Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study.
Later-onset
Nusinersen
SMArtCARE
Sitter
Spinal muscular atrophy
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
23 10 2022
23 10 2022
Historique:
received:
23
06
2022
accepted:
04
10
2022
entrez:
24
10
2022
pubmed:
25
10
2022
medline:
26
10
2022
Statut:
epublish
Résumé
The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.
Sections du résumé
BACKGROUND
The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months.
METHODS
SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM).
RESULTS
Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score.
CONCLUSION
Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.
Identifiants
pubmed: 36274155
doi: 10.1186/s13023-022-02547-8
pii: 10.1186/s13023-022-02547-8
pmc: PMC9589836
doi:
Substances chimiques
nusinersen
5Z9SP3X666
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
384Investigateurs
Lisa Ameshofer
(L)
Barbara Andres
(B)
Daniela Angelova-Toshkina
(D)
Daniela Banholzer
(D)
Christina Bant
(C)
Petra Baum
(P)
Sandra Baumann
(S)
Ute Baur
(U)
Benedikt Becker
(B)
Bettina Behring
(B)
Julia Bellut
(J)
Andrea Bevot
(A)
Jasmin Bischofberger
(J)
Lisa Bitzan
(L)
Bogdan Bjelica
(B)
Markus Blankenburg
(M)
Sandra Böger
(S)
Friederike Bonetti
(F)
Anke Bongartz
(A)
Svenja Brakemeier
(S)
Lisa Bratka
(L)
Nathalie Braun
(N)
Sarah Braun
(S)
Brigitte Brauner
(B)
Christa Bretschneider
(C)
Nadine Burgenmeister
(N)
Bea Burke
(B)
Sebahattin Cirak
(S)
Andrea Dall
(A)
Heike de Vries
(H)
Adela Della Marina
(AD)
Jonas Denecke
(J)
Marcus Deschauer
(M)
Zylfie Dibrani
(Z)
Uta Diebold
(U)
Lutz Dondit
(L)
Jessica Drebes
(J)
Joenna Driemeyer
(J)
Vladimir Dukic
(V)
Matthias Eckenweiler
(M)
Mirjam Eminger
(M)
Michal Fischer
(M)
Cornelia Fischer
(C)
Maren Freigang
(M)
Philippa Gaiser
(P)
Andrea Gangfuß
(A)
Stephanie Geitmann
(S)
Annette George
(A)
Magdalena Gosk-Tomek
(M)
Susanne Grinzinger
(S)
Kristina Gröning
(K)
Martin Groß
(M)
Anne-Katrin Güttsches
(AK)
Anna Hagenmeyer
(A)
Hans Hartmann
(H)
Julia Haverkamp
(J)
Miriam Hiebeler
(M)
Annegret Hoevel
(A)
Georg Friedrich Hoffmann
(GF)
Britta Holtkamp
(B)
Dorothea Holzwarth
(D)
Annette Homma
(A)
Viola Horneff
(V)
Carolin Hörnig
(C)
Anna Hotter
(A)
Andrea Hubert
(A)
Peter Huppke
(P)
Eva Jansen
(E)
Lisa Jung
(L)
Nadja Kaiser
(N)
Stefan Kappel
(S)
Bolte Katharina
(B)
Johannes Koch
(J)
Stefan Kölke
(S)
Brigitte Korschinsky
(B)
Franziska Kostede
(F)
Karsten Krause
(K)
Hanna Küpper
(H)
Annina Lang
(A)
Irene Lange
(I)
Thorsten Langer
(T)
Yvonne Lechner
(Y)
Helmar Lehmann
(H)
Christine Leypold
(C)
Paul Lingor
(P)
Jaqueline Lipka
(J)
Wolfgang Löscher
(W)
Antje Luiking
(A)
Gerrit Machetanz
(G)
Eva Malm
(E)
Kyriakos Martakis
(K)
Bettina Menzen
(B)
Moritz Metelmann
(M)
Gerd Meyer Zu Hörste
(G)
Federica Montagnese
(F)
Kathrin Mörtlbauer
(K)
Petra Müller
(P)
Anne Müller
(A)
Anja Müller
(A)
Lars Müschen
(L)
Christoph Neuwirth
(C)
Moritz Niesert
(M)
Josefine Pauschek
(J)
Elke Pernegger
(E)
Susanne Petri
(S)
Veronika Pilshofer
(V)
Barbara Plecko
(B)
Jürgen Pollok
(J)
Martin Preisel
(M)
Manuel Pühringer
(M)
Anna Lisa Quinten
(AL)
Sabine Raffler
(S)
Barbara Ramadan
(B)
Mika Rappold
(M)
Christian Rauscher
(C)
Kerstin Reckmann
(K)
Tabea Reinhardt
(T)
Melanie Röder
(M)
Doris Roland-Schäfer
(D)
Erdmute Roth
(E)
Lena Ruß
(L)
Afshin Saffari
(A)
Mareike Schimmel
(M)
Melina Schlag
