美国德克萨斯大学西南医学中心Raksha Jain团队在最新研究中，探讨了利用Elexacaftor+Tezacaftor+Ivacaftor三联疗法治疗携带1个Phe508del等位基因的囊性纤维化患者的疗效。10月31日，《新英格兰医学杂志》在线发表了这一成果。

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%的患者至少有一个Phe508del-CFTR突变拷贝。在涉及Phe508del-CFTR突变和最小功能突变杂合子患者的临床2期试验中，新一代CFTR校正剂Elexacaftor联合Tezacaftor+Ivacaftor可改善Phe508del-CFTR的功能和临床结局。

研究组进行了一项临床3期、随机、双盲、安慰剂对照试验，招募了403名12岁及以上，患有Phe508del最小功能基因型的囊性纤维化患者，并随机分组接受Elexacaftor+Tezacaftor+Ivacaftor或安慰剂进行治疗，持续24周。

与安慰剂组相比，Elexacaftor+Tezacaftor+Ivacaftor组预测1s内用力呼气量百分比（ppFEV1）在治疗4周时高13.8个点，在24周时高14.3个点，肺部恶化率低63%，囊性纤维化问卷-修订版评分高20.2分，汗液氯化物浓度低41.8mmol/L，差异均具有统计学意义。Elexacaftor+Tezacaftor+Ivacaftor方案总体上比较安全，患者可耐受。大多数患者仅有轻度或中度不良反应，仅有1%的患者因不良反应而中止试验。

总之，对于CFTR校正剂方案治疗无效的Phe508del最小功能基因型的囊性纤维化患者，Elexacaftor+Tezacaftor+Ivacaftor方案疗效显著。

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