Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: the international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF).

Objectives: A randomized, double-blind, placebo-controlled, phase 3 study assessed the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis (nmCF) [1]. The study showed that the activity of ataluren, a ribosome-binding drug that promotes nonsense suppression, appeared to be confounded by the use of the inhaled aminoglycoside antibiotic tobramycin, another ribosome-binding drug. A post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin, consisting of 2/3 of the patients in the study, showed a 5.7% difference (p = 0.008) in relative change from baseline in %-predicted FEV1 (ppFEV1) between the ataluren and placebo group at week 48, and 40% fewer pulmonary exacerbations in the ataluren group (p = 0.006). Methods: The Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF) was designed to confirm these findings. ACT CF is an international, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of ataluren in patients with nmCF not receiving chronic inhaled aminoglycosides. The primary endpoint was the relative change from baseline in ppFEV1. Patients were randomized according to pre-specified stratification factors: age (<18 years vs ≥18 years), chronic inhaled antibiotic use (yes vs no), and ppFEV1 (40% to <65% vs 65% to ≤90%). Results: In total, 279 patients were enrolled at 88 sites in 16 countries. Enrollment was completed in November 2015. Results are expected early in 2017, and will be presented in full at the conference. Conclusion: We will discuss the implications of this potential new therapy for the treatment of nmCF. Reference [1] Kerem E, et al. Lancet Respir Med. 2014;2:539–47.