ATALUREN TREATMENT OF PATIENTS WITH NONSENSE MUTATION DYSTROPHINOPATHY

作者：Bushby, Katharine; Finkel, Richard; Wong, Brenda; Barohn, Richard; Campbell, Craig; Comi, Giacomo P.; Connolly, Anne M.; Day, John W.; Flanigan, Kevin M.; Goemans, Nathalie; Jones, Kristi J.; Mercuri, Eugenio; Quinlivan, Ros; Renfroe, James B.; Russman, Barry; Ryan, Monique M.; Tulinius, Mar; Voit, Thomas; Moore, Steven A.; Sweeney, H. Lee; Abresch, Richard T.; Coleman, Kim L.; Eagle, Michelle; Florence, Julaine; Gappmaier, Eduard; Glanzman, Allan M.; Henricson, Erik; Barth, Jay

来源：Muscle & Nerve, 2014, 50(4): 477-487.

DOI：10.1002/mus.24332

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

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 Delta=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.

• 出版日期2014-10