Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial

Abstract

Background Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis (CF) in 10% of patients.. Methods This randomized, double-blind, placebo-controlled study enrolled 238 patients ≥6 years with nmCF to receive oral ataluren 10 mg/kg in the morning, 10 mg/kg mid-day, and 20 mg/kg in the evening or matching placebo for 48 weeks. The primary endpoint was relative change in % predicted forced expiratory volume in one second (FEV1) at Week 48; the secondary endpoint was the rate of pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT00803205. Findings There was no statistically significant difference in relative change from baseline in % predicted FEV1between ataluren and placebo at Week 48(-2•5% vs -5•5%, p=0.1235). The rate of pulmonary exacerbations was not statistically different between treatment arms (rate ratio 0.77 (95% CI 0.57, 1.05), p=0.0992). However, post hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference in relative change from baseline in % predicted FEV1 between ataluren and placebo at Week 48 (-0.7% vs -6.4%, nominal p=0•008, adjusted for multiplicity p = 0•024) and 40% fewer exacerbations in ataluren-treated patients (OR 0.60 (95% CI 0•42, 0•86), nominal p=0•006, adjusted for multiplicity p = 0•018). Interpretation While there was no statistically significant improvement in lung function or exacerbation rate in the ITT population of cystic fibrosis patients with nonsense mutations treated with ataluren, treatment might be beneficial for nmCF patients not receiving chronic inhaled tobramycin.