Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D

BackgroundIvacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment.MethodsBlood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed.Measurements and Main ResultsSignificant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight.ConclusionsIvacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.     

Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation

BackgroundRecently, ivacaftor, a CFTR-potentiator, has been shown to be effective and safe in patients with cystic fibrosis carrying a G551D mutation and moderately impaired lung function. The objective of this retrospective study was to assess efficacy and safety of ivacaftor in severely ill patients with at least one G551D mutation.MethodsData from 14 patients with a FEV1 < 40% predicted who received ivacaftor on a “named patient program” base in Germany were analyzed.ResultsOne patient took ivacaftor at a lower than recommended dose due to abundant mucus and a feeling to “suffocate.” No additional severe adverse events were reported. One further patient stopped ivacaftor due to lung transplantation, one due to perceived poor effectiveness, one due to pregnancy, and one stopped standard therapy. The remaining patients took ivacaftor regularly and did not change other therapies. FEV₁ increased by more than 5 %predicted in 5 of the 14 patients from baseline (average FEV₁ during the year prior to ivacaftor). On average, FEV₁ increased significantly by 5.2 ± 5.6%predicted (p < 0.01). The relative improvement in FEV₁ was 19.7 ± 22.1%.ConclusionIvacaftor was effective in many patients with poor lung function. The response was, however, variable. Although the drug appeared safe for most of these patients, increased bronchial secretions may warrant intensified physiotherapy and intravenous antibiotic treatment when ivacaftor is initiated.     

Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation

BackgroundIvacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation.MethodsPatients with CF ≥6 -years- old with non-G551D gating mutations received ivacaftor 150 mg q12h or placebo for 8 weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy outcome was absolute change in FEV₁ through 8 and 24 weeks of ivacaftor treatment; secondary outcomes were changes in BMI, sweat chloride, and CFQ-R and safety through 8 and 24 weeks of treatment.ResultsEight weeks of ivacaftor resulted in significant improvements in percent predicted FEV₁, BMI, sweat chloride, and CFQ-R scores that were maintained through 24 weeks. Ivacaftor was generally well tolerated.ConclusionsIvacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations.     

Ivacaftor withdrawal syndrome in cystic fibrosis patients with the G551D mutation

Ivacaftor use can lead to dramatic health improvements in cystic fibrosis (CF) patients with gating mutations. Here, we report five instances of dramatic clinical decline following withdrawal of ivacaftor in three individuals with the G551D-CFTR mutation. In each case, the patient's lung function and symptoms rapidly deteriorated after cessation of treatment. Awareness of this phenomenon should inform both clinical practices as well as the design of future clinical trials of highly active CFTR modulators.     

Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor

Background

Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects.

Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations

Background

The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor is approved for patients with CF with gating and residual function CFTR mutations. We report the results of an observational study investigating its effects in CF patients with non-G551D gating mutations.

Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations

BackgroundTezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro.MethodsParticipants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV₁) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrollment of 300 participants reached week 12 of the study.ResultsAt the time of the IA, 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV₁ or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF.ConclusionsTezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410).     

Antibacterial properties of the CFTR potentiator ivacaftor

BackgroundIvacaftor increases CFTR channel activity and improves pulmonary function for individuals bearing a G551D mutation. Because ivacaftor structurally resembles quinolone antibiotics, we tested the hypothesis that ivacaftor possesses antibacterial properties.MethodsBioluminescence, colony forming unit, and minimal inhibitory concentration assays were used to assess viability of Staphylococcus aureus, Pseudomonas aeruginosa and multiple clinical microbial isolates.ResultsIvacaftor induced a dose-dependent reduction in bioluminescence of S. aureus and decreased the number of colony forming units. We observed a similar but less robust effect in P. aeruginosa following outer membrane permeabilization. Ivacaftor inhibited the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae and exhibited positive interactions with antibiotics against lab and respiratory strains of S. aureus and S. pneumoniae.ConclusionThese data indicate that ivacaftor exhibits antibacterial properties and raise the intriguing possibility that ivacaftor might have an antibiotic effect in people with CF.     

The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation

BackgroundIvacaftor, a cystic fibrosis transmembrane regulator (CFTR) potentiator, decreased sweat chloride concentrations and improved clinical measures in cystic fibrosis (CF) patients with the G551D mutation.ResultsSweat chloride measurements at day 15 had an overall positive predictive value (PPV) of 86.3%, a negative predictive value (NPV) of 65.5%, sensitivity of 73.9%, and specificity of 80.9% for an FEV₁ improvement of ≥ 5% from baseline at week 16. For ivacaftor patients the median FEV₁ improvement was 16.7%; for placebo patients 0.4%. For patients aged 6–11 years who received ivacaftor and who had a sweat chloride decrease of ≥ 40 mmol/L from baseline at day 15, a median weight gain of 11.2% at week 16, compared to 6% for those with a smaller decrease was observed.ConclusionsChanges in sweat chloride concentration at day 15 following treatment with ivacaftor may have sufficient predictive potential to identify individuals that show improvement in pulmonary function and weight gain after 16 weeks of treatment.     

Clinical effects of the three CFTR potentiator treatments curcumin,genistein and ivacaftor in patients with the CFTR-S1251N gating mutation

BackgroundThe natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations.MethodsIn three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids.ResultsA clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma.ConclusionsWe observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.     

Idiopathic chronic pancreatitis treated with ivacaftor in a CFTR carrier with methylmalonic acidemia

CFTR mutation carriers, numbering 1 in 25 among Caucasians, have an increased risk of developing chronic pancreatitis due to the underlying dysfunction of ion channels created by the mutant allele. Carriers do not frequently manifest disease due to the remaining wild-type CFTR protein sufficiently maintaining normal pancreatic homeostasis. However, additional risk factors for pancreatitis, such as organic acidemias (as seen in our patient) that further impact function of pancreatic acinar cells can result in the precipitation of CFTR related pancreatitis. Here we report a CFTR carrier with methylmalonic acidemia who was treated with ivacaftor and subsequently experienced resolution of her chronic pancreatitis. Our report suggests that ivacaftor may rescue the function of mutant CFTR in carriers and treat pancreatitis caused by CFTR dysfunction in situations where there are additional precipitating factors.     

Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease

Objective

To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting.

Sweat chloride as a biomarker of CFTR activity: Proof of concept and ivacaftor clinical trial data

BackgroundWe examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with a G551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity.MethodsSweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing, and analysis was employed for the first time. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity.ResultsWithin-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal.ConclusionsSweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators.     

Extended-culture and culture-independent molecular analysis of the airway microbiota in cystic fibrosis following CFTR modulation with ivacaftor

BackgroundTreatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF.MethodsUsing both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes.ResultsSignificant improvement in FEV₁, BMI, sweat chloride and levels of circulating inflammatory biomarkers were observed POST-ivacaftor treatment. Extended-culture demonstrated a higher density of strict anaerobic bacteria (p = 0.024), richness (p = 1.59*10⁻⁴) and diversity (p = 0.003) POST-treatment. No significant difference in fold change was observed by qPCR for either total bacterial 16S rRNA copy number or P. aeruginosa density for oprL copy number with treatment. Culture-independent (MiSeq) analysis revealed a significant increase in richness (p = 0.03) and a trend towards increased diversity (p = 0.07). Moreover, improvement in lung function, richness and diversity displayed an inverse correlation with the main markers of inflammation (p < 0.05).ConclusionsFollowing treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers.     

IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation

Objective

Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients.

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function

BackgroundIvacaftor (KALYDECO™, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function.MethodsThe effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface.ResultsIvacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance.ConclusionsThese in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.