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Neurology. 2019 May 21;92(21):e2492-e2506. doi: 10.1212/WNL.0000000000007527. Epub 2019 Apr 24.

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

Author information

1
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.
2
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.

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.

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