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, W. G. Bradley, M. K. Schroth, J. B. Bodensteriner, C. S. Davis, R. Shell, J. Hen, E. D. Austin, S. Aziz-Zaman, J. Cappell, A. Constantinescu, R. Cruz, J. Dastgir, S. Dunaway, K. Engelstad, M. Gormley, N. Holuba La Marca, A. Khandji, S. Kramer, J. Marra, C. Ortiz-Miller, M. Popolizio, R. Salazar, L. Sanabria, L. Weimer, P. Anand, R. Gadeken, P. T. Golumbek, C. Siener, C. M. Zaidman, F. Al-Ghamdi, C. Berde, P. Ghosh, R. Graham, T. Harrington, A. Koka, R. Laine, W. Liew, E. Mirek, G. Ordonez, A. Pasternak, J. Quigley, N. Sethna, M. Souris, H. Szelag, L. Wand, J. W. Day, G. D'Souza, T. T. Duong, R. Gee, J. Kitsuwa-Lowe, D. McFall, S. Patnaik, S. Paulose, J. Perez, C. Proud, B. Purse, R. J. Ramamurthi, S. Sakamuri, J. Sampson, B. Sanjanwala, A. C. Tesi Rocha, K. Watson, L. Welsh, L. D.M. Pena, L. Case, J. Coates, S. DeArmey, M. M. Homi, C. Milleson, N. Nelson, A. Ross, E. Smith, B. Taicher, J. Wootton, E. Finanger, D. Benjamin, A. Frank, C. Roberts, B. Russman, K. Zilke, D. Berry, M. Civitello, D. Cook, J. D. Endsley, C. Johnson, M. Kasper, W. Leon, A. Lim, K. O'Reardon, L. Y. Sigurdardottir, J. Turner, F. Weber-Guzman, M. Zinn, S. T. Iannaccone, D. Castro, M. Cowie, A. Farrow-Gillespie, A. Herbert, M. Kauk, D. McElroy, N. Miller, L. Nelson, L. Smith, T. Spain, S. Trest, N. Johnson, R. Butterfield, D. DiBella, K. Mayne, T. M. Newcomb, N. Rausch, C. Blomgren, H. W. Choi, L. Epstein, S. Goldman, K. Krosschell, J. Krueger, J. Kurz, V. Rao, J. Parsons, V. Allen, A. Bielsky, K. Booker, A. Camuto, T. Carry, P. Fuhr, M. Gibbons, J. Janas, H. Johnson, C. Kelly, L. S. Lord-Halvorson, S. Nicolarsen, S. Shea, V. Tran, G. VanderVeen, M. Yang, C. Zimmerman, P. Shieh, N. Parziale, L. Rao, J. W. Said, F. Shu, C. Skura, L. Staudt, G. Tennekoon, L. Adang, J. Brandsema, M. Chadehumbe, J. Flickinger, E. Kichula, D. Stanford, M. Toms, J. Zigmont, M. Oskoui, S. Arpin, P. Dinunzio, P. M. Ingelmo, C. Poulin, G. Rivera, C. Sabapathy, M. Srour, S. Turgeon-Desilet, D. Zielinski, K. Selby, C. King, J. Lee, A. Michoulas, E. Roland, J. Vajsar, V. Chau, J. Dowling, R. Haldenby, M. Miki, S. So, S. I. Pascual Pascual, A. Martinez Bermejo, S. Epinosa Garcia, S. Garcia Guixot, M. M. Martinez Moreno, M. del Pilar Tirado Requero, M. del Mar Garcia Romero, C. Aguilar, F. Munell Casadesus, M. B. Gomez Garcia de la Banda, M. Gallardo, G. Gili, M. Alavarez Molinero, M. de Los Angeles Tormos Munoz, N. J. Palacios, B. Planas Pascual, M. del Mar Melendez Plumed, A. F. Rucian, E. Toro Tamargo, M. Gratacos Vinola, S. Borell, M. Eckenweiler, M. Krüger, A. Pechmann, B. Rippberger, S. Stein, S. Vogt, S. Wider, U. Schara, B. Andres, A. Della