Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.
Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.
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DOI：
10.1056/nejmoa1409547
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发表时间：
2015-07-16
期刊：
影响因子：
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通讯作者：
TRANSPORT Study Group
中科院分区：
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作者：
Wainwright CE;Elborn JS;Ramsey BW;Marigowda G;Huang X;Cipolli M;Colombo C;Davies JC;De Boeck K;Flume PA;Konstan MW;McColley SA;McCoy K;McKone EF;Munck A;Ratjen F;Rowe SM;Waltz D;Boyle MP;TRAFFIC Study Group;TRANSPORT Study Group
囊性纤维化是由囊性纤维化跨膜传导调节因子（CFTR）蛋白活性缺陷或缺乏引起的限制生命的疾病。Phe 508 del是最常见的CFTR突变。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lumacaftor（VX-809）与CFTR增效剂ivacaftor（VX-770）联合治疗12岁或12岁以上囊性纤维化且Phe 508 del CFTR突变纯合子患者的效果。在这两项研究中，患者被随机分配接受Lumacaftor（600 mg，每日一次或400 mg，每12小时一次）联合ivacaftor（250 mg，每12小时一次）或匹配的安慰剂治疗24周。主要终点是第24周时1秒用力呼气量（FEV 1）预测值百分比相对于基线的绝对变化。共有1108例患者接受了随机化并接受了研究药物。平均基线FEV 1为预测值的61%。在这两项研究中，两个Lumacaftor-Ivacaftor剂量组的主要终点均有显著改善;活性药物治疗组和安慰剂组之间FEV 1预测值百分比的平均绝对改善差异为2.6 - 4.0个百分点（P<0.001），相当于平均相对治疗差异为4.3 - 6.7%（P<0.001）。汇总分析显示，lumacaftor-ivacaftor组的肺部急性加重率比安慰剂组低30%至39%;导致住院或静脉注射抗生素的事件发生率在lumacaftor-ivacaftor组也较低。不良事件的发生率在Lumacaftor-Ivacaftor和安慰剂组中基本相似。由于不良事件而停药的发生率在接受Lumacaftor-Ivacaftor的患者中为4.2%，而在接受安慰剂的患者中为1.6%。这些数据表明，鲁玛卡托与依伐卡托的组合为患有Phe 508 del CFTR突变纯合子的囊性纤维化的患者提供了益处。（由Vertex Pharmaceuticals和其他公司资助; TRAFFIC和TRANSPORT ClinicalTrials.gov编号，NCT 01807923和NCT 01807949。
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. 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. 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. 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.)