Effects of Lumacaftor-Ivacaftor Therapy on CFTR Function in Phe508del Homozygous Patients with Cystic Fibrosis

Abstract

The combination of the CFTR corrector lumacaftor with the potentiator ivacaftor has recently been approved for the treatment of patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation. The pivotal phase 3 trials examined clinical outcomes, but did not evaluate CFTR function in patients. Hence, we wanted to examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous CF patients aged 12 years and older. This prospective observational study assessed clinical outcomes including FEV1 % predicted and BMI, and CFTR biomarkers including sweat chloride concentration, nasal potential difference (NPD) and intestinal current measurement (ICM) before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy. 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 18 mmol/L. Further, NPD and ICM showed partial rescue of CFTR function in nasal and rectal epithelia to levels of 10% and 18% of normal, respectively. All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes. We could show that 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 BMI.