VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
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DOI：
10.1056/nejmoa1807120
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发表时间：
2018-10-25
影响因子：
158.5
通讯作者：
Taylor-Cousar, Jennifer L.
中科院分区：
文献类型：
--
作者：
Keating, Dominic;Marigowda, Gautham;Taylor-Cousar, Jennifer L.
dvx -445是一种新一代囊性纤维化跨膜传导调节剂（CFTR）校正剂，设计用于在给予tezacaftor和ivacaftor （VX-445-tezacaftor-ivacaftor）的囊性纤维化患者中恢复Phe508del CFTR蛋白功能。方法观察vx -445- tezactor -ivacaftor对人支气管上皮细胞中Phe508del CFTR蛋白加工、转运和氯离子转运的影响。在体外活性的基础上，进行了一项随机、安慰剂对照、双盲、剂量范围的2期试验，以评估口服vx -445- tezactor -ivacaftor对Phe508del CFTR突变杂合子和最小功能突变（Phe508del- mf）患者和tezactor -ivacaftor对Phe508del CFTR突变（Phe508del-Phe508del）纯合子患者在tezactor -ivacaftor合用后的疗效。主要终点是安全性和1秒内预测用力呼气量（FEV1）相对基线的绝对变化百分比。结果在体外，vx -445- tezactor -ivacaftor在双药联合下显著改善了Phe508del CFTR蛋白的加工、转运和氯离子转运，且改善程度大于其他两种药物。在囊性纤维化患者中，vx -445-tezacaf -ivacaftor具有可接受的安全性和副作用。大多数不良事件为轻度或中度。治疗还导致Phe508del-MF组预测FEV1的百分比增加高达13.8点(P
BACKGROUNDVX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor).METHODSWe evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline.RESULTSIn vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P