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

Adolescent Child Child, Preschool Female Humans Male Oligonucleotides / therapeutic use Spinal Muscular Atrophies of Childhood / drug therapy Treatment Outcome

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
21 05 2019
Historique:
received: 12 07 2018
accepted: 25 01 2019
pubmed: 26 4 2019
medline: 21 12 2019
entrez: 26 4 2019
Statut: ppublish

Résumé

To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). 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. 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. 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. NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

Identifiants

DOI: 10.1212/WNL.0000000000007527 PMID: 31019106 PMC: PMC6541434
pubmed: 31019106
pii: WNL.0000000000007527
doi: 10.1212/WNL.0000000000007527
pmc: PMC6541434
doi:

Substances chimiques

Oligonucleotides 0
nusinersen 5Z9SP3X666

Banques de données

ClinicalTrials.gov
['NCT02052791']

Types de publication

Clinical Trial, Phase I Clinical Trial, Phase II Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2492-e2506

Subventions

Organisme : NCATS NIH HHS
ID : UL1 TR001102
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Basil T Darras (BT)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA. basil.darras@childrens.harvard.edu.

Claudia A Chiriboga (CA)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Susan T Iannaccone (ST)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Kathryn J Swoboda (KJ)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Jacqueline Montes (J)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Laurence Mignon (L)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Shuting Xia (S)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

C Frank Bennett (CF)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Kathie M Bishop (KM)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Jeremy M Shefner (JM)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Allison M Green (AM)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Peng Sun (P)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Ishir Bhan (I)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Sarah Gheuens (S)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Eugene Schneider (E)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Wildon Farwell (W)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Darryl C De Vivo (DC)

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Nusinersen in later-onset spinal muscular...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Nusinersen in later-onset spinal muscular...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Nusinersen in later-onset spinal muscular...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Nusinersen in later-onset spinal muscular...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Polynucléotides › Oligonucléotides › Nusinersen in later-onset spinal muscular...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Amyotrophies spinales infantiles › Nusinersen in later-onset spinal muscular...
questionsmedicales.fr › Qualité, accès, évaluation des soins de santé › Qualité des soins de santé › Mécanismes d'évaluation des soins de santé › Évaluation des résultats et des processus en soins de santé › Évaluation de résultat (soins) › Résultat thérapeutique › Nusinersen in later-onset spinal muscular...