(M)
Beate Schlotter-Weigel
(B)
Joanna Schneider
(J)
Jan-Christoph Schöne-Bake
(JC)
David Schorling
(D)
Isabella Schreiner
(I)
Stephanie Schüssler
(S)
Michaela Schwarzbach
(M)
Michaela Schwippert
(M)
Luisa Semmler
(L)
Karin Smuda
(K)
Alina Sprenger-Svacina
(A)
Theresa Stadler
(T)
Paula Steffens
(P)
Daniela Steuernagel
(D)
Benjamin Stolte
(B)
Corinna Stoltenburg
(C)
Gehrke Tasch
(G)
Andreas Thimm
(A)
Elke Tiefenthaler
(E)
Raffi Topakian
(R)
Matthias Türk
(M)
Lieske van der Stam
(L)
Katia Vettori
(K)
Peter Vollmann
(P)
Matthias Vorgerd
(M)
Deike Weiss
(D)
Stephan Wenninger
(S)
Svea Werring
(S)
Maria Wessel
(M)
Ute Weyen
(U)
Sabine Wider
(S)
Nils Ole Wiebe
(NO)
Anna Wiesenhofer
(A)
Sarah Wiethoff
(S)
Corinna Wirner
(C)
Camilla Wohnrade
(C)
Gilbert Wunderlich
(G)
Daniel Zeller
(D)
Michael Zemlin
(M)
Joachim Zobel
(J)
Informations de copyright
© 2022. The Author(s).
Références
Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–65. https://doi.org/10.1016/0092-8674(95)90460-3 .
doi: 10.1016/0092-8674(95)90460-3
pubmed: 7813012
Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet. 2000;9:259–65. https://doi.org/10.1093/hmg/9.2.259 .
doi: 10.1093/hmg/9.2.259
pubmed: 10607836
Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130A:307–10.
doi: 10.1002/ajmg.a.30251
pubmed: 15378550
Zerres K, Rudnik-Schöneborn S. Natural history in proximal spinal muscular atrophy: clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995;52:518–23. https://doi.org/10.1001/archneur.1995.00540290108025 .
doi: 10.1001/archneur.1995.00540290108025
pubmed: 7733848
Farrar MA, Vucic S, Johnston HM, Du Sart D, Kiernan MC. Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr. 2013;162:155–9. https://doi.org/10.1016/j.jpeds.2012.05.067 .
doi: 10.1016/j.jpeds.2012.05.067
pubmed: 22809660
Messina S, Sframeli M, Maggi L, D’Amico A, Bruno C, Comi G, Mercuri E. Spinal muscular atrophy: state of the art and new therapeutic strategies. Neurol Sci. 2021. https://doi.org/10.1007/s10072-021-05258-3 .
doi: 10.1007/s10072-021-05258-3
pubmed: 34499244
Nicolau S, Waldrop MA, Connolly AM, Mendell JR. Spinal muscular atrophy. Semin Pediatr Neurol. 2021;37:100878. https://doi.org/10.1016/j.spen.2021.100878 .
doi: 10.1016/j.spen.2021.100878
pubmed: 33892848
Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol. 2006;26:1333–46. https://doi.org/10.1128/MCB.26.4.1333-1346.2006 .
doi: 10.1128/MCB.26.4.1333-1346.2006
pubmed: 16449646
pmcid: 1367187
Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378:625–35. https://doi.org/10.1056/NEJMoa1710504 .
doi: 10.1056/NEJMoa1710504
pubmed: 29443664
Veerapandiyan A, Eichinger K, Guntrum D, Kwon J, Baker L, Collins E, Ciafaloni E. Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience. Muscle Nerve. 2020;61:222–6. https://doi.org/10.1002/mus.26769 .
doi: 10.1002/mus.26769
pubmed: 31773738
Audic F, de La Banda MGG, Bernoux D, Ramirez-Garcia P, Durigneux J, Barnerias C, et al. Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study. Orphanet J Rare Dis. 2020;15:148. https://doi.org/10.1186/s13023-020-01414-8 .
doi: 10.1186/s13023-020-01414-8
pubmed: 32532349
pmcid: 7291731
Coratti G, Pane M, Lucibello S, Pera MC, Pasternak A, Montes J, et al. Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen. Neuromuscul Disord. 2021;31:596–602. https://doi.org/10.1016/j.nmd.2021.03.012 .
