Impact of lumacaftor/ivacaftor on the bacterial and fungal respiratory pathogens in cystic fibrosis: a prospective multicenter cohort study in Sweden.

BACKGROUND: A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. OBJECTIVES: The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. DESIGN: The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. METHODS: Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. RESULTS: Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. CONCLUSION: The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.

Subtherapeutic triazole concentrations as result of a drug-drug interaction with lumacaftor/ivacaftor.

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy.

Real-life experience with a generic formulation of lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.

Effects of lumacaftor-ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in F508del homozygous patients with cystic fibrosis aged 2-11 years.

Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown. Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2-11 years before and 8-16 weeks after treatment initiation. Results: A total of 13 children with CF homozygous for F508del aged 2-11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L (p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal (p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older. Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2-11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters.

Human epididymis protein 4 (HE4) plasma concentration inversely correlates with the improvement of cystic fibrosis lung disease in p.Phe508del-CFTR homozygous cases treated with the CFTR modulator lumacaftor/ivacaftor combination.

BACKGROUND: We previously documented that elevated HE4 plasma concentration decreased in people with CF (pwCF) bearing the p.Gly551Asp-CFTR variant in response to CFTR modulator (CFTRm) ivacaftor (IVA), and this level was inversely correlated with the FEV1% predicted values (ppFEV1). Although the effectiveness of lumacaftor (LUM)/IVA in pwCF homozygous for the p.Phe508del-CFTR variant has been evaluated, plasma biomarkers were not used to monitor treatment efficacy thus far. METHODS: Plasma HE4 concentration was examined in 68 pwCF drawn from the PROSPECT study who were homozygous for the p.Phe508del-CFTR variant before treatment and at 1, 3, 6 and 12 months after administration of LUM/IVA therapy. Plasma HE4 was correlated with ppFEV1 using their absolute and delta values. The discriminatory power of delta HE4 was evaluated for the detection of lung function improvements based on ROC-AUC analysis and multiple regression test. RESULTS: HE4 plasma concentration was significantly reduced below baseline following LUM/IVA administration during the entire study period. The mean change of ppFEV1 was 2.6% (95% CI, 0.6 to 4.5) by 6 months of therapy in this sub-cohort. A significant inverse correlation between delta values of HE4 and ppFEV1 was observed especially in children with CF (r=-0.7053; p<0.0001). Delta HE4 predicted a 2.6% mean change in ppFEV1 (AUC: 0.7898 [95% CI 0.6823-0.8972]; P < 0.0001) at a cut-off value of -10.7 pmol/L. Moreover, delta HE4 independently represented the likelihood of being a responder with ≥ 5% delta ppFEV1 at 6 months (OR: 0.89, 95% CI: 0.82-0.95; P = 0.001). CONCLUSIONS: Plasma HE4 level negatively correlates with lung function improvement assessed by ppFEV1 in pwCF undergoing LUM/IVA CFTRm treatment.

Effects of Lumacaftor-Ivacaftor on Airway Microbiota-Mycobiota and Inflammation in Patients with Cystic Fibrosis Appear To Be Linked to Pseudomonas aeruginosa Chronic Colonization.

Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination approved for patients with cystic fibrosis (CF) who are homozygous for the F508del allele. This treatment showed significant clinical improvement; however, few studies have addressed the evolution of the airway microbiota-mycobiota and inflammation in patients receiving lumacaftor-ivacaftor treatment. Seventy-five patients with CF aged 12 years or older were enrolled at the initiation of lumacaftor-ivacaftor therapy. Among them, 41 had spontaneously produced sputa collected before and 6 months after treatment initiation. Airway microbiota and mycobiota analyses were performed via high-throughput sequencing. Airway inflammation was assessed by measuring the calprotectin levels in sputum; the microbial biomass was evaluated via quantitative PCR (qPCR). At baseline (n = 75), bacterial alpha-diversity was correlated with pulmonary function. After 6 months of lumacaftor-ivacaftor treatment, a significant improvement in the body mass index and a decreased number of intravenous antibiotic courses were noted. No significant changes in bacterial and fungal alpha- and beta-diversities, pathogen abundances, or calprotectin levels were observed. However, for patients not chronically colonized with Pseudomonas aeruginosa at treatment initiation, calprotectin levels were lower, and a significant increase in bacterial alpha-diversity was observed at 6 months. This study shows that the evolution of the airway microbiota-mycobiota in CF patients depends on the patient's characteristics at lumacaftor-ivacaftor treatment initiation, notably chronic colonization with P. aeruginosa. IMPORTANCE The management of cystic fibrosis has been transformed recently by the advent of CFTR modulators, including lumacaftor-ivacaftor. However, the effects of such therapies on the airway ecosystem, particularly on the microbiota-mycobiota and local inflammation, which are involved in the evolution of pulmonary damage, are unclear. This multicenter study of the evolution of the microbiota under protein therapy supports the notion that CFTR modulators should be started as soon as possible, ideally before the patient is chronically colonized with P. aeruginosa. (This study has been registered at ClinicalTrials.gov under identifier NCT03565692).

