; Rosalina Mills; William Arnold Journal: Muscle Nerve Date: 2020-12-19 Impact factor: 3.217
Authors: Maria Carmela Pera; Giorgia Coratti; Francesca Bovis; Marika Pane; Amy Pasternak; Jacqueline Montes; Valeria A Sansone; Sally Dunaway Young; Tina Duong; Sonia Messina; Irene Mizzoni; Adele D'Amico; Matthew Civitello; Allan M Glanzman; Claudio Bruno; Francesca Salmin; Simone Morando; Roberto De Sanctis; Maria Sframeli; Laura Antonaci; Anna Lia Frongia; Annemarie Rohwer; Mariacristina Scoto; Darryl C De Vivo; Basil T Darras; John Day; William Martens; Katia A Patanella; Enrico Bertini; Francesco Muntoni; Richard Finkel; Eugenio Mercuri Journal: Ann Clin Transl Neurol Date: 2021-06-24 Impact factor: 4.511