Marina, A. Ganfuss, P. Jachertz, H. Koelbel, K. Rupprich, E. S. Schroers, N. Sponemann, C. Bruno, C. Fiorillo, A. Garaventa, P. Lanteri, V. Lanzillotta, C. Manzitti, M. Pedermonte, P. Tacchetti, F. Trucco, A. Zuffi, R. De Sanctis, L. Fanelli, M. Luigetti, C. Palermo, M. Pane, M. Piastra, S. Sivo, E. Gargaun, T. Gidaro, S. Gilabert, P. L. Léger, A. G. Le Moing, C. Lilien, M. Mayer, Q. Ollievier, J. Rambaud, J. Taytard, R. Vialle, T. Voit, F. Muntoni, L. D'Argenzio, PH Lister, A. Manzur, J. Pisco Domingos, D. Ramsey, V. Ricotti, L. Schottlaender, M. Scoto, S. M. Scuplak, V. Selby, V. Straub, S. Baily, M. Bertoli, A. G. Mayhew, R. M. Lofra, A. Murphy, C. Wood, N. Darin, J. Eldblom, E. Kimber, A. K. Kroksmark, A. Lindstedt, E. Michael, K. Sofou, N. Deconinck, A. Christiaens, S. Coppens, K. DeCock, E. De Vos voor, F. Dorban, G. Gilbert, S. Rooze, V. Tahon, R. Van Coster, R. Van Der Looven, A. Vanlander, D. Vens, H. Verhelst, B. Wenderickx, S. Wittevrongel, M. Farrar, N. Berthon-Jones, M. A. Doumit, K. J. Herbert, T. Kandula, M. Morrison, J. O'Brien, S. Richardson, H. A. Ferreira Sampaio, H. L. Teoh, M. Ryan, K. M. Carroll, K. L. De Valle, D. Villano, I. Woodcock, E. M. Yiu, D. Ardicli, C. Gunbey, V. G. Haliloglu, A. A. Karaduman, B. Konuskan, F. G. Yildiz Sarikaya, E. Serdaroglu, M. Tanyildiz, C. M. Temucin, M. Yildirim, O. T. Yilmaz, R. Arakawa, Y. Chiba, K. Eto, K. Hirasawa, T. Ikai, S. Ito, Y. Ito, Y. Kaburagi, H. Kaneko, S. Matsumaru, N. Matsushima, K. Mizuochi, S. Nagata, H. Nakatsukasa, A. Nishikawa, Y. Otani, T. Sato, M. Shichiji, K. Sugimoto, A. Takeshita, T. Yanagishita, A. Yamauchi, Y. Takeshima, T. Fujino, N. Fukuda, T. Lee, K. Oriyama, T. Shibano, H. Shimomura, T. Tachikawa, Y. Tanaka, N. Taniguchi, J. H. Chae, S. A. Choi, S. M. Chun, H. Jo, H. Kim, S. Y. Kim, J. S. Lee, B. C. Lim, H. I. Shin, W. S. Son, S. Chan, A. C. Chung, C. S. Yan, C. Stella, C. K.W. Joseph, C. S. Ng, H. C.C. Alvin, I. J.K. Janice, L. W.M. Wendy, M. N. Chui-San, N. Y. Ki, T. N. Shun, W. Y. Connie, W. C. Virginia, Y. Yvonne, Y. J. Jong, T. H. Chen, P. C. Chou, Y. H. Chou, H. W. Chung, J. H. Hsu, Y. H. Ju, W. C. Liang, H. H. Shih, H. Y. Wang, Y. C. Wu, Y. S. Zeng

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)1723-1732
Number of pages10
JournalNew England Journal of Medicine
Volume377
Issue number18
DOIs
StatePublished - Nov 2 2017

ASJC Scopus subject areas

  • Medicine(all)

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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., ... Zeng, Y. S. (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