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VX-445–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-445–Tezacaftor–Ivacaftor in Patients with CF and One or Two Phe508del Alleles


Dominic Keating ... 呼吸系统疾病 其他 • 2018.10.25

摘要


背景

VX-445是下一代囊性纤维化穿膜传导调节蛋白(CFTR)校正剂,旨在与tezacaftor和ivacaftor三药联用(VX-445–tezacaftor–ivacaftor),用于恢复囊性纤维化患者的Phe508del CFTR蛋白功能。

 

方法

研究评估了VX-445–tezacaftor–ivacaftor对人支气管上皮细胞中Phe508del CFTR蛋白加工、运输和氯离子转运的影响。根据其体外活性,我们开展了一项随机、安慰剂对照、双盲、剂量范围探索的2期临床试验,在Phe508del CFTR突变杂合子和最小功能突变(minimal-function mutation)(Phe508del-MF)或Phe508del CFTR突变纯合子(Phe508del-Phe508del)患者中评估完成tezacaftor-ivacaftor导入期后,口服VX-445–tezacaftor–ivacaftor的疗效。主要终点包括安全性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

体外试验显示,VX-445–tezacaftor–ivacaftor显著改善Phe508del CFTR蛋白加工、运输和氯离子转运,改善程度超过任何上述两种药物双联用药。VX-445–tezacaftor–ivacaftor用于囊性纤维化患者的安全性及副作用在可接受范围内。不良事件多为轻或中度。VX-445–tezacaftor–ivacaftor也使Phe508del-MF患者的FEV1占预计值百分比增加,增幅达13.8个百分点(P<0.001)。在已接受tezacaftor-ivacaftor治疗的Phe508del-Phe508del基因型患者中,加用VX-445使患者的FEV1占预计值百分比增加11.0个百分点(P<0.001)。这两个患者人群的汗液氯离子浓度均降低,其修订版囊性纤维化问卷(Cystic Fibrosis Questionnaire-Revised)呼吸维度评分均改善。

 

结论

使用VX-445–tezacaftor–ivacaftor针对Phe508del CFTR蛋白进行靶向治疗,可提高体外CFTR功能,并转化为携带1个或2个Phe508del等位基因的囊性纤维化患者的病情改善。VX-445–tezacaftor–ivacaftor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;VX16-445-101和EudraCT在ClinicalTrials.gov注册号分别为NCT03227471和2017-000797-11)。





作者信息

Dominic Keating, M.D., Gautham Marigowda, M.D., Lucy Burr, Ph.D., Cori Daines, M.D., Marcus A. Mall, M.D., Edward F. McKone, M.D., Bonnie W. Ramsey, M.D., Steven M. Rowe, M.D., M.S.P.H., Laura A. Sass, M.D., Elizabeth Tullis, M.D., Charlotte M. McKee, M.D., Samuel M. Moskowitz, M.D., Sarah Robertson, Pharm.D., Jessica Savage, M.D., Christopher Simard, M.D., Fredrick Van Goor, Ph.D., David Waltz, M.D., Fengjuan Xuan, Ph.D., Tim Young, Ph.D., and Jennifer L. Taylor-Cousar, M.D., M.S.C.S. for the VX16-445-001 Study Group*
From Alfred Hospital, Melbourne, VIC (D.K.), and Mater Hospital, Brisbane, QLD (L.B.) — both in Australia; Vertex Pharmaceuticals, Boston (G.M., C.M.M., S.M.M., S.R., J.S., C.S., F.V.G., D.W., F.X., T.Y.); Banner University Medical Center, Tucson, AZ (C.D.); Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, and the German Center for Lung Research, Giessen — both in Germany (M.A.M.); St. Vincent’s University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Seattle Children’s Hospital, Seattle (B.W.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); Children’s Hospital of the King’s Daughters, Norfolk, VA (L.A.S.); St. Michael’s Hospital, Toronto (E.T.); and National Jewish Health, Denver (J.L.T.-C.). Address reprint requests to Dr. Taylor-Cousar at National Jewish Health, 1400 Jackson St., J318, Denver, CO 80206, or at taylor-cousarj@njhealth.org *A complete list of members of the VX16-445-001 Study Group is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Davies JC, Moskowitz SM, Brown C, et al. VX-659–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018;379:1599-1611.

2. Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011;108:18843-18848.

3. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-1672.

4. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013;187:1219-1225.

5. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015;373:220-231.

6. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017;377:2024-2035.

7. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 2017;377:2013-2023.

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