Ivacaftor In Patients Research Articles

Physiologically-based pharmacokinetic modeling of the drug-drug interaction between ivacaftor and lefamulin in cystic fibrosis patients.

Lefamulin is being evaluated as a treatment for bacterial exacerbations in cystic fibrosis (CF). Ivacaftor is approved for the treatment of patients with CF. Lefamulin is a moderate CYP3A inhibitor and co-administration with ivacaftor may result in a drug-drug interaction (DDI). A CF population was built based on literature using the Simcyp Simulator. A previously developed and validated physiologically-based pharmacokinetic (PBPK) model for ivacaftor was used. A PBPK model for lefamulin was developed and verified. Predicted concentrations and pharmacokinetic (PK) parameters for both ivacaftor and lefamulin in healthy subjects and patients with CF were in reasonable agreement with observed data (within 1.4-fold, majority within 1.25-fold). The lefamulin model as a CYP3A4 perpetrator was validated using a different Ki value for oral (p.o.) and intravenous (i.v.) routes. The simulated changes in area under the curve of ivacaftor in patients with CF when co-administered with p.o. and i.v. lefamulin were weak-to-moderate. The predicted change in ivacaftor PK when co-administered with oral lefamulin was less than observed between ivacaftor and fluconazole. These results suggest a low liability for a DDI between lefamulin and ivacaftor in patients with CF.

Using generic drug elexacaftor/tezacaftor/ivacaftor+ ivacaftor in patients with cystic fidosis in routine clinical practice

Cystic fibrosis (CF) is a multisystem disease of exocrine glands with a progressive course. In recent years, targeted (pathogenetic) treatment aimed at correcting the function of the chloride channel has come to the fore in addition to the symptomatic therapy. The greatest effectiveness was demonstrated with the use of the triple combination of the drug elexacaftor (ELX) / tezacaftor (TEZ) / ivacaftor (IVA) + IVA – Trikafta® (Vertex Pharmaceuticals, USA) that has become the “gold standard” of targeted therapy. Currently, there is virtually no information about the effectiveness and safety of the generic products. The aim of the study was to evaluate the efficacy and safety of the generic drug ELX/TEZ/IVA+IVA (Trilexa®) (Tutor S.A.S.I.F.I.A., Buenos Aires, Argentina) in adult patients with CF in real clinical practice.Methods. The 6-month study included patients (n = 11) aged 18 to 46 years with a diagnosis of CF who were prescribed pathogenetic treatment with ELX/TEZ/IVA+IVA. Their external respiration function (forced vital capacity, forced expiratory volume in 1 second), conductivity of sweat fluid electrolytes (sweat test), anthropometric and other clinical and functional data were analyzed. Results. This study demonstrated pronounced positive effects in relation to indicators of respiratory function, sweat test, and nutritional status. The ELX/TEZ/IVA+IVA treatment was well tolerated, with clinical improvement in the form of a decrease in cough intensity, sputum volume, improvement in daily exercise tolerance, height, and body weight. No serious adverse events were recorded and none of the patients discontinued treatment due to adverse reactions.Conclusion. Obvious clinical and functional positive dynamics and safety over 6 months were demonstrated with ELX/TEZ/IVA+IVA combination.

Modulator Therapy in Cystic Fibrosis Patients with cis Variants in F508del Complex Allele: A Short-Term Observational Case Series.

Previous studies reported the influence of cis variants in F508del cystic fibrosis (CF) patients in their responses to CFTR modulators. The current study is a prospective, observational study involving three patients with CF and pancreatic insufficiency, carrying a complex allele including F508del with A238V, I1027T, or L467F. We report clinical data before and after 4 weeks of treatment with tezacaftor (TEZ)/ivacaftor (IVA), elexacaftor (ELX)/TEZ/IVA, and lumacaftor (LUM)/IVA for patients with complex alleles A238V, I1027T, and L467F, respectively. The 50-year-old patient bearing F508del;A238V/D1152H showed a normal sweat test (13 mEq/L) and improvements in forced expiratory volume in the first second (FEV1) (+7 points), body mass index (BMI) (+0.85), and respiratory CF Questionnaire-Revised (CFQ-R) domain (+22.2 points). The 12-year-old patient bearing F508del;I1027T/R709X showed an improvement in a sweat test (−40 mEq/l), FEV1 (+9 points) and the respiratory CFQ-R domain (+16.7 points). No changes in outcomes were observed for the 6-year-old patient F508del;L467F/F508del. Our data highlight that the reported variants do not modify the phenotypic expression of F508del. Searching L467F is crucial in CF patients with F508del nonresponsive to ELX/TEZ/IVA. Further data are needed to evaluate the clinical effect of these variants after a longer follow up.

Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease.

Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended.

P053 Real-life clinical effects of therapy with lumacaftor and ivacaftor in patients with cystic fibrosis

P053 Real-life clinical effects of therapy with lumacaftor and ivacaftor in patients with cystic fibrosis

Ivacaftor improves lung disease in patients with advanced CF carrying CFTR mutations that confer residual function

BackgroundIvacaftor is an innovative treatment for CF. Ivacaftor monotherapy in a phase III trial for patients with F508del and a residual function (RF) mutation showed improvement in lung function. We evaluated the effectiveness and safety of ivacaftor in patients with severe CF carrying RF mutations. MethodsData were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use program. Data were collected 1 year before and 1 year after commencement of ivacaftor. ResultsTwenty-six patients received ivacaftor. The mean [standard deviation (SD)] percent predicted FEV1 significantly increased from 33.9% (8.3) before treatment to 44.0% (10.7) after 12 months of treatment (p < 0.00001). The mean distance in the 6-min walking-test significantly improved from 458.2 (110.5) m at baseline to 524.8 (91.9) m after 12 months (p < 0.00001). The overall number of days of antibiotic therapy decreased from 1693 during the year before ivacaftor to 714 in the year following ivacaftor, and the number of days of intravenous antibiotic treatment dropped from 714 to 88; both results were statistically significant (p < 0.00001). Patients needing intravenous therapy decreased from 23 to 5 of 26. The mean (SD) sweat chloride level decreased from a baseline of 79 (22.3) mmol/L to 65 (30.6) mmol/L, but this variation was not significant (p = 0.26). No safety concerns were registered. ConclusionsIn patients with CFTR mutations that confer RF with severe lung disease, treatment with Ivacaftor is safe and results in a clinically significant improvement that was evident at 1 month and maintained at 12 months.

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.

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

BackgroundCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor–tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del–minimal function genotypes. Patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.ResultsA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor–tezacaftor–ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor–tezacaftor–ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group.ConclusionsElexacaftor–tezacaftor–ivacaftor was efficacious in patients with cystic fibrosis with Phe508del–minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.)

Transcriptomic Responses to Ivacaftor and Prediction of Ivacaftor Clinical Responsiveness.

Ivacaftor is a drug that was recently approved by the U.S. Food and Drug Administration for the treatment of patients with cystic fibrosis (CF) and at least one copy of the G511D mutation in the CFTR (CF transmembrane conductance regulator) gene. The transcriptomic effect of ivacaftor in patients with CF remains unclear. Here, we sought to examine whether and how the transcriptome of patients is influenced by ivacaftor treatment, and to determine whether these data allow prediction of ivacaftor responsiveness. Our data originated from the G551D Observational Study (GOAL). We performed RNA sequencing (RNA-seq) on peripheral blood mononuclear cells (PBMCs) from 56 patients and compared the transcriptomic changes that occurred before and after ivacaftor treatment. We used consensus clustering to stratify patients into subgroups based on their clinical responses after treatment, and we determined differences between subgroups in baseline gene expression. A random forest model was built to predict ivacaftor responsiveness. We identified 239 genes (false discovery rate < 0.1) that were significantly influenced by ivacaftor in PBMCs. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into "good" and "moderate" responder groups based on their clinical response to ivacaftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. In conclusion, for the first time, the present study demonstrates profound transcriptomic impacts of ivacaftor in PBMCs from patients with CF, and provides a pilot statistical model for predicting clinical responsiveness to ivacaftor before treatment.

