Background Five cystic fibrosis transmembrane conductance regulator (CFTR) modulator (CFTRm) therapies are approved for patients with cystic fibrosis (CF). Despite the established efficacy and safety of CFTRm therapy, variability exists in prescribing amongst CF physicians. Here, we describe prescriber factors influencing CFTRm use. Methods This observational study used clinical vignettes of patients with CF. Participants were adult pulmonologists and pediatricians specializing in respiratory medicine from Germany, Italy, UK, Ireland, and the Netherlands. Participants took part in a 3-step data collection process: (i) 60-minute individual telephone interview; (ii) decision exercise where physicians made a treatment decision about CFTRm on 10 clinical vignettes; and (iii) 30-minute web-assisted interview to provide rationale for treatment decisions. Univariate analysis, dimensionality reduction via factor analysis, and a random-effects logistic regression model were used to identify factors impacting CFTRm prescribing. Results Thirty-eight pulmonologists and 42 pediatricians provided 800 clinical decisions. Only 45 % of pulmonologists and 29 % of pediatricians prescribed a CFTRm for all eligible adult or pediatric vignettes. Pancreatic sufficiency decreased odds of prescribing a CFTRm (OR 0.106; 95 % CI 0.046, 0.244) whereas odds increased for patients’ age >12 years (OR 3.779; 95 % CI 1.579, 9.042). Physician characteristics associated with CFTRm prescribing were being proactive/pushing boundaries (OR 1.772; 95 % CI 1.153, 2.722), having previously prescribed LUM/IVA (OR 2.732; 95 % CI 1.070, 6.974), and belief CFTRm therapies could improve adherence (OR 1.440; 95 % CI 0.946, 2.192). Conclusions Behavioral characteristics, attitudes toward CFTRm therapies, and experience with CFTRm therapies impact physician CFTRm prescribing more than individual disease factors.

Background Ivacaftor approval was extended to people with cystic fibrosis (CF) with ≥1 of 28 additional ivacaftor-responsive mutations in the USA in 2017 based on preclinical in vitro data. This retrospective, observational study assessed real-world clinical response to ivacaftor in people with CF with ≥1 of these mutations, using data from the US Cystic Fibrosis Foundation Patient Registry.Methods Participants aged ≥2 years with ≥1 of 28 eligible mutations initiating ivacaftor between May 2017 and December 2018 were included. Clinical outcomes data were evaluated for ≤1 year before and ≤2 years after ivacaftor initiation. Participants initiating ivacaftor between May and December 2017 (2017 cohort) were used for the primary analysis because up to 2 years of post-ivacaftor-initiation data were available. Analyses were descriptive; key outcomes included percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI) and BMI z-score, pulmonary exacerbations (PEx) and hospitalisations.Results The study included 1004 eligible participants. In the 2017 cohort (n=613), mean absolute change in ppFEV1 from pre-ivacaftor initiation was 1.9 (95% CI 1.4, 2.4) and 1.8 (95% CI 1.0, 2.7) percentage points in years 1 and 2 post-ivacaftor initiation, respectively; mean absolute change in BMI was 0.6 (95% CI 0.5, 0.7) and 1.0 (95% CI 0.8, 1.2) kg/m2 in years 1 and 2, respectively; BMI z-score was unchanged. Annualised event rates of PEx and hospitalisations per patient-year were lower with ivacaftor (0.24 (95% CI 0.21, 0.26) and 0.28 (95% CI 0.25, 0.31), respectively) compared with pre-ivacaftor initiation (0.41 (95% CI 0.37, 0.46) and 0.45 (95% CI 0.41, 0.49), respectively).Conclusions These real-world observational study findings support the effectiveness of ivacaftor in people with CF aged ≥2 years with selected CFTR mutations.

BackgroundLumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR).MethodsThe LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F/MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort).ResultsThe LUM/IVA cohort matched to the F/MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F/MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F/MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021.ConclusionsThis interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation.

