Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles

被引：115

作者：

Graeber, Simon Y. ^{[1
,2
,3
,4
,5
,6
]}

Vitzthum, Constanze ^{[1
,2
,3
,4
,6
]}

Pallenberg, Sophia T. ^{[7
,8
]}

Naehrlich, Lutz ^{[10
,11
]}

Stahl, Mirjam ^{[1
,2
,3
,4
,5
,6
]}

Rohrbach, Alexander ^{[1
,2
,3
,4
,6
]}

Drescher, Marika ^{[1
,2
,3
,4
,6
]}

Minso, Rebecca ^{[7
]}

Ringshausen, Felix C. ^{[8
,9
]}

Rueckes-Nilges, Claudia ^{[10
]}

Klajda, Jan ^{[10
]}

Berges, Julian ^{[12
,13
,14
]}

Yu, Yin ^{[12
,13
,14
]}

Scheuermann, Heike ^{[12
,13
,14
]}

Hirtz, Stephanie ^{[12
,13
,14
]}

Sommerburg, Olaf ^{[12
,13
,14
]}

Dittrich, Anna-Maria ^{[7
,8
]}

Tuemmler, Burkhard ^{[7
,8
]}

Mall, Marcus A. ^{[1
,2
,3
,4
,5
,6
]}

机构：

[1] Charite Univ Med Berlin, Dept Pediat Resp Med Immunol & Crit Care Med, Augustenburger Pl 1, D-13353 Berlin, Germany

[2] Charite Univ Med Berlin, Cyst Fibrosis Ctr, Berlin, Germany

[3] Free Univ Berlin, Berlin, Germany

[4] Humboldt Univ, Berlin, Germany

[5] Charite Univ Med Berlin, Berlin Inst Hlth, Berlin, Germany

[6] German Ctr Lung Res, Associated Partner Site, Berlin, Germany

[7] Hannover Med Sch, Dept Pediat Pneumol Allergol & Neonatol, Hannover, Germany

[8] Hannover Med Sch, Biomed Res Endstage & Obstruct Lung Dis Hannover, German Ctr Lung Res, Hannover, Germany

[9] Hannover Med Sch, Dept Resp Med, Hannover, Germany

[10] Justus Liebig Univ Giessen, Dept Pediat, Giessen, Germany

[11] German Ctr Lung Res, Univ Giessen & Marburg Lung Ctr, Giessen, Germany

[12] Heidelberg Univ, Dept Pediat, Div Pediat Pulmonol & Allergy, German Ctr Lung Res, Heidelberg, Germany

[13] Heidelberg Univ, Cyst Fibrosis Ctr, Dept Pediat, German Ctr Lung Res, Heidelberg, Germany

[14] Heidelberg Univ, Translat Lung Res Ctr Heidelberg, German Ctr Lung Res, Dept Translat Pulmonol, Heidelberg, Germany

来源：

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE | 2022年 / 205卷 / 05期

关键词：

CFTR biomarker; cystic fibrosis; nasal potential difference; intestinal current measurement; elexacaftor/tezacaftor/ivacaftor; CONDUCTANCE REGULATOR FUNCTION; TEZACAFTOR-IVACAFTOR; CLINICAL EFFECTIVENESS; LUMACAFTOR-IVACAFTOR; POTENTIAL DIFFERENCE; PEOPLE; PHENOTYPE; GENOTYPE; CHILDREN;

D O I：

10.1164/rccm.202110-2249OC

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Rationale: The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. Objectives: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. Methods: This prospective, observational, multicenter study assessed clinical outcomes including FEV1 % predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 107 patients with CF including 55 patients with one F508del and a minimal function mutation and 52 F508del homozygous patients were enrolled in this study. In patients with one F508del allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range [IQR], 27.5-72.4; P < 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6; P < 0.001). In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl secretion to a level of 47.4% of normal (IQR, 19.3-69.2; P < 0.001) in nasal and 45.9% (IQR, 19.7-66.6; P < 0.001) in intestinal epithelia. Conclusions: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles.

引用

页码：540 / 549

页数：10

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