In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

Abstract

Summary Rationale: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown. Methods: This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT). Human nasal epithelium (HNE) was obtained via nasal brushing and cultured. Sweat chloride concentration change was the in vivo outcome. Chloride current change in HNE cultures with ivacaftor was the in vitro outcome. Results: Three subjects had decreased sweat chloride concentration (−14.8 to −40.8 mmol/L, P<0.01). Two subjects had unchanged sweat chloride concentration. Two subjects had increased sweat chloride concentration (+23.8 and +27.3 mmol/L, P<0.001); both were heterozygous for A455E and pancreatic sufficient. Only subjects with decreased sweat chloride concentration had increased chloride current in HNE cultures. Conclusions: Some CF patients with residual CFTR function have decreased sweat chloride concentration with ivacaftor. Increased chloride current in HNE cultures among subjects with decreased sweat chloride concentrations may predict clinical response to ivacaftor. Ivacaftor can increase sweat chloride concentration in certain mutations with unclear clinical effect.

Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

“…VX-770 has been reported to increase the activity of some CFTR mutants and wild type CFTR channels, although its effect on WT-CFTR is variable (72,73). In our study VX-770 treatment did not elevate chloride current in non-CF hBE cells ( Supplementary Figure S2B, C) and provided little improvement in channel activity in c.3718-2477T cells (Figure 2), although it is possible that a VX-770 effect could be obscured by hyperphosphorylation of CFTR (74,75). Likewise, data from clinical trials showed only modest improvement in endpoints for patients with the splice mutation (29, kalydecohcp.com).…”

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

“…Responses from intestinal organoids were also demonstrated to correlate with intestinal current measurements, reduction in sweat chloride concentration and improvement in lung function of patients after CFTR modulator therapies (Dekkers et al, 2016a;Berkers et al, 2019). In N-of-1 trial series, an increase in CFTR-dependent chloride transport in nasal epithelial cell cultures was only found in the three patients who also demonstrated a reduction in sweat chloride concentration after ivacaftor treatment (McGarry et al, 2017). 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).…”

Theratyping in cystic fibrosis

“…P67L (c.200C>T) was initially identified as a class IV mutation, supported by a milder phenotype of pancreatic sufficiency, delayed onset of symptoms, but also the potential for moderate lung disease [7]. A study by Sabusap et al [8**] [27]. The authors suggested that these "N-of-1" studies could be used to investigate the effect of CFTR modulators in PWCF with varying phenotypes and genotypes.…”