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Original research
Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3
  1. Lorenzo Maggi1,
  2. Luca Bello2,
  3. Silvia Bonanno1,
  4. Alessandra Govoni3,4,
  5. Claudia Caponnetto5,
  6. Luigia Passamano6,
  7. Marina Grandis5,7,
  8. Francesca Trojsi8,
  9. Federica Cerri9,
  10. Manfredi Ferraro10,
  11. Virginia Bozzoni2,
  12. Luca Caumo2,
  13. Rachele Piras11,
  14. Raffaella Tanel12,
  15. Elena Saccani13,
  16. Megi Meneri3,
  17. Veria Vacchiano14,
  18. Giulia Ricci4,
  19. Gianni Soraru'2,
  20. Eustachio D'Errico15,
  21. Irene Tramacere16,
  22. Sara Bortolani10,
  23. Giovanni Pavesi17,
  24. Riccardo Zanin18,
  25. Mauro Silvestrini19,20,
  26. Luisa Politano6,
  27. Angelo Schenone5,7,
  28. Stefano Carlo Previtali9,
  29. Angela Berardinelli21,
  30. Mara Turri22,
  31. Lorenzo Verriello23,
  32. Michela Coccia20,
  33. Renato Mantegazza1,
  34. Rocco Liguori14,24,
  35. Massimiliano Filosto25,26,
  36. Gianni Marrosu27,
  37. Gabriele Siciliano4,
  38. Isabella Laura Simone15,
  39. Tiziana Mongini10,
  40. Giacomo Comi3,28,
  41. Elena Pegoraro2
  1. 1 Neuroimmunology and Neuromuscular Disease Unit, Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy
  2. 2 Department of Neurosciences, University of Padua, Padova, Veneto, Italy
  3. 3 Neuromuscular and Rare Disease Unit, La Fondazione IRCCS Ca' Granda Ospedale Maggiore di Milano Policlinico, Milano, Italy
  4. 4 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  5. 5 IRCCS AOU San Martino, Genova, Liguria, Italy
  6. 6 Cardiomyology and Medical Genetics Unit, Università degli Studi della Campania Luigi Vanvitelli Scuola di Medicina e Chirurgia, Napoli, Campania, Italy
  7. 7 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy
  8. 8 First Division of Neurology, Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania Luigi Vanvitelli Scuola di Medicina e Chirurgia, Napoli, Campania, Italy
  9. 9 Division of Neuroscience, Department of Neurology & INSPE, San Raffaele Hospital, Milano, Lombardia, Italy
  10. 10 Department of Neurosciences Rita Levi Montalcini, Università degli Studi di Torino, Torino, Piemonte, Italy
  11. 11 ATS Sardegna, Carbonia, Sardegna, Italy
  12. 12 U.O. Neurologia, Presidio Ospedaliero Santa Chiara, Trento, Trentino-Alto Adige, Italy
  13. 13 Specialistic Medicine Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Emilia-Romagna, Italy
  14. 14 UOC Clinica Neurologica, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Emilia-Romagna, Italy
  15. 15 Department of Basic Medical Science, Neuroscience and Sense Organs, Università degli Studi di Bari, Bari, Puglia, Italy
  16. 16 Department of Research and Clinical Development, Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Lombardia, Italy
  17. 17 Neurosciences, University of Parma, Parma, Emilia-Romagna, Italy
  18. 18 Developmental Neurology, Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy
  19. 19 Department of Experimental and Clinical Medicine, Universita Politecnica delle Marche Facolta di Medicina e Chirurgia, Ancona, Italy
  20. 20 Department of Neurological Sciences, AOU Ospedali Riuniti di Ancona, Ancona, Marche, Italy
  21. 21 Department of Child Neuropsychiatry, Fondazione Istituto Neurologico Nazionale C Mondino Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Lombardia, Italy
  22. 22 Department of Neurology/Stroke Unit, Bolzano Hospital, Bolzano, Trentino-Alto Adige, Italy
  23. 23 Neurology Unit, Department of Neurosciences, University Hospital Santa Maria della Misericordia, Udine, Friuli-Venezia Giulia, Italy
  24. 24 Department of Biomedical and Neuromotor Sciences, Universita degli Studi di Bologna, Bologna, Italy
  25. 25 ERN-EURO NMD Center for Neuromuscular Diseases and Unit of Neurology, Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Lombardia, Italy
  26. 26 University of Brescia, Brescia, Italy
  27. 27 Multiple Sclerosis Center, Ospedale Binaghi, Cagliari, Sardegna, Italy
  28. 28 Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, University of Milan, Milano, Lombardia, Italy
  1. Correspondence to Dr Lorenzo Maggi, Neuroimmunology and Neuromuscular Diseases, Foundation IRCCS Carlo Besta Neurological Institute, Milano 20133, Italy; lorenzo.maggi{at}istituto-besta.it

Abstract

Objective To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).

Methods Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).

Results We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14.

