Patients with cystic fibrosis with either 1 or 2 Phe508del alleles who were treated with a drug combination of VX-659, tezacaftor, and ivacaftor showed improved forced expiratory volume in 1 second (FEV1), sweat chloride concentrations, and questionnaire scores, according to the results of a study published in the New England Journal of Medicine.

The absolute change from baseline in the percentage of predicted FEV1 was compared between patients with cystic fibrosis who received either the triple drug combination (tezacaftor-ivacaftor-VX-659) or tezacaftor-ivacaftor-placebo. Patients who were homozygous or heterozygous for Phe508del alleles were included. Secondary end points consisted of the absolute change in sweat chloride concentration and the absolute change from baseline in the Cystic Fibrosis Questionnaire-Revised score.

Among the 29 homozygous Phe508del participants who underwent randomization, 11 were assigned to placebo (tezacaftor and ivacaftor only) and 18 were assigned to the combination therapy (VX-659, tezacaftor, and ivacaftor). VX-659, tezacaftor, and ivacaftor resulted in increases of up to 9.7 points at day 29 in predicted FEV1. Among the 25 participants who were Phe508del heterozygous, 6 were assigned to the placebo group and 19 were assigned to the drug combination group. VX-659, tezacaftor, and ivacaftor resulted in increases of up to 13.3 points at day 29 in predicted FEV1.

Furthermore, chloride sweat concentrations and Cystic Fibrosis Questionnaire-Revised scores improved in both patient populations when VX-659 was added to tezacaftor and ivacaftor.

The researchers wrote, “These trials provide proof of the concept that targeting the Phe508del CFTR protein … has the potential to represent a clinical advance … for approximately 9 of every 10 patients with the disease.”


Davies JC, Moskowitz SM, Brown C, et al; for the VX-659-101 Study Group. VX-659–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two phe508del alleles. N Engl J Med. 2018;379:1599-1611.