Nusinersen versus sham control in later-onset spinal muscular atrophy

Eugenio Maria Mercuri, Marco Piastra, Elena Stacy Mazzone, Elisabeth Margarete Ute Schneider-Moser, B. T. Darras, C. A. Chiriboga, J. W. Day, C. Campbell, A. M. Connolly, S. T. Iannaccone, J. Kirschner, N. L. Kuntz, K. Saito, P. B. Shieh, M. Tulinius, J. Montes, K. M. Bishop, Q. Yang, R. Foster, S. GheuensC. F. Bennett, W. Farwell, E. Schneider, D. C. De Vivo, R. S. Finkel

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465 Citations (Scopus)

Abstract

BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the leastsquares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. RESULTS: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537).
Original languageEnglish
Pages (from-to)625-635
Number of pages11
JournalNew England Journal of Medicine
Volume378
DOIs
Publication statusPublished - 2018

Keywords

  • Age of Onset
  • Child
  • Child, Preschool
  • Double-Blind Method
  • Female
  • Humans
  • Infant
  • Injections, Spinal
  • Least-Squares Analysis
  • Male
  • Medicine (all)
  • Motor Skills
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Spinal Muscular Atrophies of Childhood

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