三聯療法對1個Phe508del等位基因的囊性纖維化療效顯著

　　美國德克薩斯大學西南醫學中心Raksha Jain團隊在最新研究中，探討了利用Elexacaftor+Tezacaftor+Ivacaftor三聯療法治療攜帶1個Phe508del等位基因的囊性纖維化患者的療效。10月31日，《新英格蘭醫學雜志》在線發表了這一成果。

　　囊性纖維化是由編碼囊性纖維化跨膜電導調節蛋白（CFTR）的基因突變引起的，近90%的患者至少有一個Phe508del-CFTR突變拷貝。在涉及Phe508del-CFTR突變和最小功能突變雜合子患者的臨床2期試驗中，新一代CFTR校正劑Elexacaftor聯合Tezacaftor+Ivacaftor可改善Phe508del-CFTR的功能和臨床結局。

　　研究組進行了一項臨床3期、隨機、雙盲、安慰劑對照試驗，招募了403名12歲及以上，患有Phe508del最小功能基因型的囊性纖維化患者，并隨機分組接受Elexacaftor+Tezacaftor+Ivacaftor或安慰劑進行治療，持續24周。

　　與安慰劑組相比，Elexacaftor+Tezacaftor+Ivacaftor組預測1s內用力呼氣量百分比（ppFEV1）在治療4周時高13.8個點，在24周時高14.3個點，肺部惡化率低63%，囊性纖維化問卷-修訂版評分高20.2分，汗液氯化物濃度低41.8mmol/L，差異均具有統計學意義。Elexacaftor+Tezacaftor+Ivacaftor方案總體上比較安全，患者可耐受。大多數患者僅有輕度或中度不良反應，僅有1%的患者因不良反應而中止試驗。

　　總之，對于CFTR校正劑方案治療無效的Phe508del最小功能基因型的囊性纖維化患者，Elexacaftor+Tezacaftor+Ivacaftor方案療效顯著。

　　附：英文原文

　　Title: Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

　　Author: Peter G. Middleton, M.D.,, Marcus A. Mall, M.D.,, Pavel Devínek, M.D.,, Larry C. Lands, M.D.,, Edward F. McKone, M.D.,, Deepika Polineni, M.D.,, Bonnie W. Ramsey, M.D.,, Jennifer L. Taylor-Cousar, M.D.,, Elizabeth Tullis, M.D.,, Franois Vermeulen, M.D.,, Gautham Marigowda, M.D.,, Charlotte M. McKee, M.D.,, Samuel M. Moskowitz, M.D.,, Nitin Nair, Ph.D.,, Jessica Savage, M.D.,, Christopher Simard, M.D.,, Simon Tian, M.D.,, David Waltz, M.D.,, Fengjuan Xuan, Ph.D.,, Steven M. Rowe, M.D.,, and Raksha Jain, M.D.

　　Issue&Volume: October 31, 2019

　　Abstract:

　　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.

　　DOI: 10.1056/NEJMoa1908639

　　Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1908639

　　期刊信息

　　The New England Journal of Medicine：《新英格蘭醫學雜志》，創刊于1812年。隸屬于美國麻省醫學協會，最新IF：70.67

　　官方網址：http://www.nejm.org/

　　投稿鏈接：http://www.nejm.org/page/author-center/home