近日，荷兰乌得勒支大学医学中心Harry G M Heijerman研究团队，分析了Elexacaftor+Tezacaftor+Ivacaftor联合方案治疗F508del突变纯合子囊性纤维化的有效性和安全性。相关论文10月31日在线发表于《柳叶刀》。

囊性纤维化跨膜电导调节因子（CFTR）可纠正CFTR突变所引起的基本缺陷。在F508del突变纯合子的囊性纤维化患者中，CFTR校正剂和增强剂的联合应用可改善患者的健康状况，在Tezacaftor+Ivacaftor中加入Elexacaftor（VX-445），一种新一代CFTR校正剂，可进一步改善F508del突变的CFTR功能与临床结局。

2018年8月3日至12月28日，研究组在4个国家的44个研究点进行了Elexacaftor+Tezacaftor+Ivacaftor的多中心、随机、双盲、主动对照试验，招募了113名F508del突变纯合子的囊性纤维化，年龄在12岁及以上，病情稳定，预测1s内用力呼气量百分比（ppFEV1）为40-90%的患者。所有患者均先行Tezacaftor+Ivacaftor治疗4周，之后107例患者按1：1随机分组，55名接受Elexacaftor+Tezacaftor+Ivacaftor进行治疗，52名接受Tezacaftor+Ivacaftor进行治疗，均治疗4周。

Elexacaftor+Tezacaftor+Ivacaftor组的ppFEV1、汗液氯化物浓度和囊性纤维化问卷-修订版评分（CFQ-R RD）均显著优于Tezacaftor+Ivacaftor组，差异具有统计学意义。三联方案患者的耐受性较好，无停药现象。大多数不良反应为轻度或中度，Elexacaftor+Tezacaftor+Ivacaftor组中有2例（4%）患者发生严重不良事件，Tezacaftor+Ivacaftor组有1例（2%）。

综上，Elexacaftor+Tezacaftor+Ivacaftor治疗F508del突变纯合子的囊性纤维化患者，与Tezacaftor+Ivacaftor相比，具有良好的安全性，显著提高了患者的生活质量。

附：英文原文

Title: Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Author: Harry G M Heijerman, Edward F McKone, Damian G Downey, Eva Van Braeckel, Steven M Rowe, Elizabeth Tullis, Marcus A Mall, John J Welter, Bonnie W Ramsey, Charlotte M McKee, Gautham Marigowda, Samuel M Moskowitz, David Waltz, Patrick R Sosnay, Christopher Simard, Neil Ahluwalia, Fengjuan Xuan, Yaohua Zhang, Jennifer L Taylor-Cousar, Karen S McCoy, Karen McCoy, Scott Donaldson, Seth Walker, James Chmiel, Ronald Rubenstein, Deborah K. Froh, Isabel Neuringer, Manu Jain, Kathryn Moffett, Jennifer L. Taylor-Cousar, Bruce Barnett, Gary Mueller, Patrick Flume, Floyd Livingston, Nighat Mehdi, Charlotte Teneback, John Welter, Raksha Jain, Dana Kissner, Kapilkumar Patel, Francisco J. Calimano, Jimmy Johannes, Cori Daines, Thomas Keens, Herschel Scher, Subramanyam Chittivelu, Sudhakar Reddivalam, Ross Carl Klingsberg, Larry G. Johnson, Stijn Verhulst, Patricia Macedo, Damien Downey, Gary Connett, Edward Nash, Nicholas Withers, Timothy Lee, Marleen Bakker, Harry Heijerman, Francois Vermeulen, Eva Van Braeckel, Christiane Knoop, Elke De Wachter, Renske van der Meer, Petrus Merkus, Christof Majoor

Issue&Volume: October 31, 2019

Abstract: 

Background

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.

Methods

This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV 1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV 1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.

Findings

Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV 1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L [95% CI −50·1 to −40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.

Interpretation

Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.

DOI: 10.1016/S0140-6736(19)32597-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32597-8/fulltext