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VX-659–tezacaftor–ivacaftor三联疗法用于携带1或2个Phe508del等位基因的囊性纤维化患者
VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles


Jane C. Davies ... 呼吸系统疾病 其他 • 2018.10.25

摘要


背景

我们研发下一代囊性纤维化穿膜传导调节蛋白(CFTR)校正剂VX-659与tezacaftor和ivacaftor联用的三联疗法(VX-659–tezacaftor–ivacaftor),用于恢复囊性纤维化患者的Phe508del CFTR蛋白功能。

 

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、运输和功能产生的影响。然后通过随机、对照、双盲、多中心试验评估一系列口服VX-659–tezacaftor–ivacaftor三联疗法剂量,上述试验纳入的囊性纤维化患者包括:Phe508del CFTR突变杂合子和最小功能(minimal function)CFTR突变(Phe508del-MF基因型),或Phe508del CFTR突变纯合子(Phe508del-Phe508del基因型)。主要终点是安全性以及第一秒用力呼气量(FEV1)占预计值百分比较基线水平的绝对变化。

 

结果

VX-659–tezacaftor–ivacaftor在体外显著改善了Phe508del CFTR蛋白的加工和运输以及氯离子转运。患者使用VX-659–tezacaftor–ivacaftor的安全性和副作用在可接受范围之内。不良事件多为轻或中度。在Phe508del-MF基因型患者中,至第29日时,VX-659–tezacaftor–ivacaftor使其FEV1占预计值百分比平均值显著增加(P<0.001),增幅达13.3个百分点;在已在接受tezacaftor-ivacaftor的Phe508del-Phe508del基因型患者中,加用VX-659使患者的FEV1占预计值百分比进一步增加9.7个百分点。在这两个患者人群中,汗液氯离子浓度及修订版囊性纤维化问卷(Cystic Fibrosis Questionnaire-Revised)呼吸维度评分均得到改善。

 

结论

VX-659–tezacaftor–ivacaftor以Phe508del CFTR蛋白为靶点,该三联疗法的稳健体外活性转化为Phe508del-MF或Phe508del-Phe508del基因型患者的改善。VX-659三联疗法具备治疗约90%囊性纤维化患者的根本病因的潜力(由Vertex Pharmaceuticals资助;VX16-659-101和VX16-659-001在ClinicalTrials.gov注册号分别为NCT03224351和NCT03029455)。





作者信息

Jane C. Davies, M.D., Samuel M. Moskowitz, M.D., Cynthia Brown, M.D., Alexander Horsley, Ph.D., Marcus A. Mall, M.D., Edward F. McKone, M.D., Barry J. Plant, M.D., Dario Prais, M.D., Bonnie W. Ramsey, M.D., Jennifer L. Taylor-Cousar, M.D., M.S.C.S., Elizabeth Tullis, M.D., Ahmet Uluer, D.O., Charlotte M. McKee, M.D., Sarah Robertson, Pharm.D., Rebecca A. Shilling, M.D., Christopher Simard, M.D., Fredrick Van Goor, Ph.D., David Waltz, M.D., Fengjuan Xuan, Ph.D., Tim Young, Ph.D., and Steven M. Rowe, M.D., M.S.P.H. for the VX16-659-101 Study Group*
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.). Address reprint requests to Dr. Rowe at the University of Alabama at Birmingham, Gregory Fleming James Cystic Fibrosis Research Center MLCM 706, 1918 University Blvd., Birmingham, AL 35294, or at smrowe@uab.edu. *A complete list of investigators in the VX16-659-101 and VX16-659-001 trials is provided in the Supplementary Appendix, available at NEJM.org.

 

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