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

Abstract

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 FEV% predicted and body mass index. Clinical trial registered with www.clinicaltrials.gov (NCT02807415).

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…Furthermore, responses in F508del-homozygous patient-derived nasal epithelial cells were correlated to improvements in ppFEV 1 and intestinal current measurements, but not with nasal potential difference after co-treatment with lumacaftor/ ivacaftor (Pranke et al, 2019). Nevertheless, no significant correlations were found among responses in intestinal current measurement, nasal potential difference and sweat chloride concentration, despite high concordance for all CFTRdependent biomarkers in another study evaluating the cotreatment with lumacaftor/ivacaftor (Graeber et al, 2018). Further studies are certainly needed to better correlate and validate drug effectiveness in patient-derived specimens with clinical features, and identification of novel biomarkers may also enrich strategies in efficacy trials.…”

“…Furthermore, longerterm use of lumacaftor/ivacaftor has demonstrated continued benefits in patients, including improvement in BMI, reduction in the incidence of pulmonary exacerbations and hospitalizations, and slower deterioration of lung function (Konstan et al, 2017). Moreover, an observational study measured certain CFTR biomarkersnasal potential differences and intestinal current measurementsand demonstrated that co-treatment with lumacaftor/ivacaftor results in partial correction of F508del-CFTR function to similar levels of the lower range of CFTR activity usually observed in patients with residual function mutations (Graeber et al, 2018). More recently, co-treatment with lumacaftor/ivacaftor has been extended for F508delhomozygous patients aged ≥2 years after phase III clinical trials demonstrating safety and efficacy in younger patients (Milla et al, 2017;Ratjen et al, 2017;McNamara et al, 2019).…”

Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function

“…For now, our data suggest that FIS appears informative for individual disease classification in the context of borderline SCC and ICM or when SCC and ICM disagree, but further validation remains necessary in a larger group of patients. ICM provides fast and sensitive measurement of CFTR function in freshly isolated native tissue from CF patients, which integrates the individual CFTR genotype and other genes that have an impact on ion transport, and also environmental factors such as CFTR modulators that can affect CFTR function [42,43]. For patients 4 and 12, we observed relatively high ICM responses that appeared not to be aligned with the clinical phenotype and other biomarkers of CFTR function and largely exceeded the values found in the other infants homozygous for F508del (see the original tracings in supplementary material S6).…”

“…Early indicators for patients at risk for severe long-term outcomes might be helpful to decide when to start CFTR-modulating therapy. Several case studies showed that ex vivo and in vivo responses to CFTR-regulating therapeutics are clearly correlated [11,43,51,52], indicating that the FIS assay can play a role in determining both timing and efficacy of drug treatment in individual patients. Furthermore, intestinal organoids can be used in the preclinical phase of CFTR modulator development [53], and after measurements of residual CFTR function and response to CFTR modulators, cells can be biobanked for future analyses without requiring further sampling and patient discomfort [54].…”

Cystic fibrosis year in review 2018, part 1

“…The initial phase 3 trials of lumacaftor/ivacaftor in patients 12 years and older did not measure sweat chloride changes. In a prospective observational study in 52 patients who are homozygous for deltaF508, over age 12 years, who took lumacaftor/ivacaftor, consistent partial rescue of CFTR function was demonstrated as assessed via nasal potential difference (NPD) and intestinal current measurement and was found to have less heterogeneity compared with clinical outcomes …”