BACKGROUND The F508del and G551D mutations affect CFTR in different ways. VX-661 increases the quantity of functional F508del-CFTR at the cell surface, and ivacaftor (IVA) increases CFTR gating; effects are additive in vitro. METHODS This randomized, double-blind, placebo-controlled, multi-cohort, phase 2 study evaluated escalating doses of VX-661 alone and in combination with IVA (150 mg q12h) in F508del/F508del patients, or the addition of VX-661 (100 mg qd) to F508del/G551D patients on prescribed IVA. Primary outcomes were safety and change in sweat chloride through Day 28. Percent predicted FEV1 (ppFEV1) was a secondary endpoint. RESULTS The reported cohorts included 128 patients homozygous for F508del and 18 with F508del/G551D. In patients homozygous for F508del, at Day 28, VX-661 monotherapy resulted in reductions in sweat chloride but non-significant increases in ppFEV1, whereas VX-661/IVA decreased sweat chloride 5.7 mmol/L (P<0.05 within group; n = 14) and increased ppFEV1 4.8 absolute points (P = 0.01 vs placebo; n = 15). In F508del/G551D patients, through Day 28, VX-661/IVA led to a mean reduction in sweat chloride of 7.0 mmol/L (P = 0.053; n = 13) and significant within-group changes in absolute ppFEV1 (4.6 points, P = 0.012; n = 14). The overall incidence of AEs in VX-661/IVA-treated patients was similar across treatment groups and was comparable to placebo; the most common events were pulmonary exacerbation, cough, headache, nausea, and increased sputum. CONCLUSION These data show that the VX-661/IVA combination may benefit patients with CF who are homozygous for F508del and may enhance the benefit of IVA in CF patients with F508del/G551D.
Pilewski, J. M., Cooke, J., Lekstrom-Himes, J., & Donaldson, S. (2015). WS01.4 VX-661 in combination with ivacaftor in patients with cystic fibrosis and the F508del-CFTR mutation. Journal of Cystic Fibrosis, 14, S1. https://doi.org/10.1016/s1569-1993(15)30004-7