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.
(1) Hoffman LaRoche (2) Cytokinetics, Inc. (3) BMS, Inc (4) Sarepta Therapeutics (5) Biogen (6) AveXis (6) PTC Therapeutics (7) AveXis Ad hoc SAB member; no financial interests in these companies
(1) PTC Therapeutics (2) Valerion Therapeutics (MTM) (3) Sarepta Therapeutics (4) Biogen (5) Summit (6) AveXis (7) Roche (8) Fibrogen (9) Santhera (10) Cytokinetics
(1) NIH/NINDS, 1U10NS077269, Site-PI/PD, 2018-2023. (2) NIH/NINDS, 5U01NS061799, FOR-DMD, Site-PI, 2012-2016. (3) NIH/NINDS via Skulpt Inc., 5RNS073188, Site-PI, 2015- 2016.
(1) SMA Foundation (2) Muscular Dystrophy Association (3) Slaney Family Fund for SMA
Member DSMB, Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study anaLyzing Pharmacokinetics at three dose Levels In Children and Adolescents with Assessment of Safety and Tolerability of Omigapil Santhera AveXis Ad Board Sarepta Ad Board
Editorial board: Neuromuscular Disorders, Journal of Pediatric Rehabilitation Medicine
Site PI for: PTC sponsored clinical trial of Ataluren in Duchenne muscular dystrophy: A Phase 2b Efficacy and Safety Study of PTC124 in Subjects with Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy Extension Study of Ataluren in Subjects with Nonsense- Mutation-Mediated Duchenne and Becker Muscular Dystrophy, PTC Therapeutics, 3 patients previously enrolled now in open label. 2011 - present An Open-Label, Multi-Center, 48-Week Study with a Concurrent Untreated Control Arm to Evaluate the Efficacy and Safety of Eteplirsen in Duchenne Muscular Dystrophy Sarepta 2014 - present Biogen SHINE, site coPI AveXis STRIVE, STRONG, SPRINT, site PI Capricor HOPE2, site PI
Site CoPI for NIH sponsored NeuroNEXT 2018-2023 Site CoPI for Wellstone Center for Muscular Dystrophy (NIH U54 AR068791-01 ) 2015-2020
Muscular Dystrophy Association, Care Center grant: coDirector Cure SMA Center of Excellence, coDirector
Cure SMA Scientific Advisory Board AHC foundation Scientific Advisory Board Biogen Scientific Advisory Board
1. Biogen: PI for NURTURE, phase 2 trial of nusinursen in pre- symptomatic infants with SMA; April 2016-present 2. AveXis: PI for SPR1NT, phase 3 Pre-Symptomatic Study of Intravenous AVXS-101 in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2; July 2018-present
NIH RO1-HD69045 for newborn screening pilot study for SMA, PI, 2011-18, NICHD And NIH R21-NS108015, NINDS, Pathologic studies in SMA, PI, 2018-2020
Professor, Adjunct, University of Utah Department of Neurology Lecturer, Harvard Medical School
Cure SMA clinical support grant, PI, 2018-2019 Cure SMA research grant, PI, 2018-2020
National Institute of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development (K01HD084690), Principal Imvestigator; 2016-2021
(1) SMA Foundation (2) Muscular Dystrophy Association Clinical Trials Travel Grant (575870).
Unpaid scientific advisory board member for the non- profit groups the Myotonic Dystrophy Foundation and the Spinal Muscular Atrophy Foundation
I was a full-time employee of Isis Pharmaceuticals from September 2009 to March 2015. Currently a full-time employee of Otonomy Inc.
I served on a Scientific Advisory Boards sponsored by Biogen-Idec, AveXis, Orphazyme, Brainstorm and Cytokinetics related to new ALS therapies. I am also the Medical Monitor for the Braingate Brain-Computer Interface Program.
non-profit: I received an honorarium for giving Grand Rounds Massachusetts General Hospital.
UpToDate, Neuromuscular Section Editor, 2007-present. Editorial Board, Neurotherapeutics and the ALS Journal.
Biogen Idec, clinical trial management. Cytokinetics, clinical trial management and site investigator. Amylyx, clinical trial management Brainstorm, clinical trial management
NIH through subcontracts from the Massachusetts General Hospital, trial management. NIH: 1U24NS107204-01, Principal Investigator, 2018-2013
ALS Association,principal investigator of TREAT ALS grant and experimental markers of ALS progression grant. ALS Finding a Cure Foundation
SMA Foundation. The Hope for Children Research Foundation. Pediatric Neurotransmitter Disease Association. International Reye Syndrome Foundation. The Will Foundation Chairman, Data Safety Monitoring Board, Cytokinetics Chairman, Canavan Disease Foundation Advisory Board, NYC Scientific Advisory Board, Metafora Glut1 Deficiency Foundation The Grace Science Foundation
Current Opinion in Neurology, Editorial Board Medlink in Neurology, Editorial Board Journal of Pediatric Neurology Editorial Board (Turkish journal)
Gene therapy for Glut1 Deficiency patent International PCT Patent Application No. PCT/US2016/021810 Based on U.S. Provisional Patent Application Serial No.: 62/130,899 Title: RECOMBINANT GLUT1 ADENO-ASSOCIATED VIRAL VECTOR CONSTRUCTS AND RELATED METHODS FOR RESTORING GLUT1 EXPRESSION Filed: March 10, 2016 Our Ref.: 01001/003887-WO0
Ionis Pharmaceuticals Biogen Pharmaceuticals Ultragenyx Pharmaceuticals Sarepta Therapeutics PTC Therapeutics
SMA Foundation. The Hope for Children Research Foundation. The Will Foundation The Pediatric Neurotransmitter Disease Association The Glut1 Deficiency Foundation
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.
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