Ataluren in nonsense mutation cystic fibrosis patients not receiving chronic inhaled tobramycin: Evaluation of exacerbations and lung function

Introduction Atalurenfunctions by interacting with ribosomes to promote read-through of nonsense mutationsin CF. Ataluren9s activity was shown to be inhibited by certain aminoglycosides such as tobramycinthat also bind to the ribosome. Aim To investigate the effect of atalurenon lung function (LF) and pulmonary exacerbations. Methods A post-hoc analysiswas performed on a recent randomized, double-blind, placebo-controlled, phase 3 study to determine the efficacy and safety of atalurenin patients with nonsense mutationcystic fibrosis (nmCF) (Kerem E, et al. Lancet Respir Med. 2014;2:539-47) on %-predicted FEV 1 (ppFEV 1 ) and exacerbationsby use of chronic inhaled tobramycinat baseline. Results Patients not receiving chronic inhaled tobramycin(non-TOBI; n=146), showed a 5.7% difference in relative ppFEV 1 between atalurenand placebo (−0.7% vs −6.4%; p=0.0082) and 40% fewer exacerbations(1.42 vs 2.18; p=0.0061). Non-TOBI patients ≥6 to 1 between atalurenand placebo (4.9% vs −3.3%; p=0.026) and a 60% lower exacerbationrate favoring ataluren(p=0.030). In all intent-to-treat patients (N=232) at week 48, including tobramycinpatients, neither relative change from baseline in ppFEV 1 (−2.5% vs −5.5%; p=0.12), nor number of exacerbations(1.42 vs 1.78; p=0.099) significantly differed between atalurenand placebo. Conclusions Atalurensignificantly reduced exacerbationsand improved LF in nmCF patients not receiving chronic inhaled tobramycin, with markedly improved treatment effect in children and adolescents. Atalurenthus shows promise as a disease-modifying therapy in nmCF.