Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies

ISIS-396443-CS2/ISIS-396443-CS12 Study Groups

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

OBJECTIVE: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). METHODS: Analyses 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. RESULTS: Twenty-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. CONCLUSIONS: Nusinersen 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. CLINICALTRIALSGOV IDENTIFIER: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

Original languageEnglish (US)
Pages (from-to)e2492-e2506
JournalNeurology
Volume92
Issue number21
DOIs
StatePublished - May 21 2019

Fingerprint

Spinal Muscular Atrophies of Childhood
Spinal Muscular Atrophy
Upper Extremity
Action Potentials
Muscles
Natural History
Multicenter Studies
Therapeutics
Safety
ISIS 396443

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Nusinersen in later-onset spinal muscular atrophy : Long-term results from the phase 1/2 studies. / ISIS-396443-CS2/ISIS-396443-CS12 Study Groups.

In: Neurology, Vol. 92, No. 21, 21.05.2019, p. e2492-e2506.

Research output: Contribution to journalArticle

ISIS-396443-CS2/ISIS-396443-CS12 Study Groups. / Nusinersen in later-onset spinal muscular atrophy : Long-term results from the phase 1/2 studies. In: Neurology. 2019 ; Vol. 92, No. 21. pp. e2492-e2506.
@article{2b7514e8819347bcaec19cd5a8658f01,
title = "Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies",
abstract = "OBJECTIVE: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). METHODS: Analyses 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. RESULTS: Twenty-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. CONCLUSIONS: Nusinersen 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. CLINICALTRIALSGOV IDENTIFIER: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.",
author = "{ISIS-396443-CS2/ISIS-396443-CS12 Study Groups} and Darras, {Basil T.} and Chiriboga, {Claudia A.} and Iannaccone, {Susan T} and Swoboda, {Kathryn J.} and Jacqueline Montes and Laurence Mignon and Shuting Xia and Bennett, {C. Frank} and Bishop, {Kathie M.} and Shefner, {Jeremy M.} and Green, {Allison M.} and Peng Sun and Ishir Bhan and Sarah Gheuens and Eugene Schneider and Wildon Farwell and {De Vivo}, {Darryl C.}",
year = "2019",
month = "5",
day = "21",
doi = "10.1212/WNL.0000000000007527",
language = "English (US)",
volume = "92",
pages = "e2492--e2506",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "21",

}

TY - JOUR

T1 - Nusinersen in later-onset spinal muscular atrophy

T2 - Long-term results from the phase 1/2 studies

AU - ISIS-396443-CS2/ISIS-396443-CS12 Study Groups

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.

PY - 2019/5/21

Y1 - 2019/5/21

N2 - OBJECTIVE: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). METHODS: Analyses 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. RESULTS: Twenty-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. CONCLUSIONS: Nusinersen 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. CLINICALTRIALSGOV IDENTIFIER: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

AB - OBJECTIVE: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). METHODS: Analyses 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. RESULTS: Twenty-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. CONCLUSIONS: Nusinersen 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. CLINICALTRIALSGOV IDENTIFIER: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

UR - http://www.scopus.com/inward/record.url?scp=85065524661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065524661&partnerID=8YFLogxK

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 -