Conclusions Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

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Footnotes

  • Contributors LM planned the study, performed data analysis and their interpretation, drafted the manuscript and submitted the manuscript. LB performed data analysis and their interpretation and drafted the manuscript. SB collected data, contributed to data interpretation and revised the manuscript. AG collected data and revised the manuscript. CC collected data and revised the manuscript. LP collected data and revised the manuscript. MG collected data and revised the manuscript. FT collected data and revised the manuscript. FC collected data and revised the manuscript. MF collected data and revised the manuscript. VB collected data and revised the manuscript. LC collected data and revised the manuscript. RP collected data and revised the manuscript. RT collected data and revised the manuscript. ES collected data and revised the manuscript. MM collected data and revised the manuscript. GC collected data and revised the manuscript. G Soraru collected data and revised the manuscript. VV collected data and revised the manuscript. EDE collected data and revised the manuscript. TT performed data analysis and their interpretation. SB collected data and revised the manuscript. GP contributed to interpretation of data and revised the manuscript. RZ collected data, contributed to interpretation of data and revised the manuscript. MS contributed to interpretation of data and revised the manuscript. LP contributed to interpretation of data and revised the manuscript. AS contributed to interpretation of data and revised the manuscript. SCP contributed to interpretation of data and revised the manuscript. AB collected data, contributed to interpretation of data and revised the manuscript. MT collected data, contributed to interpretation of data and revised the manuscript. LV collected data, contributed to interpretation of data and revised the manuscript. MC collected data, contributed to interpretation of data and revised the manuscript. RM contributed to interpretation of data and revised the manuscript. RL contributed to interpretation of data and revised the manuscript. MF collected data, contributed to interpretation of data and revised the manuscript. GM contributed to interpretation of data and revised the manuscript. GS contributed to interpretation of data and revised the manuscript. ILS contributed to interpretation of data and revised the manuscript. TM contributed to interpretation of data and revised the manuscript. GC planned the study, contributed to interpretation of data and drafted the manuscript. EP planned the study, contributed to interpretation of data and drafted the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests LM has received honoraria for speaking and compensation for congress participations from: Sanofi Genzyme and Biogen. LB reports speaker honoraria from PTC Therapeutics, participation in advisory boards for PTC Therapeutics and Sarepta Therapeutics and participation in research sponsored by Santhera Pharmaceuticals. SB received funds for travel and congress participation from Sanofi Genzyme and Biogen. LP has received compensation for congress participations from: Sanofi Genzyme and Biogen. MG received honoraria for speaking and grants to attend scientific meetings from Sanofi-Genzyme and Pfizer. VB compensation for congress participations from Biogen and Sanofi Genzyme. LC received compensation for congress participations from Biogen. RP has received compensation for congress participation from Sanofi Genzyme and Biogen. RT has received compensation for congress participations from Sanofi Genzyme, Biogen and Roche. ES has received compensation for congress participations from: Biogen. GR has received compensation for congress participations from Sanofi Genzyme, CSL Behring, Santhera and Biogen. RZ has received funds for travel and congress participation from Biogen. MS has received speaker’s honoraria from ITALFARMACO, PIAM, Boheringer and Novartis Pharmaceuticals. LP received compensation for congress participations from Biogen Inc, Italy. AS received honoraria for speaking and grants to attend scientific meetings from Sanofi-Genzyme, Alnylam Pharmaceuticals, Akcea Therapeutics and Pfizer. LV has received compensation for congress participation from Sanofi Genzyme and Biogen. RM received compensation for participating on advisory boards in relation to MG clinical trial design, congress participations and research support in the last 5 years from: Catalyst Pharmaceuticals, Alexion Pharmaceuticals, ARGENX Pharma, Biomarin. RL has received: Lecture fees from LT3 s.r.l., NICO s.r.l., SUMMEET s.r.l. and GALEN SYMPOSION s.r.o.; fees for consultancy (Advisory Board) from LT3 s.r.l. and PREX s.r.l.; fees for scientific meeting organization from I & C s.r.l.; Chair meeting fees from PLANNING CONGRESSI s.r.l. GC in the last two years has received compensation for advisory board compensation from: Sanofi Genzyme, Spark, Roche, Lupin and Santhera, congress participations from: Sanofi Genzyme, CSL Behring, Sarepta and Biogen. ILS received compensation for congress participation from Biogen, Italy. TM has received compensation for Scientific Board participations from Sanofi Genzyme; for congress participation from Biogen. GC received compensation for participation ad advisory board for Roche, Sarepta and Italfarmaco. EP reports personal fees from Sarepta, grants and non-financial support from Santhera, personal fees and non-financial support from PTC Pharmaceuticals, non-financial support from Genzyme, personal fees from Roche, outside the submitted work.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All anonymised data from this study will be shared by request from any qualified investigator. Data are available from ORCID identifier is 0000-0002-0932-5173. Data reuse is permitted only for academic purposes.

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