鲁马卡托-依伐卡托用于携带苯丙氨酸508位缺失CFTR基因纯合突变的囊性纤维化患者。
Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.
作者信息
Wainwright Claire E, Elborn J Stuart, Ramsey Bonnie W, Marigowda Gautham, Huang Xiaohong, Cipolli Marco, Colombo Carla, Davies Jane C, De Boeck Kris, Flume Patrick A, Konstan Michael W, McColley Susanna A, McCoy Karen, McKone Edward F, Munck Anne, Ratjen Felix, Rowe Steven M, Waltz David, Boyle Michael P
机构信息
From Queensland Children's Medical Research Institute, Royal Children's Hospital, Lady Cilento Children's Hospital, and University of Queensland School of Medicine, Brisbane, Australia (C.E.W.); Queens University of Belfast, Belfast (J.S.E.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London (J.C.D.) - all in the United Kingdom; Seattle Children's Hospital and University of Washington School of Medicine, Seattle (B.W.R.); Vertex Pharmaceuticals, Boston (G.M., X.H., D.W.); Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona (M.C.), and Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan (C.C.) - both in Italy; University Hospital Gasthuisberg, Leuven, Belgium (K.D.B.); Medical University of South Carolina, Charleston (P.A.F.); Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland (M.W.K.), and the Department of Pediatrics, Pulmonary Division, Nationwide Children's Hospital and Ohio State University, Columbus (K.M.) - both in Ohio; Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, Chicago (S.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory Department, CF Center, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris (A.M.); Division of Respiratory Medicine, Department of Pediatrics, Physiology, and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto (F.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); and Johns Hopkins Medicine, Baltimore (M.P.B.).
出版信息
N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa1409547. Epub 2015 May 17.
BACKGROUND
Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.
METHODS
We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.
RESULTS
A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.
CONCLUSIONS
These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).
背景
囊性纤维化是一种危及生命的疾病，由囊性纤维化跨膜传导调节因子（CFTR）蛋白活性缺陷或不足引起。苯丙氨酸508缺失（Phe508del）是最常见的CFTR突变。
方法
我们进行了两项3期随机双盲安慰剂对照研究，旨在评估CFTR校正剂鲁马卡托（VX-809）与CFTR增强剂依伐卡托（VX-770）联合使用对12岁及以上患有囊性纤维化且为Phe508del CFTR突变纯合子患者的影响。在两项研究中，患者被随机分配接受鲁马卡托（每日一次600 mg或每12小时400 mg）与依伐卡托（每12小时250 mg）联合用药或匹配的安慰剂，疗程为24周。主要终点是第24周时1秒用力呼气量（FEV1）预测值百分比相对于基线的绝对变化。
结果
共有1108例患者进行了随机分组并接受了研究药物治疗。平均基线FEV1为预测值的61%。在两项研究中，鲁马卡托-依伐卡托两个剂量组的主要终点均有显著改善；活性治疗组与安慰剂组在预测FEV1百分比的平均绝对改善方面的差异为2.6至4.0个百分点（P<0.001），这相当于平均相对治疗差异为4.3至6.7%（P<0.001）。汇总分析显示，鲁马卡托-依伐卡托组的肺部恶化发生率比安慰剂组低30%至39%；导致住院或使用静脉抗生素的事件发生率在鲁马卡托-依伐卡托组中也较低。鲁马卡托-依伐卡托组和安慰剂组的不良事件发生率总体相似。因不良事件停药的发生率在接受鲁马卡托-依伐卡托治疗的患者中为4.2%，而在接受安慰剂治疗的患者中为1.6%。
结论
这些数据表明，鲁马卡托与依伐卡托联合使用对Phe508del CFTR突变纯合子的囊性纤维化患者有益。（由Vertex制药公司等资助；TRAFFIC和TRANSPORT临床试验注册号，NCT01807923和NCT01807949。）
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