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Clinical Trial
. 2019 Oct;60(4):409-414.
doi: 10.1002/mus.26633. Epub 2019 Jul 27.

Nusinersen Improves Walking Distance and Reduces Fatigue in Later-Onset Spinal Muscular Atrophy

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Free PMC article
Clinical Trial

Nusinersen Improves Walking Distance and Reduces Fatigue in Later-Onset Spinal Muscular Atrophy

Jacqueline Montes et al. Muscle Nerve. .
Free PMC article

Abstract

Introduction: Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied.

Methods: Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12.

Results: Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%).

Discussion: These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA.

Keywords: 6-minute walk test; fatigue; neuromuscular junction; nusinersen; spinal muscular atrophy.

Conflict of interest statement

J.M. has been an advisory board member for Astellas, Biogen, Cytokinetics, Roche, and Scholar Rock; a consultant to Biogen and Ionis Pharmaceuticals, Inc; and has received research support from the Muscular Dystrophy Association and the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health. S.D.Y. has been an advisory board member for Biogen, Roche, and Scholar Rock; received personal compensation for activities with Biogen, Cure SMA, and Scholar Rock as a consultant; and received research support from the SMA Foundation. E.S.M. has been an advisory board member for Biogen, Roche, and Scholar Rock; and been a consultant for AveXis, Cytokinetics, Ionis Pharmaceuticals, Inc, and Roche. A.P. has received research support from the SMA Foundation; serves as a consultant for Biogen; and has been an advisory board member for AveXis, Biogen, Roche, and Scholar Rock. A.M.G. received travel/lodging and compensation from Biogen to serve on an advisory board; licensing fees from Children's Hospital of Philadelphia for development of the CHOP INTEND motor scale; institutional support from AveXis, Biogen, and Roche for trial training; and personal compensation from ATOM International and Mallinckrodt for trial training. R.S.F. received grants and advisor fees from Biogen and Ionis Pharmaceuticals, Inc during ENDEAR and CHERISH and from Biogen during NURTURE and SHINE, and grants from Cytokinetics; outside the submitted work, he has received advisor fees and grants from AveXis and Roche, and has served as an advisor to Novartis; he has served in an advisory capacity for the nonprofit organizations Cure SMA, SMA Europe, the SMA Foundation, and SMA Reach (UK); he has been on the data safety monitoring board for the AveXis AVXS‐101 phase I gene transfer study and the Roche Moonfish phase IIb study; received personal compensation for serving as coeditor of Swaiman's Pediatric Neurology text (2018); received licensing fees from Children's Hospital of Philadelphia for development of the CHOP INTEND motor scale; and was recipient of grants from AveXis, Cytokinetics, Ionis Pharmaceuticals, Inc/Biogen, and Roche. B.T.D. has been an advisory board member for AveXis, Biogen, Cytokinetics, Dynacure, PTC, Roche, and Sarepta; received research support from Cure SMA, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the SMA Foundation, and the Working on Walking Fund; and received grants from Biogen and Ionis Pharmaceuticals, Inc during the ENDEAR, CHERISH, CS2, CS12, and CS11 studies, and also from Cytokinetics, Fibrogen, PTC, Roche, Santhera, Sarepta, and Summit, and reports no personal financial interests in these companies. F.M. is principal investigator for ongoing AveXis, Ionis Pharmaceuticals, Inc/Biogen, and Roche clinical trials; has received funding from Biogen, SMA Europe, and the SMA Trust; and has been an advisory board member for AveXis, Biogen, Novartis, Pfizer, PTC, Roche, Sarepta, Summit, and Wave, and has no financial interests in these companies. E.M. has been a an advisory board member for SMA studies for AveXis, Biogen, Ionis Pharmaceuticals, Inc, Novartis, and Roche; is principal investigator for ongoing AveXis, Ionis Pharmaceuticals, Inc/Biogen, and Roche clinical trials; and received funding from Famiglie SMA Italy, Italian Telethon, and SMA Europe. D.C.D. has been an advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc, Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation, with no financial interests in these companies; received grants from the Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, the National Institutes of Health, and the SMA Foundation; and received clinical trial funding from Biogen, Mallinckrodt, PTC, Sarepta, Scholar Rock, and Ultragenyx. K.M.B. is an employee of Otonomy, Inc; and is an unpaid advisor to the nonprofit organizations Myotonic Dystrophy Foundation and SMA Foundation. E.S. and C.F.B. are employees of and hold stock/stock options in Ionis Pharmaceuticals, Inc. R.F. and W.F. are employees of and hold stock/stock options in Biogen.

Figures

Figure 1
Figure 1
Median (25th, 75th percentile) change from baseline in 6MWT (A) distance and (B) fatigue over time. *Study visits up to and including day 253 occurred during the CS2 study, subsequent study visits occurred during the CS12 study. The day of the first study visit attended in the CS12 study depended upon the time between the end of the CS2 study and first dose in the CS12 study and the windowing of study visits described as follows. Median (range) time from the end of the CS2 study to first dose in the CS12 study was 118.0 (19–233) days. Study days were derived from the first day of CS2 dosing for all CS2 and CS12 study visits and were assigned visit days as follows: study visits that took place >50 and ≤131 days from the first dose in the CS2 study were labeled day 92, visits >131 and ≤211 days from the first dose in CS2 were labeled day 169, those >211 and ≤302 days were labeled day 253, those >302 and ≤400 days were labeled day 350, and study visits >X − 50 to ≤X + 50 were labeled day X (starting at day 450 and increasing by 100 until day 1050), times between visit days were not equal, but were similar. 6MWT, 6‐minute walk test

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