依伐卡托与泰比卡托和艾克卡托三联复方药物治疗携带单个 F508del 突变的囊性纤维化
Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.
机构信息
From the Department of Respiratory and Sleep Medicine, Westmead Hospital and CF Research Group, Ludwig Engel Centre for Respiratory Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia (P.G.M.); the Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, the Berlin Institute of Health, and the German Center for Lung Research, Berlin (M.A.M.); the Department of Medical Microbiology, Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic (P.D.); the Pediatric Respiratory Medicine and Pediatric Cystic Fibrosis Clinic, McGill University Health Centre, Montreal (L.C.L.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); the Department of Internal Medicine, University of Kansas Medical Center, Kansas City (D.P.); the Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle (B.W.R.); the Departments of Medicine and Pediatrics, National Jewish Health, Denver (J.L.T.-C.); the Division of Respirology, St. Michael's Hospital, University of Toronto, Toronto (E.T.); the Cystic Fibrosis Reference Center, Department of Pediatrics, Catholic University of Leuven, Leuven, Belgium (F.V.); Vertex Pharmaceuticals, Boston (G.M., C.M.M., S.M.M., N.N., J.S., C.S., S.T., D.W., F.X.); the Departments of Medicine, Pediatrics, and Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham (S.M.R.); and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (R.J.).
出版信息
N Engl J Med. 2019 Nov 7;381(19):1809-1819. doi: 10.1056/NEJMoa1908639. Epub 2019 Oct 31.
BACKGROUND
Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.
METHODS
We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV) at week 4.
RESULTS
A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.
CONCLUSIONS
Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).
背景
囊性纤维化是由编码囊性纤维化跨膜电导调节因子（CFTR）蛋白的基因突变引起的，近 90%的患者至少携带一份 Phe508del 突变。在一项涉及杂合 Phe508del 突变和最小功能突变（Phe508del-最小功能基因型）的患者的 2 期试验中，下一代 CFTR 校正剂 elexacaftor 与 tezacaftor 和 ivacaftor 联合使用，改善了 Phe508del CFTR 功能和临床结局。
方法
我们进行了一项 3 期、随机、双盲、安慰剂对照试验，以确认 elexacaftor-tezacaftor-ivacaftor 在携带 Phe508del-最小功能基因型的 12 岁及以上囊性纤维化患者中的疗效和安全性。患者被随机分配接受 elexacaftor-tezacaftor-ivacaftor 或安慰剂治疗 24 周。主要终点是第 4 周时预测的用力呼气量（FEV）的绝对值百分比与基线相比的变化。
结果
共有 403 名患者接受了随机分组，并接受了至少一剂活性治疗或安慰剂。与安慰剂相比，elexacaftor-tezacaftor-ivacaftor 在第 4 周时的预测 FEV 百分比高出 13.8 个百分点，在第 24 周时高出 14.3 个百分点，肺部恶化率降低 63%，囊性纤维化问卷修订版（范围为 0 到 100，得分越高表示患者对呼吸道症状的生活质量报告越高；最小临床重要差异为 4 分）的呼吸域评分高出 20.2 分，汗液氯化物浓度降低 41.8mmol/L（所有比较均<0.001）。elexacaftor-tezacaftor-ivacaftor 通常是安全的，具有可接受的副作用谱。大多数患者的不良事件为轻度或中度。导致试验方案中断的不良事件发生在 elexacaftor-tezacaftor-ivacaftor 组患者中 1%。
结论
elexacaftor-tezacaftor-ivacaftor 对携带 Phe508del-最小功能基因型的囊性纤维化患者有效，这些患者之前的 CFTR 调节剂治疗方案无效。（由 Vertex Pharmaceuticals 资助；VX17-445-102 临床试验.gov 编号，NCT03525444。）
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