Ataluren in nonsense mutation cystic fibrosis patients not receiving chronic inhaled tobramycin: Evaluation of exacerbations and lung function
2016
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.
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