Abstract
Background
Nusinersen recently became available as the first treatment for Spinal Muscular Atrophy (SMA) and data on its effectiveness and safety in adult SMA patients are still scarce.
Methods
We evaluated the effectiveness and safety of nusinersen treatment during 14 months in 16 adult patients with SMA types 3 and 4 in a prospective study, and retrospectively detailed the natural history of 48 adult SMA patients types 2, 3 and 4.
Results
Hand grip strength (p = 0.03), hand motor function (p = 0.04) as assessed by a sub-score of the Revised Upper Limb Module (RULM) and the Medical Research Council (MRC) sum score (p = 0.04) improved significantly at month 14. Importantly, the MRC sum score had declined significantly (p < 0.01) prior to start of treatment in these patients. A minimal clinically important difference (MCID) in the Hammersmith Functional Motor Scale Expanded (HFMSE) and RULM scores was achieved in 31% and 50% of the patients, respectively, but the mean changes from baseline failed to reach significance. Forced Vital Capacity (FVC) transiently increased at month 6 (p = 0.01), whereas the Peak Expiratory Flow (PEF) did not. The Activity Limitations scale declined significantly prior to start of treatment (p < 0.01) and showed an improvement with nusinersen which was not significant. The safety evaluation did not reveal serious adverse events and no signs of nephrotoxicity or antisense oligonucleotide (ASO)-mediated inflammation.
Conclusions
We conclude that hand grip strength and hand motor function, as well as MRC sum scores improved significantly in nusinersen-treated adult patients with SMA types 3 and 4.
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Data availability
The supporting datasets analysed during the current study and the RStudio code used for statistical analyses are available from the corresponding author on reasonable request.
Abbreviations
- SMA:
-
Spinal Muscular Atrophy
- SMN:
-
Survival of motor neuron protein
- FAGG:
-
Belgian Federal Agency for Medicines and Health Products
- CT:
-
Computed Tomography
- MRC:
-
Medical Research Council
- FVC:
-
Forced Vital Capacity
- PEF:
-
Peak Expiratory Flow
- 6MWD:
-
Six-minute walk distance
- CPAP:
-
Continuous positive airway pressure
- OSAS:
-
Obstructive sleep apnoea syndrome
- HFMSE:
-
Hammersmith Functional Motor Scale Expanded
- RULM:
-
Revised Upper Limb Module
- SF-36:
-
36-Item Short Form Health Survey
- ActivLim:
-
Activity Limitations scale
- PROM:
-
Patient-reported outcome measure
- CK:
-
Creatine kinase
- MCID:
-
Minimal clinically important difference
- PPH:
-
Post-puncture headache
References
Zerres K, Schöneborn SR (1995) natural history in proximal spinal muscular atrophy: clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 52(5):518–523
Mercuri E, Bertini E, Iannaccone ST (2012) Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol 11(5):443–452
Alías L, Bernal S, Fuentes-Prior P, Barceló MJ, Also E, Martínez-Hernández R et al (2009) Mutation update of spinal muscular atrophy in Spain: Molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum Genet 125(1):29–39
Chaytow H, Huang Y, Gillingwater TH, Faller KME (2018) The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci 75:3877–3894
Lorson CL, Androphy EJ (2000) An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 9(2):259–266
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC et al (2016) Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388(10063):3017–3026
Singh NK, Singh NN, Androphy EJ, Singh RN (2006) 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 26(4):1333–1346
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J et al (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377(18):1723–1732
Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM et al (2018) Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 378(7):625–635
Walter MC, Wenninger S, Thiele S, Stauber J, Hiebeler M, Greckl E et al (2019) Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3: a prospective observational study. J Neuromuscul Dis 6(4):453–465
Hagenacker T, Wurster CD, Günther R, Schreiber-Katz O, Osmanovic A, Petri S et al (2020) Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Lancet Neurol 19(4):317–325
Merlini L, Mazzone ES, Solari A, Morandi L (2002) Reliability of hand-held dynamometry in spinal muscular atrophy. Muscle Nerve 26(1):64–70
Seferian AM, Moraux A, Canal A, Decostre V, Diebate O, Le Moing AG et al (2015) Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: An observational multicenter trial. PLoS ONE 10:4
Kleyweg RP, Van Der Meché FGA, Schmitz PIM (1991) Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve 14(11):1103–1109
Dunaway Young S, Montes J, Kramer SS, Marra J, Salazar R, Cruz R et al (2016) Six-minute walk test is reliable and valid in spinal muscular atrophy. Muscle Nerve 54(5):836–842
O’Hagen JM, Glanzman AM, McDermott MP, Ryan PA, Flickinger J, Quigley J et al (2007) An expanded version of the Hammersmith functional motor scale for SMA II and III patients. Neuromuscul Disord 17(9–10):693–697
Mazzone ES, Mayhew A, Montes J, Ramsey D, Fanelli L, Young SD et al (2017) Revised upper limb module for spinal muscular atrophy: development of a new module. Muscle Nerve 55(6):869–874
