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N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.

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

Collaborators (377)

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

Author information

1
From the Division of Neurology, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL (R.S.F.); the Department of Pediatric Neurology, Catholic University, Rome (E.M.); the Department of Neurology, Boston Children's Hospital, Boston (B.T.D.), and Biogen, Cambridge (Z.J.Z., S.G., W.F.) - both in Massachusetts; the Department of Neurology, St. Louis Children's Hospital, St. Louis (A.M.C.); the Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital, Chicago (N.L.K.); the Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany (J.K.); the Departments of Neurology (C.A.C., J.M.) and Rehabilitation and Regenerative Medicine (J.M.), Columbia University, and the Departments of Neurology and Pediatrics, Columbia University Medical Center (D.C.D.V.), New York; the Institute of Medical Genetics and Department of Pediatrics, Tokyo Women's Medical University, Tokyo (K.S.); the Institute of Motion, Paris (L.S.); the Department of Clinical and Molecular Genetics and Rare Diseases Unit, Hospital Vall d'Hebron, and Centro de Investigacíon Biomédica en Red Enfermedades Raras (CIBERER), Barcelona (E.T.); the Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey (H.T.); the Department of Pediatrics, Gothenburg University, Queen Silvia Children's Hospital, Gothenburg, Sweden (M.T.); the Department of Physical Therapy, Children's Hospital of Philadelphia, Philadelphia (A.M.G.); and Ionis Pharmaceuticals, Carlsbad, CA (K.B., C.F.B., E.S.).

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. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).

PMID:
29091570
DOI:
10.1056/NEJMoa1702752
[Indexed for MEDLINE]
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