VX-659-泰泽卡托维伐替卡与依伐卡托维在携带一个或两个 Phe508del 等位基因的囊性纤维化患者中的疗效。
VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.
机构信息
From Imperial College London and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.), and the Manchester Adult Cystic Fibrosis Centre, Manchester (A.H.) - both in the United Kingdom; Vertex Pharmaceuticals (S.M.M., C.M.M., S.R., R.A.S., C.S., F.V.G., D.W., F.X., T.Y.) and Boston Children's Hospital and Brigham and Women's Hospital (A.U.) - all in Boston; Indiana University School of Medicine, Indianapolis (C.B.); Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, and the German Center for Lung Research, Giessen - all in Germany (M.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.), and Cork University Hospital and University College Cork, Cork (B.J.P.) - all in Ireland; Schneider Children's Medical Center of Israel, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (D.P.) - both in Israel; Seattle Children's Hospital, Seattle (B.W.R.); National Jewish Health, Denver (J.L.T.-C.); St. Michael's Hospital, Toronto (E.T.); and the University of Alabama at Birmingham, Birmingham (S.M.R.).
出版信息
N Engl J Med. 2018 Oct 25;379(17):1599-1611. doi: 10.1056/NEJMoa1807119. Epub 2018 Oct 18.
BACKGROUND
The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.
METHODS
We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV).
RESULTS
VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations.
CONCLUSIONS
Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).
背景
下一代囊性纤维化跨膜电导调节剂（CFTR）校正剂 VX-659 与 tezacaftor 和 ivacaftor（VX-659-tezacaftor-ivacaftor）三联合用，旨在恢复囊性纤维化患者 Phe508del CFTR 蛋白的功能。
方法
我们使用人支气管上皮细胞评估 VX-659-tezacaftor-ivacaftor 对 Phe508del CFTR 蛋白的加工、转运和功能的影响。然后，在涉及携带 Phe508del CFTR 突变和最小功能 CFTR 突变（Phe508del-MF 基因型）的杂合子或纯合子 Phe508del CFTR 突变（Phe508del-Phe508del 基因型）的囊性纤维化患者中，进行了一系列口服 VX-659-tezacaftor-ivacaftor 三联组合的随机、对照、双盲、多中心试验，评估了各种剂量的 VX-659-tezacaftor-ivacaftor。主要终点是安全性和从基线到第 29 天预测的 1 秒用力呼气量（FEV）的绝对变化百分比。
结果
VX-659-tezacaftor-ivacaftor 显著改善了 Phe508del CFTR 蛋白的加工和转运以及体外氯离子转运。在患者中，VX-659-tezacaftor-ivacaftor 具有可接受的安全性和副作用谱。大多数不良事件为轻度或中度。在携带 Phe508del-MF 基因型的患者中，通过第 29 天（P<0.001），VX-659-tezacaftor-ivacaftor 可使预测 FEV 的百分比平均增加高达 13.3 个点；在已接受 tezacaftor-ivacaftor 治疗的 Phe508del-Phe508del 基因型患者中，添加 VX-659 可使预测 FEV 的百分比进一步增加 9.7 个点。汗液氯化物浓度和囊性纤维化问卷修订版呼吸域评分在两个患者群体中均有所改善。
结论
针对 Phe508del CFTR 蛋白的 VX-659-tezacaftor-ivacaftor 的强大体外活性转化为对携带 Phe508del-MF 或 Phe508del-Phe508del 基因型的患者的改善。VX-659 三联组合疗法有可能治疗约 90%的囊性纤维化患者的疾病根本原因。（由 Vertex 制药公司资助；VX16-659-101 和 VX16-659-001 临床试验.gov 编号，NCT03224351 和 NCT03029455）。
Zotero 插件