三聯療法可有效治療F508del突變純合子囊性纖維化
作者：
小柯機器人發布時間：2019/11/1 16:03:59
近日，荷蘭烏得勒支大學醫學中心Harry G M Heijerman研究團隊，分析了Elexacaftor+Tezacaftor+Ivacaftor聯合方案治療F508del突變純合子囊性纖維化的有效性和安全性。相關論文10月31日在線發表於《柳葉刀》。
囊性纖維化跨膜電導調節因子（CFTR）可糾正CFTR突變所引起的基本缺陷。在F508del突變純合子的囊性纖維化患者中，CFTR校正劑和增強劑的聯合應用可改善患者的健康狀況，在Tezacaftor+Ivacaftor中加入Elexacaftor（VX-445），一種新一代CFTR校正劑，可進一步改善F508del突變的CFTR功能與臨床結局。
2018年8月3日至12月28日，研究組在4個國家的44個研究點進行了Elexacaftor+Tezacaftor+Ivacaftor的多中心、隨機、雙盲、主動對照試驗，招募了113名F508del突變純合子的囊性纖維化，年齡在12歲及以上，病情穩定，預測1s內用力呼氣量百分比（ppFEV1）為40-90%的患者。所有患者均先行Tezacaftor+Ivacaftor治療4周，之後107例患者按1：1隨機分組，55名接受Elexacaftor+Tezacaftor+Ivacaftor進行治療，52名接受Tezacaftor+Ivacaftor進行治療，均治療4周。
Elexacaftor+Tezacaftor+Ivacaftor組的ppFEV1、汗液氯化物濃度和囊性纖維化問卷-修訂版評分（CFQ-R RD）均顯著優於Tezacaftor+Ivacaftor組，差異具有統計學意義。三聯方案患者的耐受性較好，無停藥現象。大多數不良反應為輕度或中度，Elexacaftor+Tezacaftor+Ivacaftor組中有2例（4%）患者發生嚴重不良事件，Tezacaftor+Ivacaftor組有1例（2%）。
綜上，Elexacaftor+Tezacaftor+Ivacaftor治療F508del突變純合子的囊性纖維化患者，與Tezacaftor+Ivacaftor相比，具有良好的安全性，顯著提高了患者的生活質量。
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