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Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.

Publication ,  Journal Article
Finkel, RS; Mercuri, E; Darras, BT; Connolly, AM; Kuntz, NL; Kirschner, J; Chiriboga, CA; Saito, K; Servais, L; Tizzano, E; Topaloglu, H ...
Published in: N Engl J Med
November 2, 2017

BACKGROUND: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODS: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTS: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

November 2, 2017

Volume

377

Issue

18

Start / End Page

1723 / 1732

Location

United States

Related Subject Headings

  • Survival of Motor Neuron 2 Protein
  • Survival Analysis
  • Spinal Muscular Atrophies of Childhood
  • Respiration, Artificial
  • RNA, Messenger
  • Oligonucleotides, Antisense
  • Oligonucleotides
  • Motor Skills
  • Male
  • Injections, Spinal
 

Citation

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Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., … ENDEAR Study Group. (2017). Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med, 377(18), 1723–1732. https://doi.org/10.1056/NEJMoa1702752
Finkel, Richard S., Eugenio Mercuri, Basil T. Darras, Anne M. Connolly, Nancy L. Kuntz, Janbernd Kirschner, Claudia A. Chiriboga, et al. “Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.N Engl J Med 377, no. 18 (November 2, 2017): 1723–32. https://doi.org/10.1056/NEJMoa1702752.
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723–32.
Finkel, Richard S., et al. “Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.N Engl J Med, vol. 377, no. 18, Nov. 2017, pp. 1723–32. Pubmed, doi:10.1056/NEJMoa1702752.
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC, ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723–1732.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

November 2, 2017

Volume

377

Issue

18

Start / End Page

1723 / 1732

Location

United States

Related Subject Headings

  • Survival of Motor Neuron 2 Protein
  • Survival Analysis
  • Spinal Muscular Atrophies of Childhood
  • Respiration, Artificial
  • RNA, Messenger
  • Oligonucleotides, Antisense
  • Oligonucleotides
  • Motor Skills
  • Male
  • Injections, Spinal