Nusinersen versus sham control in later-onset spinal muscular atrophy

E. Mercuri*, 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, E. S. Mazzone, J. Montes, K. M. Bishop, Q. Yang, R. Foster, S. Gheuens, C. F. Bennett, W. FarwellE. Schneider, D. C. De Vivo, R. S. Finkel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1014 Scopus citations

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 (US)
Pages (from-to)625-635
Number of pages11
JournalNew England Journal of Medicine
Volume378
Issue number7
DOIs
StatePublished - Feb 15 2018

Funding

Supported by Biogen and Ionis Pharmaceuticals. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the patients who participated in the trial and their parents, guardians, and family members; all contributors to the trial, including the clinical monitors, trial coordinators, physical therapists, pharmacists, laboratory technicians, and members of patient advocacy groups (who assisted in promoting awareness of the trial); and Malcom Darkes, Alison Gagnon, and Elizabeth Cassell (Excel Scientific Solutions) for medical writing assistance.

ASJC Scopus subject areas

  • General Medicine

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