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged >= 4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received >= 1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Background Ivacaftor approval was extended to people with cystic fibrosis (CF) and an R117H variant in 2014 in the USA. This observational, real-world, postapproval study evaluated long-term outcomes among people with CF and an R117H variant on ivacaftor using data from the US Cystic Fibrosis Foundation Patient Registry. Methods Key outcomes were evaluated in ivacaftor-treated people with CF and an R117H variant for up to 36 months before and after treatment initiation using within-group comparisons. Analyses were descriptive in nature, focused on evaluation of observed outcome patterns over time and were performed both overall and for age groups ≥2 to <6 years, ≥6 to <18 years and ≥18 years. Key outcomes included lung function, body mass index (BMI), pulmonary exacerbations (PEx) and hospitalisations. Results The ivacaftor cohort included 369 people with CF and an R117H variant who initiated therapy between 1 January 2015 and 31 December 2016. During each of the 12-month intervals following treatment initiation, the mean observed percent predicted forced expiratory volume in 1 s (ppFEV1) and BMI values were higher and the mean annualised number of PEx and hospitalisation events were lower than pretreatment values. Mean change in ppFEV1 from pretreatment baseline was an increase of 1.5 (95% CI 0.8 to 2.3), 1.7 (95% CI 0.7 to 2.7) and 1.8 (95% CI 0.6 to 3.0) percentage points in the first, second and third years of treatment, respectively. Similar trends were observed in adult and paediatric subgroups. Conclusions The results support the clinical effectiveness of ivacaftor in people with CF and an R117H variant, including adult and paediatric subgroups.

Background Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks. Methods Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate. Results 464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A. Conclusions TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged >= 2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was 229.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to,2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population.

In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on-treatment and off-treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin-induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R-CFTR: exon 17 truncation, exons 13-15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.

Background: Tezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people >12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation ( F /gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants >12 years of age with F /gating genotypes. Methods: Enrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV 1 ). Key secondary endpoints were relative change in ppFEV 1 and absolute change in CF Questionnaire?Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8. Results: Sixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV 1 or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants >12 years of age with CF. Conclusions: This Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants >12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111). (c) 2020 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated. Methods Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry. Results Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries. Conclusions Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment.

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

Introduction Mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR ) affect the quantity and/or function of CFTR protein reaching the cell surface. Ivacaftor, a CFTR potentiator that enhances chloride transport, increases the channel-open probability of normal and dysfunctional CFTR. Initially approved for people with CF (pwCF) with G551D-CFTR gating mutations, ivacaftor demonstrated clinical benefit in pwCF with other gating mutations and certain residual function mutations, including R117H-CFTR, in clinical studies. We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged 6 years and older with non- G551D-CFTR ivacaftor-responsive mutations. Methods Efficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 ( R117H-CFTR mutations), Study 111 (non– G551D-CFTR gating mutations), and Study 113 ( n -of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks. Results Forty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints. Conclusions Ivacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in pwCF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes. Trial Registration NCT01707290

Background: Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years. Methods: Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity. Results: US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012-2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, -0.7 percentage points with ivacaftor vs -8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m(2) with ivacaftor vs +1.6 kg/m(2) in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings. Conclusions: This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor. (C) 2019 The Authors. Published by Elsevier B.V.

BackgroundKIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.MethodsChildren received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function.ResultsAll 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters.ConclusionsIvacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Background: Ivacaftor shows benefit in patients with cystic fibrosis (CF) and CFTR mutations associated with residual CF transmembrane conductance regulator (CFTR) function. Here we further assess the effect of ivacaftor in such patients using an N-of-1 study design. Methods: Patients aged >= 12 years with CF with clinical or molecular evidence of residual CFTR function were randomized to 1 of 4 treatment sequences for two 4-week, double-blind crossover cycles (each divided into 2 weeks of ivacaftor treatment and placebo) followed by 8 weeks of open-label ivacaftor treatment. The primary endpoint was absolute change from cycle baseline of percent predicted forced expiratory volume in 1 s (ppFEV(1)) after 2 weeks of treatment with ivacaftor relative to placebo. Results: Absolute change (SD) from study baseline in ppFEV(1) favored ivacaftor by 2.3 (1.0) percentage points (95% credible interval, 0.4-4.1) after 2 weeks of treatment. Absolute mean change (SD) from open-label baseline (defined as day 1 of the open-label ivacaftor treatment period) in ppFEV1 after 8 weeks of treatment was 4.7 (4.2) percentage points (P<.0001). Safety of ivacaftor was consistent with that observed in prior studies. Conclusions: Ivacaftor improved lung function during the double-blind and open-label treatment periods in patients with CF and CFTR mutations associated with residual CFTR function. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

BACKGROUND:Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers.OBJECTIVE:This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability.METHODS:Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here.RESULTS:Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function.CONCLUSIONS:While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor.EU PAS REGISTRATION NUMBER:EUPAS4270.