One year of treatment with elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis homozygous for the F508del mutation causes a significant increase in liver biochemical indexes.

Introduction: Modulators of cystic fibrosis transmembrane conductance regulator mutated protein significantly improved the outcome of patients with cystic fibrosis (CF). We describe 63 patients who were independently followed up in two CF regional centers (i.e., Campania and Tuscany regions). Methods: All patients were homozygous for the F508del mutation and were treated with lumacaftor/ivacaftor (LI) for 3 years, followed by 1 year of treatment with elexacaftor/tezacaftor/ivacaftor (ETI). We studied the biochemical parameters of liver damage and cholesterol metabolism. Results: Beyond the improvement of BMI and lung function with LI treatment and even more with ETI, we found that the 3 years of LI treatment significantly improved liver function parameters (total and conjugated bilirubin, ALT, AP, and GGT), while the subsequent ETI treatment caused a significant increase of such parameters. Discussion: We confirm that treatment with LI does not correct hypocholesterolemia, whereas treatment with ETI significantly increases serum cholesterol. Such an increase is likely due to enhanced de novo biosynthesis, as indicated by the significant increase in serum lathosterol, and it is likely that the subsequent liver cholesterol accumulation may contribute to triggering inflammation and worsening liver biochemical indexes. The increase in serum bilirubin and ALT that we observed in approximately 94% and 84% of patients treated with ETI, respectively, suggests further investigation of the impact of ETI therapy on liver function indexes.

Real life evaluation of the multi-organ effects of Lumacaftor/Ivacaftor on F508del homozygous cystic fibrosis patients.

BACKGROUND: Lumacaftor/Ivacaftor (LUM-IVA), a cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector-potentiator combination, improves lung function and reduces pulmonary exacerbations (PEx) in F508del homozygous CF patients. However, the systemic effects of LUM-IVA outside the respiratory system have not yet been thoroughly investigated. METHODS: A prospective, real-world, yearlong study was performed on F508del homozygous adult CF patients who commenced treatment with LUM-IVA. Pancreatic function, bone metabolism, fertility status, nutritional and pulmonary factors were evaluated. RESULTS: Twelve patients, mean age 28.3 years (18.6-43.9) were recruited. Following 12 months of treatment, no changes were detected in glucose, insulin, c-peptide or BMI values. A significant relative decrease in mean alkaline-phosphatase levels (122.8 U/L vs 89.4, p = 0.002) and a trend toward an increase in calcium levels (9.5 vs 9.9 mg/dL, p = 0.074) were observed. A non-significant improvement in mean DEXA spine t-score after a year of treatment (-2.1 vs -1.6, n = 4, p = 0.11) was detected. Sweat chloride concentrations decreased significantly (-21.4 mEq/L; p = 0.003). Pulmonary outcome revealed improvement in spirometry values during the first three months (FEV1 by 5.7% p = 0.009, FEF25-75 by 4.3% p = 0.001) with no change in chest CT Bhalla score and CFQR after one year. There was also a significant decrease in parenteral antibiotic events (17 vs 8, p = 0.039) with shift from IV to oral antibiotics for PEx treatment. CONCLUSIONS: After one year of treatment, stabilization was observed in the pancreatic indices, nutritional status, structure and function of the lungs, with a beneficial effect on bone mineral metabolism and CFTR function. Additional studies should investigate the effect of CFTR modulators on extra-pulmonary manifestations.

Profiling the response to lumacaftor-ivacaftor in children with cystic between fibrosis and new insight from a French-Italian real-life cohort.

INTRODUCTION: Clinical trials for CFTR modulators consider mean changes of clinical status at the cohort level, and thus fail to assess the heterogeneity of the response. We aimed to study the different response profiles to lumacaftor-ivacaftor according to age in children with cystic fibrosis (CF). METHODS: A mathematical framework, including principal component analysis, data clustering, and data completion, was applied to a multicenter cohort of 112 children aged 6-18 years, treated with lumacaftor-ivacaftor. Studied parameters at baseline and 6 months included body mass index (BMI), number of days of antibiotics (ATB), Sweat test (ST), forced expiratory volume in 1 s expressed in percentage predicted (ppFEV1 ), forced vital capacity (ppFVC), and forced expiratory flow at 25%-75% of FVC (ppFEF25-75 ). RESULTS: Change in ppFEV1 was the most significant parameter in characterizing response heterogeneity among the 12-18-year-old patients. Patients with minimal changes in ppFEV1 were further separated by change in BMI and ATB course. In the 6-12-year-old children both BMI and ppFEV1 evolution were the most relevant. ST change was not associated with a clinical response. CONCLUSIONS: Change in ppFEV1 , BMI, and ATB course are the most relevant outcomes to discriminate clinical response profiles in children treated with lumacaftor-ivacaftor. Prepubertal and pubertal children display different response profiles.

Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis.

BACKGROUND: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). METHODS: In this study, 21 CF patients aged 10-25 underwent oral glucose tolerance test (OGTT) before and after 12-18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. ß-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between ß-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. RESULTS: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. CONCLUSIONS: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

Change in exercise capacity measured by Cardio-pulmonary Exercise Testing (CPET) in Danish people with cystic fibrosis after initiation of treatment with Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor.

BACKGROUND: Since 2015, when the first cystic fibrosis transmembrane conductance regulator (CFTR) modulators were approved for people with cystic fibrosis (CF) homozygous for F508del-CFTR, studies have shown improved lung function after initiation of the treatment and patients experience improved physical capacity. The aim of this study was to investigate change in exercise capacity after initiation of Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor treatment (LUM/IVA, TEZ/IVA). METHODS: We performed a single group prospective observational cohort study with follow-up at six and 12 months. The study examined change in exercise capacity in people with CF initiating treatment with LUM/IVA and TEZ/IVA, measured by cardio-pulmonary exercise testing (CPET). Inclusion criteria were people with CF homozygous for F508del-CFTR aged 12 years or older eligible for LUM/IVA and TEZ/IVA treatment from June 2017 until June 2019. Primary outcomes were change in VO2peak and maximal workload. Secondary outcomes were change in muscle strength, muscle power and body composition in a subgroup of the study population. RESULTS: A total of 91 patients were included in the analysis. The mean change in VO2peak and VO2peak divided by body weight from baseline to 12-months follow-up was 145.7 (91.2;200.2) ml/min and 1.07 (95% CI 0.19;1.95) ml/min/kg, respectively. The mean change in maximal workload between baseline and 12 months was 14.2 Watt (95% CI 9.1;19.2). All improvements in exercise capacity were statistically significant. CONCLUSIONS: Patients in this study improved their exercise capacity by a statistically significant increase in VO2peak and maximal workload 12 months after initiation of treatment with LUM/IVA and TEZ/IVA.

Ex vivo model predicted in vivo efficacy of CFTR modulator therapy in a child with rare genotype.

BACKGROUND: New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases. METHOD: We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow-up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found. CONCLUSION: Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.

Lumacaftor/ivacaftor in cystic fibrosis: effects on glucose metabolism and insulin secretion.

PURPOSE: The question whether the new cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs aimed at restoring CFTR protein function might improve glucose metabolism is gaining attention, but data on the effect of lumacaftor/ivacaftor treatment (LUMA/IVA) on glucose tolerance are limited. We evaluated the variation in glucose metabolism and insulin secretion in CF patients homozygous for Phe508del CFTR mutation after one-year treatment with LUMA/IVA in comparison to patients with the same genotype who did not receive such treatment. METHODS: We performed a retrospective case-control study on 13 patients with a confirmed diagnosis of CF, homozygous for the Phe508del CFTR mutation, who received LUMA/IVA for one year (cases) and 13 patients with identical genotype who did not receive this treatment (controls). At the beginning and conclusion of the follow-up, all subjects received a modified 3 h OGTT, sampling at baseline, and at 30 min intervals for plasma glucose, serum insulin, and c-peptide concentrations to evaluate glucose tolerance, and quantify by modeling beta-cell insulin secretion responsiveness to glucose, insulin clearance and insulin sensitivity. RESULTS: LUMA/IVA did not produce differences in glucose tolerance, insulin secretory parameters, clearance and sensitivity with respect to matched controls over one-year follow-up. CONCLUSION: We found no evidence of improvements in glucose tolerance mechanisms in patients with CF after one-year treatment with LUMA/IVA.

Effects of Lumacaftor-Ivacaftor on Lung Clearance Index, Magnetic Resonance Imaging, and Airway Microbiome in Phe508del Homozygous Patients with Cystic Fibrosis.

