Nusinersen versus sham control in infantile-onset spinal muscular atrophy

Richard S. Finkel; Eugenio Mercuri; Basil T. Darras; Anne M. Connolly; Nancy L. Kuntz; Janbernd Kirschner; Claudia A. Chiriboga; Kayoko Saito; Laurent Servais; Eduardo Tizzano; Haluk Topaloglu; Már Tulinius; Jacqueline Montes; Allan M. Glanzman; Kathie Bishop; Z. John Zhong; Sarah Gheuens; C. Frank Bennett; Eugene Schneider; Wildon Farwell; Darryl C. De Vivo

doi:10.1056/NEJMoa1702752

Nusinersen versus sham control in infantile-onset spinal muscular atrophy

Richard S. Finkel^*, Eugenio Mercuri, Basil T. Darras, Anne M. Connolly, Nancy L. Kuntz, Janbernd Kirschner, Claudia A. Chiriboga, Kayoko Saito, Laurent Servais, Eduardo Tizzano, Haluk Topaloglu, Már Tulinius, Jacqueline Montes, Allan M. Glanzman, Kathie Bishop, Z. John Zhong, Sarah Gheuens, C. Frank Bennett, Eugene Schneider, Wildon FarwellDarryl C. De Vivo

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

1649 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1723-1732
Number of pages	10
Journal	New England Journal of Medicine
Volume	377
Issue number	18
DOIs	https://doi.org/10.1056/NEJMoa1702752
State	Published - Nov 2 2017

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); Allison Green from Excel Scientific Solutions for providing writing assistance with earlier versions of the manuscript according to input from authors; and Jacqueline Atkinson from Excel Scientific Solutions for copy editing an earlier version of the manuscript.

ASJC Scopus subject areas

General Medicine

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10.1056/NEJMoa1702752

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Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., Chiriboga, C. A., Saito, K., Servais, L., Tizzano, E., Topaloglu, H., Tulinius, M., Montes, J., Glanzman, A. M., Bishop, K., Zhong, Z. J., Gheuens, S., Bennett, C. F., Schneider, E., ... De Vivo, D. C. (2017). Nusinersen versus sham control in infantile-onset spinal muscular atrophy. New England Journal of Medicine, 377(18), 1723-1732. https://doi.org/10.1056/NEJMoa1702752

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title = "Nusinersen versus sham control in infantile-onset spinal muscular atrophy",

abstract = "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.",

author = "Finkel, {Richard S.} and Eugenio Mercuri and Darras, {Basil T.} and Connolly, {Anne M.} and Kuntz, {Nancy L.} and Janbernd Kirschner and Chiriboga, {Claudia A.} and Kayoko Saito and Laurent Servais and Eduardo Tizzano and Haluk Topaloglu and M{\'a}r Tulinius and Jacqueline Montes and Glanzman, {Allan M.} and Kathie Bishop and Zhong, {Z. John} and Sarah Gheuens and Bennett, {C. Frank} and Eugene Schneider and Wildon Farwell and {De Vivo}, {Darryl C.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2017 Massachusetts Medical Society.",

year = "2017",

month = nov,

day = "2",

doi = "10.1056/NEJMoa1702752",

language = "English (US)",

volume = "377",

pages = "1723--1732",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

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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 2017, 'Nusinersen versus sham control in infantile-onset spinal muscular atrophy', New England Journal of Medicine, vol. 377, no. 18, pp. 1723-1732. https://doi.org/10.1056/NEJMoa1702752

TY - JOUR

T1 - Nusinersen versus sham control in infantile-onset spinal muscular atrophy

AU - Finkel, Richard S.

AU - Mercuri, Eugenio

AU - Darras, Basil T.

AU - Connolly, Anne M.

AU - Kuntz, Nancy L.

AU - Kirschner, Janbernd

AU - Chiriboga, Claudia A.

AU - Saito, Kayoko

AU - Servais, Laurent

AU - Tizzano, Eduardo

AU - Topaloglu, Haluk

AU - Tulinius, Már

AU - Montes, Jacqueline

AU - Glanzman, Allan M.

AU - Bishop, Kathie

AU - Zhong, Z. John

AU - Gheuens, Sarah

AU - Bennett, C. Frank

AU - Schneider, Eugene

AU - Farwell, Wildon

AU - De Vivo, Darryl C.

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

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Nusinersen versus sham control in infantile-onset spinal muscular atrophy

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