Data di Pubblicazione:
2018
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 least-squares 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 .).
Tipologia CRIS:
14.a.1 Articolo su rivista
Keywords:
Age of Onset; Child; Child, Preschool; Double-Blind Method; Female; Humans; Infant; Injections, Spinal; Least-Squares Analysis; Male; Motor Skills; Oligonucleotides; Oligonucleotides, Antisense; Spinal Muscular Atrophies of Childhood; Medicine (all)
Elenco autori:
Mercuri, E.; Darras, B. T.; Chiriboga, C. A.; Day, J. W.; Campbell, C.; Connolly, A. M.; Iannaccone, S. T.; Kirschner, J.; Kuntz, N. L.; Saito, K.; Shieh, P. B.; Tulinius, M.; Mazzone, E. S.; Montes, J.; Bishop, K. M.; Yang, Q.; Foster, R.; Gheuens, S.; Bennett, C. F.; Farwell, W.; Schneider, E.; De Vivo, D. C.; Finkel, R. S.; Bradley, Wg; Kaufmann, P; Dickson, Pi; Reingold, Sc; Davis, Cs; Arredondo, K; Castro, D; Cowie, M; Farrow-Gillespie, A; Hebert, A; Kauk, M; Miller, N; Nelson, L; Spain, T Jr; Cappell, J; Constantinescu, A; Cruz, R; Dastgir, J; Dunaway, S; Engelstad, K; Khandji, Ag; Kramer, S; Marra, J; Popolizio, M; Salazar, R; Weimer, Lh; Aziz-Zaman, S; Lamarca, N; Ghosh, P; Al-Ghamdi, F; Liew, W; Graham, R; Berde, C; Sethna, N; Koka, A; Wang, L; Laine, R; Souris, M; Ordonez, G; Harrington, T; Szelag, H; Pasternak, A; Mirek, E; Quigley, J; Berry, D; Civitello, M; Endsley, Jd; Eden, C; Leon, W; O'Reardon, K; Sigurdardottir, L; Johnson, C; Turner, J; Vega, M; Weber-Guzman, F; Zinn, M; Tesi Rocha, Ac; Watson, K; D'Souza, G; Ramamurthi, Rj; Gee, R; Kitsuwa-Lowe, J; Hagerman, K; Crasta, S; Welsh, L; Paulose, S; Mcfall, D; Perez, J; Patnaik, S; Sanjanwala, B; Sakamuri, S; Proud, C; Purse, Bp; Duong, Tt; Sampson, J; Tennekoon, G; Brandsema, J; Glanzman, A; Flickinger, J; Toms, M; Adang, L; Stanford, D; Mayer, O; Zigmont, J; Chadehumbe, M; Kichula, E; Finanger, E; Russman, B; Roberts, C; Frank, A; Benjamin, D; Zilke, K; Golumbek, Pt; Zaidman, Cm; Anand, P; Gadeken, R; Siener, C; Epstein, L; Krueger, J; Goldman, S; Krosschell, K; Blomgren, C; Choi, Hw; Kurz, J; Parsons, J; Janas, J; Yang, M; Ballard, A; Carry, T; Shea, S; Bielsky, A; Booker, K; Camuto, A; Lord-Halvorson, S; Gibbons, M; Zimmerman, C; Allen, V; Fuhr, P; Kelley, C; Johnson, H; Tran, V; Vanderveen, G; Fowler, E; Parziale, N; Rao, L; Skura, C; Shu, F; Oskoui, M; Zielinski, D; Poulin, C; Ingelmo, Pm; Desilets, St; Dinunzio, P; Rivera, G; Srour, M; Arpin, S; Goobie, S; Gibson, P; Scholtes, C; Mcdonald, W; Zapata, E; Nguyen, Ce; Servais, L; Gargaun, E; Le Moing, Ag; Gidaro, T; Vialle, R; Guye, Ml; Lilien, C; Olliver, G; Gilabert, S; Borell, S; Wider, S; Stein, S; Vogt, S; Krüger, M; Pechmann, A; Rippberger, B; Eckenweiler, M; Schara, U; Koelbel, H; Andres, B; Rupprich, K; Gangfuss, A; Jachertz, P; Della Marina, A; Sponemann, N; Pane, M; Palermo, C; Piastra, M; Fanelli, L; De Sanctis, R; Genovese, O; Antonaci, L; Pera, Mc; Lamendola, P; Messina, S; Vita, G; Di Bella, V; Sframeli, M; La Rosa, M; Barcellona, C; Distefano, Mg; Cavallaro, F; Versaci, A; De Luca, F; Vita, G; Nacimento Osorio, A; Tizzano, E; Ortez Gonzalez, Ci; Ortigoza Escobar, Jd; Colomer Oferil, J; Medina Cantillo, J; Rotger, Af; Vigo Morancho, M; Eldblom, J; Darin, N; Kroksmark, Ak; Lindstedt, A; Michael, E; Kimber, E; Wahlgren, L; Chan, Sh; Chim, S; Chiu, J; Ho, Acc; Ip, Jkj; Lam, Wwm; Ng, Mc; Wan, C; Wong, Vcn; Yue, Y; Arakawa, R; Yamauchi, A; Nagata, S; Ito, Y; Nakatsukasa, H; Takeshita, A; Hirasawa, K; Ikai, T; Eto, K; Otamni, Y; Takeshima, Y; Fukuda, N; Tanaka, Y; Shimomura, H; Lee, T; Shibano, T; Tachikawa, T; Chae, Jh; Lim, Bc; Shin, Hi; Kim, Sy; Choi, Sa; Son, Ws; Jo, H; Chun, Sm; Kim, H.
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