Abstract
IntroductionMutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) affect the quantity and/or function of CFTR protein reaching the cell surface. Ivacaftor, a CFTR potentiator that enhances chloride transport, increases the channel-open probability of normal and dysfunctional CFTR. Initially approved for people with CF (pwCF) with G551D-CFTR gating mutations, ivacaftor demonstrated clinical benefit in pwCF with other gating mutations and certain residual function mutations, including R117H-CFTR, in clinical studies. We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations.MethodsEfficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 (R117H-CFTR mutations), Study 111 (non–G551D-CFTR gating mutations), and Study 113 (n-of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks.ResultsForty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints.ConclusionsIvacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in pwCF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes.Trial RegistrationNCT01707290Electronic supplementary materialThe online version of this article (10.1007/s41030-020-00129-2) contains supplementary material, which is available to authorized users.
Highlights
We evaluated the long-term safety and efficacy of ivacaftor in people with CF (pwCF) aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations
We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged C6 years with non–G551D-CFTR ivacaftorresponsive mutations in a rollover extension of three parent studies
Follow-up visit at w108d who had a non-G551D-CFTR gating mutation; N is for the full analysis set. cStudy 113 was a randomized crossover trial of ivacaftor vs. placebo for a total of 4 weeks per treatment, followed by 8 weeks of open-label ivacaftor, in pwCF who had phenotypic or molecular evidence of residual CFTR function; N is for the full analysis set. dFollow-up visit occurred 4 weeks (± 7 days) after the last ivacaftor dose for participants who did not continue immediately on ivacaftor
Summary
K. De Boeck Faculty of Medicine, University Hospital of Leuven, Herestraat 49, 3000 Leuven, Belgium. Nick National Jewish Health, 1400 Jackson St, Denver, CO 80206, USA. Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR)
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