Long-Term Ivacaftor in People Aged 6 Years and Older with Cystic Fibrosis with Ivacaftor-Responsive Mutations

Abstract

Introduction: Mutations 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.

Methods: Efficacy 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.

Results: Forty-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.

Conclusions: Ivacaftor 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 registration: NCT01707290.

Keywords: Gating mutation; Ivacaftor; Long-term efficacy; Long-term safety; Non-G551D mutation; R117H; Residual function.

Figures

Fig. 1

Study design. aStudy 110 was a randomized controlled trial of ivacaftor vs. placebo for 24 weeks in pwCF who had an R117H-CFTR mutation; N is for the full analysis set. bStudy 111 was a randomized crossover trial of ivacaftor vs. placebo for 8 weeks per treatment, followed by 16 weeks of open-label ivacaftor, in pwCF 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. If applicable, an early termination visit occurred as soon as possible after the last ivacaftor dose. CFTR cystic fibrosis transmembrane conductance regulator, d day, pwCF people with cystic fibrosis, q12h once every 12 h, w week

Fig. 2

Absolute change from baseline in ppFEV1 in Extension Study 112 by parent-study subgroup. Data are least-squares means based on a mixed-effects model for repeated measures, and error bars indicate standard errors. BL baseline, ppFEV1 percent predicted forced expiratory volume in 1 s

Fig. 3

Absolute change from baseline in sweat chloride concentration in Extension Study 112 by parent-study subgroup. Data are least-squares means based on a mixed-effects model for repeated measures, and error bars indicate standard errors. Solid gray line (zero) represents no change from Extension Study 112 baseline. BL baseline