提示: 手机请竖屏浏览!

Phe508del门控和残余功能基因型囊性纤维化的三联疗法
Triple Therapy for Cystic Fibrosis Phe508del–Gating and –Residual Function Genotypes


Peter J. Barry ... 呼吸系统疾病 • 2021.08.26
相关阅读
• 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-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

3期试验证实三联疗法有效治疗Phe508del门控或残余功能突变囊性纤维化

 

王昊,徐保平*

国家儿童医学中心;首都医科大学附属北京儿童医院呼吸科;国家呼吸系统疾病临床研究中心

*通讯作者

 

囊性纤维化(CF)是高加索人群中最常见的致死性遗传性疾病,发病率为1/1,800~1/2,500。1938年Dorothy Andersen首次描述了49例存在胰腺CF的患者在随后的病程中出现肺部感染和失盐的表现。随着医学的发展,在西方国家CF患者的中位数生存期从1938年的不足2年已逐步提升至41.1年1

查看更多

摘要


背景

elexacaftor-tezacaftor-ivacaftor是小分子囊性纤维化穿膜传导调节蛋白(CFTR)调节剂治疗方案,研究已证明该方案对携带至少一个Phe508del等位基因的患者有效,这表明该联合治疗方案可调节单一Phe508del等位基因。对于另外一个CFTR等位基因包含门控或残余功能突变,并且既往CFTR调节剂(ivacaftor或tezacaftor-ivacaftor)已经可以有效治疗的患者,通过恢复Phe508del CFTR蛋白功能而产生进一步益处的可能性尚不明确。

 

方法

我们对≥12岁的Phe508del门控或Phe508del残余功能基因型囊性纤维化患者开展了一项3期、双盲、随机、活性药对照试验。经过4周接受ivacaftor或tezacaftor-ivacaftor治疗的导入期后,我们将患者随机分配接受8周elexacaftor-tezacaftor-ivacaftor或活性药对照治疗。主要终点是在elexacaftor-tezacaftor-ivacaftor组中,截至第8周时,第1秒用力呼气量(FEV1)占预计值百分比相对于基线的绝对变化。

 

结果

完成导入期后,132患者接受了elexacaftor-tezacaftor-ivacaftor治疗,126例接受了活性药对照治疗。elexacaftor-tezacaftor-ivacaftor使FEV1占预计值百分比比基线高3.7个百分点(95%置信区间[CI],2.8~4.6),比活性药对照组高3.5个百分点(95% CI,2.2~4.7),并且使汗液氯离子浓度比基线低22.3 mmol/L(95% CI,20.2~24.5),比活性药对照组低23.1 mmol/L(95% CI,20.1~26.1)(所有比较的P<0.001)。在elexacaftor-tezacaftor-ivacaftor组和活性药对照组中,修订版囊性纤维化问卷(Cystic Fibrosis Questionnaire-Revised)呼吸维度评分(范围,0~100分,评分较高表示生活质量较好)相对于基线的变化分别为10.3分(95% CI,8.0~12.7)和1.6分(95% CI,-0.8~4.1)。两组的不良事件发生率相似;不良事件导致elexacaftor-tezacaftor-ivacaftor组1例患者(转氨酶水平升高)和活性药对照组2例患者(焦虑或抑郁,以及肺病加重)停止治疗。

 

结论

elexacaftor-tezacaftor-ivacaftor对Phe508del门控或Phe508del残余功能基因型患者安全有效,并且与既往CFTR调节剂相比产生了进一步益处(由Vertex Pharmaceuticals资助,VX18-445-104在ClinicalTrials.gov注册号为NCT04058353)。





作者信息

Peter J. Barry, M.D., Marcus A. Mall, M.D., Antonio Álvarez, M.D., Carla Colombo, M.D., Karin M. de Winter-de Groot, M.D., Isabelle Fajac, M.D., Ph.D., Kimberly A. McBennett, M.D., Ph.D., Edward F. McKone, M.D., Bonnie W. Ramsey, M.D., Sivagurunathan Sutharsan, M.D., Jennifer L. Taylor-Cousar, M.D., M.S.C.S., Elizabeth Tullis, M.D., Neil Ahluwalia, M.D., Lucy S. Jun, Ph.D., Samuel M. Moskowitz, M.D., Valentin Prieto-Centurion, M.D., Simon Tian, M.D., David Waltz, M.D., Fengjuan Xuan, Ph.D., Yaohua Zhang, Ph.D., Steven M. Rowe, M.D., M.S.P.H., and Deepika Polineni, M.D., M.P.H. for the VX18-445-104 Study Group*
From Manchester University NHS Foundation Trust, Manchester, United Kingdom (P.J.B.); Charité–Universitätsmedizin Berlin, the Berlin Institute of Health, and the German Center for Lung Research, Berlin (M.A.M.), and the Division of Cystic Fibrosis, Department of Pulmonary Medicine, University Medicine Essen–Ruhrlandklinik, University of Duisburg–Essen, Essen (S.S.) — all in Germany; Vall d’Hebron Barcelona Hospital Campus, Barcelona (A.A.); Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and the University of Milan — both in Milan (C.C.); Wilhelmina Children’s Hospital–University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (K.M.W.-G.); Assistance Publique–Hôpitaux de Paris (AP-HP) Centre–Université de Paris Hôpital Cochin AP-HP, Paris (I.F.); Rainbow Babies and Children’s Hospital, Cleveland (K.A.M.); St. Vincent’s University Hospital, Dublin (E.F.M.); Seattle Children’s Hospital, Seattle (B.W.R.); National Jewish Health, Denver (J.L.T.-C.); St. Michael’s Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.A., L.S.J., S.M.M., V.P.-C., S.T., D.W., F.X., Y.Z.); the University of Alabama at Birmingham, Birmingham (S.M.R.); and the University of Kansas Medical Center, Kansas City (D.P.). Address reprint requests to Dr. Polineni at the Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., MS 3007, Kansas City, KS 66160, or at dpolineni@kumc.edu. *The members of the VX18-445-104 Study Group are listed in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020;8:65-124.

2. De Boeck K, Amaral MD. Progress in therapies for cystic fibrosis. Lancet Respir Med 2016;4:662-674.

3. Elborn JS. Cystic fibrosis. Lancet 2016;388:2519-2531.

4. Accurso FJ, Van Goor F, Zha J, et al. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data. J Cyst Fibros 2014;13:139-147.

5. Cystic Fibrosis Mutation Database (CFTR1). 2011 (http://www.genet.sickkids.on.ca/).

6. The Clinical and Functional TRanslation of CFTR (CFTR2). 2011 (https://cftr2.org/).

7. Cystic Fibrosis Foundation patient registry: 2018 annual data report. Bethesda, MD: Cystic Fibrosis Foundation, 2019.

8. 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.

9. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 2009;106:18825-18830.

10. 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.

11. Van Goor F. Nonclinical profile of the CFTR corrector VX-661. Presented at the 30th annual North American Cystic Fibrosis Conference, Orlando, FL, October 27–29, 2016. (Poster.)

12. 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.

13. Keating D, Marigowda G, Burr L, et al. VX-445–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018;379:1612-1620.

14. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019;381:1809-1819.

15. Mall MA, Mayer-Hamblett N, Rowe SM. Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications. Am J Respir Crit Care Med 2020;201:1193-1208.

16. De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014;13:674-680.

17. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019;394:1940-1948.

18. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest 2009;135:1610-1618.

19. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017;181:Suppl:S4-S15.e1.

20. Wilschanski M, Dupuis A, Ellis L, et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med 2006;174:787-794.

服务条款 | 隐私政策 | 联系我们