Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation

Abstract

Cystic fibrosis (CF) is an autosomal recessive lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for CFTR, an epithelial cell-surface expressed protein responsible for the transport of chloride (Cl(-)). Gating mutations associated with defective conductance can be modulated by CFTR potentiators. Ivacaftor is a CFTR potentiator approved for the treatment of CF patients >6 yrs of age with at least one copy of the G551D-CFTR mutation. Herein, the clinical trial development programme for ivacaftor will be reviewed, including two pivotal studies in adolescents/adults and in children. These studies report sustained improvements in lung function and sweat chloride concentrations, and a reduction in pulmonary exacerbations over a 48-week treatment period. In the era of personalised medicine, ivacaftor offers an effective and well-tolerated treatment for the clinical management of CF patients with the G551D mutation. A long-term, open-label study will report the effects of ivacaftor over a further 48 weeks.

Figure 1.

Design of adult and paediatric studies investigating the efficacy and tolerability of ivacaftor [16, 17]. PERSIST: An Open-Label Rollover Study to Evaluate the Safety and Efficacy of VX-770 in Cystic Fibrosis Patients; STRIVE: Evaluating the Efficacy and Safety of Treatment with VX-770 in CF patients with G551D Mutations; ENVISION: Evaluation of Efficacy and Safety of VX-770 in children six to eleven years old with CF; CFTR: cystic fibrosis transmembrane conductance regulator; FEV₁: forced expiratory volume in 1 s; % pred: % predicted.

Figure 2.

Results from the the STRIVE study of forced expiratory volume in 1 s (FEV₁) absolute change from baseline. Treatment effect from baseline to week 24: +10.6%, p<0.0001. Treatment effect from baseline to week 48: +10.5%, p=0.0001. Data are presented as mean (95% CI). % pred: % prediced.

Figure 3.

Time to first pulmonary exacerbation in adults treated with ivacaftor or placebo according to the modified Fuch’s criteria. The dotted lines represent weeks 24 (168 days) and 48 (336 days), respectively. Week 24: hazard ratio=0.40, p=0.0016. Week 48: hazard ratio= +10.5%, p=0.0001.

Figure 4.

Sweat chloride concentrations from baseline to week 48 of the study. Treatment effect from baseline to week 24: -47.9 mmol·L⁻¹, p<0.0001. Treatment effect from baseline to week 48: -48.1 mmol·L⁻¹, p<0.0001. Data are presented as mean (95% CI). ········: diagnostic threshold.