TY - JOUR
T1 - Nusinersen in later-onset spinal muscular atrophy
T2 - Long-term results from the phase 1/2 studies
AU - Darras, Basil T.
AU - Chiriboga, Claudia A.
AU - Iannaccone, Susan T.
AU - Swoboda, Kathryn J.
AU - Montes, Jacqueline
AU - Mignon, Laurence
AU - Xia, Shuting
AU - Bennett, C. Frank
AU - Bishop, Kathie M.
AU - Shefner, Jeremy M.
AU - Green, Allison M.
AU - Sun, Peng
AU - Bhan, Ishir
AU - Gheuens, Sarah
AU - Schneider, Eugene
AU - Farwell, Wildon
AU - De Vivo, Darryl C.
N1 - Funding Information:
The authors thank the patients who participated in CS2 and CS12 and their parents/guardians and family members; and the CS2 and CS12 study investigators and all the contributors to CS2 and CS12, including the clinical monitors, Data Safety and Monitoring Board members, study coordinators, physical therapists, pharmacists and laboratory technicians, and patient advocacy groups, who assisted in promoting awareness of these studies. This integrated analysis was funded by Biogen and Ionis Pharmaceuticals, Inc. Biogen provided funding for medical writing support in the development of this paper; Allison Green, PhD, from Excel Scientific Solutions wrote the first draft of the manuscript based on input from authors; and Kristen DeYoung from Excel Scientific Solutions copyedited and styled the manuscript per the journal requirements. Biogen and Ionis Pharmaceuticals, Inc. reviewed and provided feedback on the manuscript to the authors. The authors had full editorial control of the manuscript and provided their final approval of all content.
Funding Information:
Biogen and Ionis Pharmaceuticals Inc.
Funding Information:
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Biogen.
Publisher Copyright:
© 2019 American Academy of Neurology.
PY - 2019/5/21
Y1 - 2019/5/21
N2 - ObjectiveTo report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).MethodsAnalyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.ResultsTwenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.ConclusionsNusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.Clinicaltrials.gov identifierNCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).Classification of evidenceThis study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.
AB - ObjectiveTo report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).MethodsAnalyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.ResultsTwenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.ConclusionsNusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.Clinicaltrials.gov identifierNCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).Classification of evidenceThis study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.
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U2 - 10.1212/WNL.0000000000007527
DO - 10.1212/WNL.0000000000007527
M3 - Article
C2 - 31019106
AN - SCOPUS:85065524661
SN - 0028-3878
VL - 92
SP - e2492-e2506
JO - Neurology
JF - Neurology
IS - 21
ER -