doi: 10.1016/j.nmd.2021.03.012
pubmed: 34099377
Mendonça RH, Polido GJ, Matsui C, Silva AMS, Solla DJF, Reed UC, Zanoteli E. Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience. JND. 2021;8:101–8. https://doi.org/10.3233/JND-200551 .
doi: 10.3233/JND-200551
pubmed: 33074187
Szabó L, Gergely A, Jakus R, Fogarasi A, Grosz Z, Molnár MJ, et al. Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: real world data from Hungarian patients. Eur J Paediatr Neurol. 2020;27:37–42. https://doi.org/10.1016/j.ejpn.2020.05.002 .
doi: 10.1016/j.ejpn.2020.05.002
pubmed: 32456992
Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, et al. Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology. 2019;92:e2492–506. https://doi.org/10.1212/WNL.0000000000007527 .
doi: 10.1212/WNL.0000000000007527
pubmed: 31019106
pmcid: 6541434
Pechmann A, König K, Bernert G, Schachtrup K, Schara U, Schorling D, et al. SMArtCARE: a platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet J Rare Dis. 2019;14:18. https://doi.org/10.1186/s13023-019-0998-4 .
doi: 10.1186/s13023-019-0998-4
pubmed: 30665421
pmcid: 6341722
Mercuri E, Finkel R, Scoto M, Hall S, Eaton S, Rashid A, et al. Development of an academic disease registry for spinal muscular atrophy. Neuromuscul Disord. 2019;29:794–9. https://doi.org/10.1016/j.nmd.2019.08.014 .
doi: 10.1016/j.nmd.2019.08.014
pubmed: 31558335
Wijnhoven TM, de Onis M, Onyango AW, Wang T, Bjoerneboe G-EA, Bhandari N, et al. Assessment of gross motor development in the WHO Multicentre growth reference study. Food Nutr Bull. 2004;25:S37-45. https://doi.org/10.1177/15648265040251S105 .
doi: 10.1177/15648265040251S105
pubmed: 15069918
Glanzman AM, O’Hagen JM, McDermott MP, Martens WB, Flickinger J, Riley S, et al. Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol. 2011;26:1499–507. https://doi.org/10.1177/0883073811420294 .
doi: 10.1177/0883073811420294
pubmed: 21940700
Mazzone ES, Mayhew A, Montes J, Ramsey D, Fanelli L, Young SD, et al. Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle Nerve. 2017;55:869–74. https://doi.org/10.1002/mus.25430 .
doi: 10.1002/mus.25430
pubmed: 27701745
Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf. 1999;20:109–17. https://doi.org/10.2165/00002018-199920020-00002 .
doi: 10.2165/00002018-199920020-00002
pubmed: 10082069
Pera MC, Coratti G, Forcina N, Mazzone ES, Scoto M, Montes J, et al. Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol. 2017;17:39. https://doi.org/10.1186/s12883-017-0790-9 .
doi: 10.1186/s12883-017-0790-9
pubmed: 28231823
pmcid: 5324197
Pane M, Coratti G, Pera MC, Sansone VA, Messina S, D’Amico A, et al. Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy. Ann Clin Transl Neurol. 2022. https://doi.org/10.1002/acn3.51514 .
doi: 10.1002/acn3.51514
pubmed: 35166467
pmcid: 8935309
Coratti G, Lucibello S, Pera MC, Duong T, Muni Lofra R, Civitello M, et al. Gain and loss of abilities in type II SMA: A 12-month natural history study. Neuromuscul Disord. 2020;30:765–71. https://doi.org/10.1016/j.nmd.2020.07.004 .
doi: 10.1016/j.nmd.2020.07.004
pubmed: 32893082
Coratti G, Carmela Pera M, Montes J, Scoto M, Pasternak A, Bovis F, et al. Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes. Neuromuscul Disord. 2022;32(1):36–42. https://doi.org/10.1016/j.nmd.2021.10.009 .
doi: 10.1016/j.nmd.2021.10.009
pubmed: 34980538
Pane M, Coratti G, Sansone VA, Messina S, Catteruccia M, Bruno C, et al. Type I SMA “new natural history”: long-term data in nusinersen-treated patients. Ann Clin Transl Neurol. 2021;8:548–57. https://doi.org/10.1002/acn3.51276 .
doi: 10.1002/acn3.51276
pubmed: 33547876
pmcid: 7951096
Trucco F, Ridout D, Scoto M, Coratti G, Main ML, Muni Lofra R, et al. Respiratory Trajectories in type 2 and 3 spinal muscular atrophy in the iSMAC cohort study. Neurology. 2021;96:e587–99. https://doi.org/10.1212/WNL.0000000000011051 .
doi: 10.1212/WNL.0000000000011051
pubmed: 33067401
pmcid: 7905794