for Cystic Fibrosis A new combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, tezacaftor and ivacaftor, proved effective and safe in treating patients 12 years or older with CFTR gene mutations, according to 2 trials recently published in the New England Journal of Medicine. Tezacaftor, an investigational CFTR corrector, increases CFTR cell surface expression. Ivacaftor, an FDA-approved CFTR potentiator, enhances CFTR channel function. In the first trial, 509 patients homozygous for the most common CFTR mutation that impairs CFTR cell surface expression, Phe508del, were randomly assigned to receive a combination of tezacaftor plus ivacaftor (100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily) or placebo. Throughout the 24-week trial, the tezacaftorivacaftor group had significant improvement in the primary outcome measure of lung function compared with the placebo group (3.4 vs −0.6 percentage points mean absolute change from baseline in forced expiratory volume in 1 second [FEV1]). Pulmonary exacerbation was 35% lower in the tezacaftorivacaftor group than in the placebo group. The rate of serious adverse events was lower with tezacaftor-ivacaftor than with placebo (12.4% vs 18.2%). The companion trial randomly assigned 248patientsheterozygousforthePhe508del deletion and a residual-function CFTR gene mutation to receive tezacaftor-ivacaftor therapy, ivacaftor monotherapy, or placebo. The residual-function mutation, present in approximately 5% of patients with cystic fibrosis, causes slower disease progression than does the Phe508del CFTR mutation. Relative to the placebo group, the tezacaftor-ivacaftor group and ivacaftor-alone group had significant improvement in the primary outcome measure of lung function (6.8 vs 4.7 percentage points absolute change in the percentage of predicted FEV1). The difference in the primary outcome measure betweentezacaftor-ivacaftorandivacaftoralone significantlyfavoredtezacaftor-ivacaftor.Rates of adverse events, which were mild or moderate, were similar in both intervention groups. According to the authors, tezacaftorivacaftor therapy could offer an alternative to lumacaftor-ivacaftor therapy, which can cause adverse respiratory effects.

中文翻译：

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囊性纤维化的新联合疗法

用于囊性纤维化 根据最近发表在《新英格兰医学杂志》上的 2 项试验，囊性纤维化跨膜电导调节剂 (CFTR) 调节剂、tezacaftor 和 ivacaftor 的新组合被证明可有效且安全地治疗 12 岁或以上的 CFTR 基因突变患者. Tezacaftor 是一种研究性 CFTR 校正剂，可增加 CFTR 细胞表面表达。Ivacaftor 是 FDA 批准的 CFTR 增效剂，可增强 CFTR 通道功能。在第一项试验中，509 名患有损害 CFTR 细胞表面表达的最常见 CFTR 突变纯合子 Phe508del 的患者被随机分配接受 tezacaftor 加依伐卡托的组合（100 mg tezacaftor 每天一次和 150 mg ivacaftor 每天两次）或安慰剂。在整个 24 周的试验中，与安慰剂组相比，tezacaftrivacaftor 组在肺功能的主要结果指标上有显着改善（1 秒内用力呼气量 [FEV1] 相对于基线的平均绝对变化为 3.4 与 -0.6 个百分点）。tezacaftrivacaftor 组的肺部恶化比安慰剂组低 35%。tezacaftor-ivacaftor 的严重不良事件发生率低于安慰剂（12.4% vs 18.2%）。伴随试验将 248 名 Phe508del 缺失和残留功能 CFTR 基因突变的患者随机分配接受 tezacaftor-ivacaftor 治疗、ivacaftor 单药治疗或安慰剂。残留功能突变存在于大约 5% 的囊性纤维化患者中，与 Phe508del CFTR 突变相比，它导致疾病进展更慢。相对于安慰剂组，tezacaftor-ivacaftor 组和 ivacaftor 单药组在肺功能的主要结果指标方面有显着改善（预测 FEV1 百分比的绝对变化为 6.8 与 4.7 个百分点）。tezacaftor-ivacaftor 和ivacaftoralone 之间主要结果测量的差异显着有利于tezacaftor-ivacaftor。两个干预组的轻度或中度不良事件发生率相似。这组作者说，tezacaftorivacaftor 疗法可以替代 lumacaftor-ivacaftor 疗法，后者会导致呼吸系统不良反应。tezacaftor-ivacaftor 和ivacaftoralone 之间主要结果测量的差异显着有利于tezacaftor-ivacaftor。两个干预组的轻度或中度不良事件发生率相似。这组作者说，tezacaftorivacaftor 疗法可以替代 lumacaftor-ivacaftor 疗法，后者会导致呼吸系统不良反应。tezacaftor-ivacaftor 和ivacaftoralone 之间主要结果测量的差异显着有利于tezacaftor-ivacaftor。两个干预组的轻度或中度不良事件发生率相似。这组作者说，tezacaftorivacaftor 疗法可以替代 lumacaftor-ivacaftor 疗法，后者会导致呼吸系统不良反应。