Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis

被引：93

作者：

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

Dopfer, Christian ^{[7
,8
]}

Naehrlich, Lutz ^{[9
,10
,11
]}

Gyulumyan, Lena ^{[7
]}

Scheuermann, Heike ^{[1
]}

Hirtz, Stephanie ^{[1
]}

Wege, Sabine ^{[12
]}

Mairbaeurl, Heimo ^{[4
,12
,13
]}

Dorda, Marie ^{[7
,8
]}

Hyde, Rebecca ^{[7
,8
]}

Bagheri-Hanson, Azadeh ^{[9
]}

Rueckes-Nilges, Claudia ^{[9
,10
,11
]}

Fischer, Sebastian ^{[7
,8
]}

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

Tuemmler, Burkhard ^{[7
,8
]}

机构：

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

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

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

[4] Heidelberg Univ, German Ctr Lung Res, Translat Lung Res Ctr Heidelberg, Heidelberg, Germany

[5] Charite Univ Med Berlin, Dept Pediat Pulmonol & Immunol, Berlin, Germany

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

[7] Hannover Med Sch, German Ctr Lung Res, Clin Pediat Pneumol Allergol & Neonatol, Hannover, Germany

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

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

[10] Univ Giessen, Giessen, Germany

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

[12] Univ Hosp Heidelberg, Thoraxklin, Dept Pneumol & Resp Crit Care Med, Heidelberg, Germany

[13] Heidelberg Univ Hosp, Sports Med, Med Clin 7, Heidelberg, Germany

来源：

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE | 2018年 / 197卷 / 11期

关键词：

cystic fibrosis transmembrane conductance regulator biomarker; cystic fibrosis; sweat test; nasal potential difference; intestinal current measurement; AGED; 6-11; YEARS; SWEAT CHLORIDE; POTENTIATOR IVACAFTOR; CFTR POTENTIATOR; LUNG-DISEASE; MUTATION; F508DEL-CFTR; PHENOTYPE; CHILDREN; PROTEIN;

D O I：

10.1164/rccm.201710-1983OC

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Rationale: The combination of the CFTR (cystic fibrosis transmembrane conductance regulator) corrector lumacaftor with the potentiator ivacaftor has been approved for the treatment of patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. The phase 3 trials examined clinical outcomes but did not evaluate CFTR function in patients. Objectives: To examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous patients with cystic fibrosis aged 12 years and older. Methods: This prospective observational study assessed clinical outcomes includingFEV(1)% predicted and bodymass index, andCFTR biomarkers including sweat chloride concentration, nasal potential difference, and intestinal currentmeasurement before and 8-16weeks after initiation of lumacaftor-ivacaftor. Measurements and Main Results: A total of 53 patients were enrolled in the study, and 52 patients had baseline and follow-up measurements. After initiation of lumacaftor-ivacaftor sweat chloride concentrations were reduced by 17.8 mmol/L (interquartile range [IQR], 225.9 to 26.1; P < 0.001), nasal potential difference showed partial rescue of CFTR function in nasal epithelia to a level of 10.2% (IQR, 0.0-26.1; P< 0.011), and intestinal current measurement showed functional improvement in rectal epithelia to a level of 17.7% of normal (IQR, 10.8-29.0; P < 0.001). All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes. Conclusions: Lumacaftor-ivacaftor results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations. Functional improvement was detected even in the absence of short-term improvement of FEV1% predicted and body mass index.

引用

页码：1433 / 1442

页数：10

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