P255 Clinical stabilisation following ivacaftor in patients with cystic fibrosis, severe lung disease and rare CFTR mutation: a report of two cases

P255 Clinical stabilisation following ivacaftor in patients with cystic fibrosis, severe lung disease and rare CFTR mutation: a report of two cases

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface.Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles.Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.

VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

BackgroundVX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445–tezacaftor–ivacaftor).MethodsWe evaluated the effects of VX-445–tezacaftor–ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445–tezacaftor–ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del) after tezacaftor–ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline.ResultsIn vitro, VX-445–tezacaftor–ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del–MF group (P<0.001). In patients in the Phe508del–Phe508del group, who were already receiving tezacaftor–ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised.ConclusionsThe use of VX-445–tezacaftor–ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471; and EudraCT number, 2017-000797-11.)

VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

BackgroundThe next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659–tezacaftor–ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.MethodsWe evaluated the effects of VX-659–tezacaftor–ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1).ResultsVX-659–tezacaftor–ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659–tezacaftor–ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del–MF genotypes; in patients with the Phe508del–Phe508del genotype already receiving tezacaftor–ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised improved in both patient populations.ConclusionsRobust in vitro activity of VX-659–tezacaftor–ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del–MF or Phe508del–Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455.)

PND80 - AN OBSERVATIONAL STUDY OF IVACAFTOR IN PATIENTS WITH CYSTIC FIBROSIS IN FRANCE: FIRST INTERIM ANALYSIS OF HEALTH CARE RESOURCE UTILIZATION FROM THE BRIO STUDY

The efficacy of ivacaftor in cystic fibrosis (CF) patients has been demonstrated in Phase 3 randomized-controlled trials. BRIO is a real-world study assessing effectiveness of ivacaftor in patients with CF and ivacaftor-responsive mutations in France. This interim analysis describes the impact of ivacaftor on healthcare resource utilization (HCRU) in patients ≥6 years. BRIO is an ongoing observational, non-interventional multi-centre study. Of 55 CF centers contacted, 33 participated. Ivacaftor-naive and -treated patients were eligible. Patient data are collected prospectively for two years after enrolment, and retrospectively for 12 months preceding initiation of ivacaftor, and up to enrolment in the study. This interim analysis describes HCRU, including all-cause hospitalisation and antibiotics use (oral/IV/inhaled) due to pulmonary exacerbations (PEx), for 12 months pre-ivacaftor initiation and 12 months post-ivacaftor initiation. HCRU analysis used a negative binomial model adjusted for time on study in the 12-month period, with baseline defined as ivacaftor initiation date. Of 107 enrolled patients, 100 received ≥12 months treatment with ivacaftor. At baseline, mean (SD) age was 21.1 (14.3) years, 56% were male. All-cause hospitalisations showed a substantial reduction per patient year (PPY) in 12 months post-ivacaftor initiation vs 12 months pre-ivacaftor initiation (rate ratio [RR] 0.40; 95% CI: 0.26–0.61). Corresponding hospitalisation days PPY were reduced from 5.3 days pre-ivacaftor to 2.5 days post-ivacaftor (RR 0.46; 95% CI: 0.22–0.95). Number of unique antibiotics PPY for treatment of PEx was also reduced 12 months post-ivacaftor vs 12 months pre-ivacaftor (RR 0.47; 95% CI: 0.32–0.68). Corresponding days of antibiotic use PPY declined from 20.9 days pre-ivacaftor to 11.4 days post-ivacaftor (RR: 0.54; 95% CI: 0.40–0.72). Treatment of CF patients with ivacaftor in a real-world setting in France led to substantial reduction in HCRU, as evidenced by decreased all-cause hospitalisations and antibiotics use due to PEx.

SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis.

