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Muscle Nerve. 2014 Oct;50(4):477-87. doi: 10.1002/mus.24332.

Ataluren treatment of patients with nonsense mutation dystrophinopathy.

Collaborators (243)

Ryan MM, Kornberg AJ, Wray A, Carroll K, Kennedy R, Villano D, de Valle K, Jones KJ, North KN, Dexter M, Wicks S, Rose K, Goemans N, Buyse GM, van den Hauwe M, Vrijsen B, Campbell C, Janmohammad A, Scholtes C, Mah JK, Wright CJ, Chiu A, Walker LM, Sarnat HB, Selby K, King C, Meisner L, Voit T, Doppler V, De Castro D, Decostre V, Chabrol B, Levy N, Halbert C, Pereon Y, Magot A, Perrier J, Mahe JY, Perrau AS, Chasserieau R, Schara U, Lutz S, Busse M, Della Marina A, Bosbach T, Kirschner J, Stanescu A, Pohl A, Rensing-Zimmerman C, Eisele U, Fetzer I, Vogt S, Bertini E, D'Amico A, Kofler A, Gesu PB, Carlesi A, Bonetti AM, Gagliardi MG, Santecchia L, Emma F, Bergami G, Mercuri EM, Vasco G, Bianco F, Mazzone ES, Pane M, De Sanctis R, Comi GP, Magri F, Lucchini V, Corti SP, Moggio MG, Sciacco M, Govoni A, Bresolin N, Nevo Y, Dor-Wollman T, Bar-Lev A, Krojanker-Yaffe D, Weisband E, Vilchez JJ, Muelas N, Sevilla T, Smeyers P, Calle F, González M, de la Osa A, Colomer J, Ortez CI, Nascimento A, Febrer A, Medina J, Muni R, Tulinius M, Thorarinsdottir B, Darin N, Sterky U, Kroksmark AK, Berglund L, Sejersen T, Hovmöller M, Trulsson E, Hök A, Kipping P, Bushby KM, Guglieri M, Straub V, Sàrközy A, Willis T, Eagle M, Mayhew A, McCallum M, Smith L, Bell G, Muntoni F, Manzur AY, Robb SA, Main M, Ash M, Scoto M, Cirak S, Quinlivan RC, Smith MR, Pandey R, James S, Emery N, Groves L, Kulshrestha R, Wong BL, Collins J, McGuire M, McCormick A, Morehart P, Hu S, Brown R, Finkel RS, Bonnemann CG, Yang ML, Foley AR, Murphy-Kotzer L, Dorsey L, Estilow T, Glanzman AM, Paisley A, Yum S, Thomas T, Smith K, Gappmaier E, Bromberg MB, McGerty B, Heidarian LL, Swoboda K, Gappmaier V, Day JW, Karachunski PI, Margolis M, Naughton C, Buser KK, Dalton J, Matthews KD, Stephan CM, Laubenthal KS, Darras BT, Kang PB, Riley SO, Quigley J, Butler H, Parsons J, Apkon SD, Gibbons M, Carey T, Barohn RJ, Dasouki MJ, Anderson HS, Arthur A, Burns JM, Dimachkie MM, Pasnoor M, Wang YI, Herbelin L, Myles R, Ciafaloni E, Heatwole C, Eichinger K, Pandya S, Connolly A, Pestronk A, Al-Lozi M, Lopate G, Golumbek P, Sommerville RB, Wang L, Wojcicka-Mitchell A, Godbey A, Malkus B, Schierbecker J, Siener C, Lu M, Harms M, Varadachary A, Iyadurai S, Rojas L, Iannacone ST, Gilbreath H, Khonghatithum C, Merryman R, Nelson L, Andersen M, Greene M, Kern S, Sproule DM, Kaufmann P, De Vivo D, Battista V, Constantinescu A, Montes J, Dunaway S, Montgomery M, Marra J, McDonald CM, Han J, Henricson E, Abresch RT, Joyce N, Goude E, Johnson L, Nicorici A, Cregan M, Renfroe JB, Bougher G, Keohane T, Russman BS, Sussman MD, Zilke K, del Rosario E, Wechsler SB, Juel VC, Hobson-Webb L, Smith EC, Mackey J, Case L, Ollendick K.

Abstract

INTRODUCTION:

Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders.

METHODS:

Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48.

RESULTS:

Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo.

CONCLUSIONS:

As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

Copyright © 2014 Wiley Periodicals, Inc.

KEYWORDS:

Duchenne muscular dystrophy; genetic; nonsense mutation; orphan; pediatric

PMID:
25042182
[PubMed - indexed for MEDLINE]
PMCID:
PMC4241581
Free PMC Article
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