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:
She has received grants from Biogen, Ionis Pharmaceuticals, Inc., the NIH, and the SMA Foundation. S. Iannaccone has been a consultant for Ionis Pharmaceuticals, Inc.; has been a member of advisory boards for AveXis, Biogen, Santhera, and Sarepta; and has received research grants from the Muscular Dystrophy Association and the NIH. K. Swoboda has received support from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (R01-HD69045); has been a member of advisory boards for AveXis and Biogen; and has received clinical trial funding from Biogen and Ionis Pharmaceuticals, Inc. for the CS1, CS2, CS12, and NURTURE studies. J. Montes has been a member of advisory boards for Biogen, Cytokinetics, Roche, Scholar Rock, and the SMA Foundation; has been a consultant for Biogen and Ionis Pharmaceuticals, Inc.; has received research support from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (1K01HD084690-01A1); and has received a conference grant from the Muscular Dystrophy Association. L. Mignon is an employee of and holds stock/stock options in Ionis Pharmaceuticals, Inc. S. Xia is an employee of and holds stock/ stock options in Ionis Pharmaceuticals, Inc. C. Bennett is an employee of and holds stock/stock options in Ionis Pharmaceuticals, Inc. K. Bishop was an employee of Ionis Pharmaceuticals, Inc. at the time these studies were conducted; is currently an employee of Otonomy; and has acted in an advisory capacity for the following nonprofit organizations: the Myotonic Dystrophy Foundation and the SMA Foundation. J. Shefner has been an advisor/ consultant for AveXis, Biogen, Cytokinetics, and Ionis Pharmaceuticals, Inc.; and has received research support from the ALS Association, ALS Finding a Cure, Biogen, Cytokinetics, and Neuraltus. A. Green is an employee of Excel Scientific Solutions. Biogen provided funding for medical writing support in the development of this report to Excel Scientific Solutions. P. Sun is an employee of and holds stock/stock options in Biogen. I. Bhan is an employee of and holds stock/stock options in Biogen. S. Gheuens is an employee of and holds stock/stock options in Biogen. E. Schneider is an employee of and holds stock/stock options in Ionis Pharmaceuticals, Inc. W. Farwell is an employee of and holds stock/stock options in Biogen. D. De Vivo has been an advisor/consultant for AveXis, Biogen, Cytoki-netics, Ionis Pharmaceuticals, Inc., Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation, with no financial interests in these companies; has received grants from the Department of Defense, Hope for Children Research Foundation, the NIH, and the SMA Foundation; and has received clinical trial funding from Biogen, Mallinckrodt, PTC, Sarepta, and Ultragenyx. Go to Neurology.org/N for full disclosures.
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:
B. Darras has been a member of advisory boards for AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC, Roche, Santhera, and Sarepta; has received research support from the NIH/National Institute of Neurologic Disorders and Stroke, the Slaney Family Fund for SMA, the SMA Foundation, and the Working on Walking Fund; has received grants from Biogen, CureSMA, and Ionis Pharmaceuticals, Inc. during the ENDEAR, CHERISH, CS2, CS12, and CS11 studies, and from AveXis, Cytokinetics, Fibrogen, PTC, Roche, Santhera, Sarepta, and Summit; and reports no personal financial interests in these companies. C. Chiriboga has been a member of advisory boards for SMA studies for AveXis, Biogen, Ionis Pharmaceuticals, Inc., Genentech, and Roche; and reports no financial interest in these companies.
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
VL - 92
SP - e2492-e2506
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 21
ER -