Connett G J
National Institute for Health Research, Southampton Respiratory Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK.
Drug Des Devel Ther. 2019 Jul 19;13:2405-2412. doi: 10.2147/DDDT.S153719. eCollection 2019.
Lumacaftor-ivacaftor is a combination of two small molecule therapies targeting the basic defect in cystic fibrosis (CF) at a cellular level. It is a precision medicine and its effects are specific to individuals with two copies of the p.Phe508del gene mutation. The drug combination works by restoring functioning CF transmembrane conductance regulator (CFTR) protein in cell surface membranes and was the first CFTR modulator licensed for the homozygous p.Phe508del genotype. The drug is a combination of a CFTR corrector and potentiator. Lumacaftor, the corrector, works by increasing the trafficking of CFTR proteins to the outer cell membrane. Ivacaftor, the potentiator, works by enabling the opening of what would otherwise be a dysfunctional chloride channel. In vivo lumacaftor-ivacaftor improves Phe508del-CFTR activity in airways, sweat ducts and intestine to approximately 10-20% of normal CFTR function with greater reductions in sweat chloride levels in children versus adults. Its use results in a modest improvement in lung function and a decreased rate of subsequent decline. Perhaps more importantly, those treated report increased levels of well-being and their rate of respiratory exacerbations is significantly improved. This review traces the development and use of this combination of CFTR modulators, the first licensed drug for treating the homozygous p.Phe508del CF genotype at the intracellular level by correcting the protein defect.
鲁马卡托-依伐卡托是两种小分子疗法的组合，在细胞水平上针对囊性纤维化（CF）的基本缺陷。它是一种精准药物，其效果特定于具有两个拷贝p.Phe508del基因突变的个体。该药物组合通过恢复细胞表面膜中起作用的囊性纤维化跨膜传导调节因子（CFTR）蛋白来发挥作用，是首个被批准用于纯合p.Phe508del基因型的CFTR调节剂。该药物是CFTR校正剂和增强剂的组合。校正剂鲁马卡托通过增加CFTR蛋白向细胞外膜的转运来发挥作用。增强剂依伐卡托通过使原本功能失调的氯离子通道打开来发挥作用。在体内，鲁马卡托-依伐卡托可将气道、汗腺和肠道中的Phe508del-CFTR活性提高至正常CFTR功能的约10%-20%，儿童汗液氯化物水平的降低幅度大于成人。其使用导致肺功能有适度改善，后续下降速率降低。也许更重要的是，接受治疗的患者报告幸福感增强，呼吸加重发作率显著改善。本综述追溯了这种CFTR调节剂组合的研发和使用情况，这是首个通过纠正蛋白质缺陷在细胞内水平治疗纯合p.Phe508del CF基因型的获批药物。