Ivacaftor is a drug used to treat cystic fibrosis (CF) patients carrying specific gating CFTR mutations. Interpatient variability in the lung response has been shown to be partly explained by rs7512462 in the Solute Carrier Family 26 Member 9 (SLC26A9) gene. In an independent and larger cohort, we aimed to evaluate whether SLC26A9 variants contribute to the variability of the lung phenotype and if they influence the lung response to ivacaftor. We genotyped the French CF Gene Modifier Study cohort (n = 4,840) to investigate whether SLC26A9 variants were involved in the lung phenotype heterogeneity. Their influence in the response to ivacaftor was tested in the 30 treated patients who met the inclusion criteria: older than 6 years of age, percent-predicted forced expiratory volume measured in 1 s (FEV1pp) in the 3 months before treatment initiation ranging between 40 and 90%. Response to treatment was determined by the change in FEV1pp from baseline, averaged in 15–75 days, and the 1st-year post-treatment. We observed that SLC26A9 variants were not associated with lung function variability in untreated patients and that gain of lung function in patients treated with ivacaftor was similar to clinical trials. We confirmed that rs7512462 was associated with variability in ivacaftor-lung response, with a significant reduction in lung function improvement for patients with the C allele. Other SLC26A9 SNPs also contributed to the ivacaftor-response. Interindividual variability in lung response to ivacaftor is associated with SLC26A9 variants in French CF patients. Pharmacogenomics and personalized medicine will soon be part of CF patient care.

WS05.4 Clinical effectiveness results from the first interim analysis of the VOCAL study; an observational study of ivacaftor in patients with cystic fibrosis and selected non-G551D gating mutations

WS05.4 Clinical effectiveness results from the first interim analysis of the VOCAL study; an observational study of ivacaftor in patients with cystic fibrosis and selected non-G551D gating mutations

IPD2.05 Effects of ivacaftor in patients with cystic fibrosis and severe lung disease carrying CFTR mutations with residual function

IPD2.05 Effects of ivacaftor in patients with cystic fibrosis and severe lung disease carrying CFTR mutations with residual function

IPD2.04 Long-term effects of ivacaftor in patients with G551D mutation and mild lung disease

IPD2.04 Long-term effects of ivacaftor in patients with G551D mutation and mild lung disease

PSY58 - An Observational Study of Ivacaftor in Patients with Cystic Fibrosis and Selected Non-G551D Gating Mutations in UK, Italy and Netherlands: Healthcare Resource Utilization from the First Interim Analysis of the Vocal Study

The efficacy of ivacaftor in cystic fibrosis (CF) patients with non-G551D gating mutations was demonstrated in a Phase 3 randomized-controlled trial (KONNECTION). An observational study (VOCAL) is ongoing to evaluate real world outcomes of ivacaftor in the non-G551D gating population; this interim analysis describes healthcare resource utilization (HCRU) over 12 months from the VOCAL study. VOCAL is a Phase 4, multi-center, multinational observational study of patients with CF on ivacaftor in UK, Italy and Netherlands, aged ≥6 years, with one non-G551D gating mutation. VOCAL has 4 years of planned prospective data collection from time of enrollment. In the current interim analysis, HCRU including hospitalizations and antibiotic use were evaluated as exploratory endpoints for 12 months before and 12 months after ivacaftor initiation using a negative binomial model. 71 of 73 enrolled patients completed 12 months of treatment. 25 (34%) were male. Mean (SD) age was 26.9 (13.5) years, with 23 (32%) <18 years old. All-cause hospitalizations per patient year (PPY) showed a significant reduction from 0.44 pre-IVA to 0.17 post-IVA (rate ratio (RR) 0.38; 95% CI 0.15, 0.94); corresponding hospitalization days significantly reduced from 5.4 days PPY pre-IVA to 2.0 days post-IVA (RR 0.37; 95% CI 0.17, 0.84). Pulmonary exacerbations (PEx) requiring hospitalization significantly reduced from 0.33 PPY pre-IVA to 0.07 post-IVA (RR 0.21; 95% CI 0.08, 0.54). PEx-related antibiotic use showed significant reduction from 1.28 courses PPY pre-IVA to 0.29 courses post-IVA (RR 0.23; 95% CI 0.12, 0.44); corresponding antibiotic use days significantly reduced from 15.2 PPY pre-IVA to 3.4 post-IVA (RR 0.23; 95% CI 0.11, 0.48). This study demonstrates the significant impact of ivacaftor on HCRU including hospitalizations and antibiotic use in CF patients with non-G551D gating mutations, following initiation of ivacaftor treatment in a real-world setting.