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al (2012) Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 40(6):1324–1343
Batcho CS, Van den Bergh P, Van Damme P, Roy AJ, Thonnard JL, Penta M et al (2016) How robust is ACTIVLIM for the follow-up of activity limitations in patients with neuromuscular diseases? Neuromuscul Disord 26(3):211–220
Banks P, Martin CR, Petty RKH (2012) The factor structure of the SF-36 in adults with progressive neuromuscular disorders. J Eval Clin Pract 18(1):32–36
Levin AA, Henry SP (2010) Toxicology of oligonucleotide therapeutics and understanding the relevance of the toxicities. In: Gad SC (ed), Pharmaceuticalsciences encyclopedia, p 1–38
Engelhardt JA (2016) Comparative renal toxicopathology of antisense oligonucleotides. Nucleic Acid Ther 26(4):199–209
Viollet L, Gailey S, Thornton DJ, Friedman NR, Flanigan KM, Mahan JD et al (2009) Utility of cystatin C to monitor renal function in duchenne muscular dystrophy laurence. Muscle Nerve 40(3):438–442
Frazier KS (2015) Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol Pathol 43(1):78–89
Biogen Idec Ireland. Spinraza (nusinersen): communicating hydrocephalus not related to meningitis or bleeding reported. Internet Document: [3 pages], 31 Jul 2018. Reactions Weekly 1714, 3. Available from: https://www.hpra.ie/docs/default-source/default-document-library/important-safetyinformation
Wadman RI, van der Pol WL, Bosboom WMJ, Asselman FL, van den Berg LH, Iannaccone ST et al (2020) Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2020:1
Koch BM, Simenson RL (1992). Upper extremity strength and function in children with spinal muscular atrophy type II. Arch Phys Med Rehabil 73
Werlauff U, Steffensen BF, Bertelsen S, Fløytrup I, Kristensen B, Werge B (2010) Physical characteristics and applicability of standard assessment methods in a total population of spinal muscular atrophy type II patients. Neuromuscul Disord 20(1):34–43
Wadman RI, Wijngaarde CA, Stam M, Bartels B, Otto LAM, Lemmink HH et al (2018) Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c–4. Eur J Neurol 25(3):512–518
Sivo S, Mazzone E, Antonaci L, De Sanctis R, Fanelli L, Palermo C et al (2015) Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. Neuromuscul Disord 25(3):212–215
Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ et al (2010) SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of l-carnitine and valproic acid in spinal muscular atrophy. PLoS ONE 5:8
McGraw S, Qian Y, Henne J, Jarecki J, Hobby K, Yeh WS (2017) A qualitative study of perceptions of meaningful change in spinal muscular atrophy. BMC Neurol 17(1):1–9
Wijngaarde CA, Veldhoen ES, Van Eijk RPA, Stam M, Otto LAM, Asselman FL et al (2020) Natural history of lung function in spinal muscular atrophy. Orphanet J Rare Dis 15(1):1–11
Osmanovic A, Ranxha G, Kumpe M, Müschen L, Binz C, Wiehler F et al (2020) Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy. J Neurol 267:2398–2407
Barp A, Carraro E, Albamonte E, Salmin F, Lunetta C, Comi G Pietro et al. (2020) Muscle MRI in two SMA patients on nusinersen treatment: a two years follow-up. J Neurol Sci 417:117067. https://doi.org/10.1016/j.jns.2020.117067
Otto LAM, van der Pol WL, Schlaffke L, Wijngaarde CA, Stam M, Wadman RI et al (2020) Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3. NMR Biomed 33(10):e4357
Safety team leader review NDA 209531 Spinraza (nusinersen) 2017 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000MedR.pdf [cited 2020 Jun 9]
Acknowledgements
The authors thank the patients for their participation in the study. They are grateful to the colleagues from the Radiology Department at UZ Leuven for their imaging support during some of the nusinersen injections. They thank Eveline Dewaege, Elise Lenaerts, Chris Schrevens, Kimberly Tielens, Cindy Thys, Leonie Vandenhoudt, Ann Van Der Vennet and Marielle Verbeek for their administrative and/or technical support. KGC is Chairholder of the Emil von Behring Chair for Neuromuscular and Neurodegenerative Disorders by CSL Behring. KGC is member of the European Reference Network for Rare Neuromuscular Diseases (ERN Euro-NMD) and of the European Reference Network for Rare Neurological Diseases (ERN-RND).
Funding
This study was partially funded by Biogen.
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Conflicts of interest
KGC received advisory board honoraria from Alnylam, Biogen, CSL Behring, Sanofi-Genzyme and travel reimbursement from Sanofi-Genzyme, unrelated to this work. The other authors report no conflicts of interest.
Ethical standards
Written informed consent was obtained from the patients. Both the Ethics Committee Research UZ/KU Leuven and the Belgian Federal Agency for Medicines and Health Products (FAGG) approved the study (EudraCT-nr: 2019-005007-40), which has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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De Wel, B., Goosens, V., Sobota, A. et al. Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4. J Neurol 268, 923–935 (2021). https://doi.org/10.1007/s00415-020-10223-9
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DOI: https://doi.org/10.1007/s00415-020-10223-9