Rationale: Previous studies showed that lumacaftor-ivacaftor therapy results in partial rescue of CFTR (cystic fibrosis [CF] transmembrane conductance regulator) activity and a moderate improvement of spirometry in Phe508del homozygous patients with CF. However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown. Objectives: To investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation. Methods: In this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome, and proinflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy. Results: Lumacaftor-ivacaftor had no effects on forced expiratory volume in 1 second (FEV1% predicted) (1.7%; 95% confidence interval [CI], -1.0% to 4.3%; P = 0.211) but improved LCI (-1.6; 95% CI, -2.6 to -0.5; P < 0.01) and MRI morphology (-1.3; 95% CI, -2.3 to -0.3; P < 0.05) and perfusion score (-1.2; 95% CI, -2.3 to -0.2; P < 0.05) in our study cohort. Furthermore, lumacaftor-ivacaftor decreased the total bacterial load (-1.8; 95% CI, -3.3 to -0.34; P < 0.05) and increased the Shannon diversity of the airway microbiome (0.4; 95% CI, 0.1 to 0.8; P < 0.05), and reduced IL-1ß (interleukin-1ß) concentration (median change, -324.2 pg/ml; 95% CI, -938.7 to 290.4 pg/ml; P < 0.05) in sputum of Phe508del homozygous patients. Conclusions: This study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology, and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV1% predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).

Measuring the impact of CFTR modulation on sweat chloride in cystic fibrosis: Rationale and design of the CHEC-SC study.

BACKGROUND: The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design. METHODS: GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride. RESULTS: Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement. CONCLUSIONS: Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators.

Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508). METHODS: Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin. RESULTS: Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced. CONCLUSIONS: These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.

Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation.

BACKGROUND: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation. METHODS: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated. RESULTS: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively. CONCLUSIONS: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).

Patients with cystic fibrosis and advanced lung disease benefit from lumacaftor/ivacaftor treatment.

BACKGROUND: Several studies have assessed safety and efficacy outcomes for lumacaftor/ivacaftor therapy. We report on lumacaftor/ivacaftor's impact on lung function, physical performance, and health-related quality of life (HRQOL) in a subpopulation of Danish people with Cystic Fibrosis (CF; PWCF) with advanced pulmonary disease who would not fulfill inclusion criteria for these studies. METHODS: This follow-up study examined lumacaftor/ivacaftor's effect in a highly selected CF population. Inclusion criteria included low percent predicted forced expiratory volume in one second (ppFEV1 ), fast deteriorating ppFEV1 , low body mass index (BMI), and difficult-to-treat infections. Primary endpoints included change in ppFEV1 slope, cardiopulmonary exercise testing (CPET), and all domains of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Secondary outcomes included change in ppFEV1 , BMI Z-score, and sweat chloride concentration. RESULTS: A total of 21 patients homozygous for the F508del mutation and a median ppFEV1 of 38.7 were included. We found significant improvements in ppFEV1 (+4.2 p < .01, +5.8 p < .01, +4.8 p < .01 and +3.8 p = .03 ppFEV1 after 3, 6, 9, and 12 months of treatment compared to baseline), ppFEV1 slope (+6.84 ppFEV1 /year between the year before and the year after treatment initiation; p = .02), and saturation at CPET initiation (+1.4%, p < .02) and termination (+2.6%, p < .01) after 6 months of treatment. Finally, HRQOL improved significantly in all CFQ-R domains except Emotion and Treat. CONCLUSIONS: Our findings suggest that lumacaftor/ivacaftor reduces lung function decline, improves lung function, physical performance, and HRQOL to a greater extent in PWCF with severe lung disease than previously recognized.

Practitioner Due Diligence: Real-World Lumacaftor/Ivacaftor Use.

OBJECTIVE: Previous trials evaluated the efficacy of lumacaftor/ivacaftor in Phe508del homozygotes. These trials are limited by manufacturer sponsorship and were conducted under strict protocol. Additionally, this therapy is costly and does not allow for reduction in daily cystic fibrosis therapies. This study assessed the efficacy of lumacaftor/ivacaftor therapy and its effect on health care utilization in a real-world setting. METHODS: Retrospective chart review comparing the first 12 months of therapy to the 24 months prior was conducted to evaluate the impact of lumacaftor/ivacaftor on pulmonary function following a streamlined process for therapy introduction. The impact on body mass index and healthcare utilization were also evaluated. The following measurements were assessed: percent predicted forced expiratory volume in 1 second, body mass index and z-scores, number of admissions, length of stay, number of emergency department visits. RESULTS: Mean ppFEV1 was improved for the first 12 months on lumacaftor/ivacaftor treatment when compared with the 24 months prior: 78.8 (95% CI: 72.6, 84.9) vs 76.2 (95% CI: 70.1, 82.3) (p = 0.03). Body mass index significantly improved (patients ≥20 years), but improvement in BMI z-score (patients <20 years) was not significant. Number of admissions and LOS were significantly decreased, but ED visits were not. CONCLUSIONS: Lumacaftor/ivacaftor is effective for improving ppFEV1 and BMI and for reducing health care utilization. However, this small reduction does not overcome the financial cost of treatment. Long-term outcomes and use must be studied to determine the overall effect of this therapy on cystic fibrosis interventions and their costs.