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 CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR 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 (FEV1) 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 FEV1 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.).

中文翻译：

---

用于具有单个 Phe508del 等位基因的囊性纤维化的 Elexacaftor-Tezacaftor-Ivacaftor。

背景技术囊性纤维化是由编码囊性纤维化跨膜电导调节蛋白（CFTR）的基因突变引起的，近90%的患者至少有一份Phe508del CFTR突变。在涉及 Phe508del CFTR 突变杂合子和最小功能突变（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 功能和临床结果。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 12 岁或以上 Phe508del 最小功能基因型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 周预测的第 1 秒用力呼气容积 (FEV1) 百分比相对于基线的绝对变化。 结果 共有 403 名患者接受了随机分组，并接受了至少一剂积极治疗或安慰剂。与安慰剂相比，Elexacaftor-tezacaftor-ivacaftor 导致预计 FEV1 的百分比在 4 周时高出 13.8 分，在 24 周时高出 14.3 分，肺部恶化率降低 63%，呼吸域评分在囊性纤维化问卷修订版（范围，0 到 100，分数越高表示患者报告的呼吸系统症状方面的生活质量越高；最小临床重要差异，4 分）为 20。高 2 分，汗液氯化物浓度降低 41.8 毫摩尔/升（所有比较 P < 0.001）。Elexacaftor-tezacaftor-ivacaftor 通常是安全的并且具有可接受的副作用。大多数患者有轻度或中度的不良事件。elexacaftor-tezacaftor-ivacaftor 组中 1% 的患者发生了导致试验治疗方案终止的不良事件。结论 Elexacaftor-tezacaftor-ivacaftor 对具有 Phe508del-最小功能基因型的囊性纤维化患者有效，之前的 CFTR 调节剂方案对这些患者无效。（由 Vertex Pharmaceuticals 资助；VX17-445-102 ClinicalTrials.gov 编号，NCT03525444。）。Elexacaftor-tezacaftor-ivacaftor 通常是安全的并且具有可接受的副作用。大多数患者有轻度或中度的不良事件。elexacaftor-tezacaftor-ivacaftor 组中 1% 的患者发生了导致试验治疗方案终止的不良事件。结论 Elexacaftor-tezacaftor-ivacaftor 对具有 Phe508del-最小功能基因型的囊性纤维化患者有效，之前的 CFTR 调节剂方案对这些患者无效。（由 Vertex Pharmaceuticals 资助；VX17-445-102 ClinicalTrials.gov 编号，NCT03525444。）。Elexacaftor-tezacaftor-ivacaftor 通常是安全的并且具有可接受的副作用。大多数患者有轻度或中度的不良事件。elexacaftor-tezacaftor-ivacaftor 组中 1% 的患者发生了导致试验治疗方案终止的不良事件。结论 Elexacaftor-tezacaftor-ivacaftor 对具有 Phe508del-最小功能基因型的囊性纤维化患者有效，之前的 CFTR 调节剂方案对这些患者无效。（由 Vertex Pharmaceuticals 资助；VX17-445-102 ClinicalTrials.gov 编号，NCT03525444。）。结论 Elexacaftor-tezacaftor-ivacaftor 对具有 Phe508del-最小功能基因型的囊性纤维化患者有效，之前的 CFTR 调节剂方案对这些患者无效。（由 Vertex Pharmaceuticals 资助；VX17-445-102 ClinicalTrials.gov 编号，NCT03525444。）。结论 Elexacaftor-tezacaftor-ivacaftor 对具有 Phe508del-最小功能基因型的囊性纤维化患者有效，之前的 CFTR 调节剂方案对这些患者无效。（由 Vertex Pharmaceuticals 资助；VX17-445-102 ClinicalTrials.gov 编号，NCT03525444。）。