Background Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months. Methods The ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study. Children received 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight >= 14 to <25 kg) ivacaftor orally every 12 h. In study part A, children received ivacaftor for 3 days plus one morning. In study part B, children received 24 weeks of treatment. Children were enrolled into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven). Primary endpoints were pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor. Secondary endpoints in part B were pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration. We also explored changes in growth parameters and markers of pancreatic function. This study is registered with ClinicalTrials.gov , number NCT02725567. Findings Children aged 12 to <24 months were enrolled between Aug 25, 2016, and Nov 1, 2017. Seven children were enrolled in part A, of whom five received 50 mg and two received 75 mg ivacaftor. All completed treatment. Of 19 children enrolled in part B, including one from part A, all received 50 mg ivacaftor and 18 completed treatment (one withdrew because of difficulty with blood draws). All children received at least one dose of ivacaftor. Pharmacokinetics indicated exposure was similar to that in children aged 2 to <6 years and adults. No children discontinued because of adverse events or safety findings. In part A, three (43%) of seven children had treatment-emergent adverse events, all of which were mild and deemed not to be or unlikely to be related to ivacaftor. By 24 weeks in part B, treatment-emergent adverse events had been reported in 18 (95%) of 19 children, of which most were mild or moderate and the most frequent was cough (14 [74%] children). Two children in part B had four serious adverse events: one had constipation (possibly related to ivacaftor), distal intestinal obstruction syndrome, and eczema herpeticum, and one had persistent cough, all needing hospital admission. In five (28%) of 18 children aspartate or alanine aminotransferase concentrations rose to more than three times the upper limit of normal (to more than eight times in two children with concurrent infections). At week 24, the mean absolute change from baseline in sweat chloride concentration was -73.5 (SD 17.5) mmol/L. Growth parameters for age were normal at baseline and at week 24. At week 24, concentrations of faecal elastase-1 had increased and concentrations of immunoreactive trypsinogen had decreased from baseline. Mean serum lipase and amylase were raised at baseline and rapidly decreased after treatment was started. Interpretation Ivacaftor was generally safe and well tolerated in children aged 12 to <24 months for up to 24 weeks and was associated with rapid and sustained reductions in sweat chloride concentrations. Improvements in biomarkers of pancreatic function suggest that ivacaftor preserves exocrine pancreatic function if started early. The study is continuing in infants younger than 12 months.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) is known for its impact on the lung and pancreas of individuals; however, impaired growth is also a common complication. We hypothesized that targeting the biological defect in the CF transmembrane conductance regulator (CFTR) protein may affect growth outcomes. METHODS: In this post hoc analysis, we assessed linear growth and weight in 83 children (aged 6–11 years) enrolled in 2 clinical trials, the longitudinal-observation GOAL study and the placebo-controlled ENVISION study, to evaluate the effects of ivacaftor, a CFTR potentiator. We calculated height and weight z scores and height and weight growth velocities (GVs). RESULTS: In ivacaftor-treated children in GOAL, height and weight z scores increased significantly from baseline to 6 months (increases of 0.1 [P < .05] and 0.26 [P < .0001], respectively); height GV increased significantly from 3 to 6 months (2.10-cm/year increase; P < .01). In ivacaftor-treated children in ENVISION, height and weight z scores increased significantly from baseline to 48 weeks (increases of 0.17 [P < .001] and 0.35 [P < .001], respectively). Height and weight GVs from baseline to 48 weeks were also significantly higher with ivacaftor than with placebo (differences of 1.08 cm/year [P < .05] and 3.11 kg/year [P < .001], respectively). CONCLUSIONS: Ivacaftor treatment in prepubescent children may help to address short stature and altered GV in children with CF; results from these analyses support the existence of an intrinsic defect in the growth of children with CF that may be ameliorated by CFTR modulation.

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.METHODS:Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients≥12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx.RESULTS:Fewer patients receiving ivacaftor experienced a PEx than patients receiving placebo (33.7% vs. 56.4%; P=0.004) and had a lower adjusted incidence rate of PEx (0.589 vs. 1.382; P<0.001). The proportion of PEx followed by full short-term recovery of percent predicted forced expiratory volume in 1s was similar (ivacaftor vs. placebo, 57.1% vs. 53.7), as was the proportion of patients having long-term recovery (46.4% vs. 47.7%).CONCLUSIONS:Ivacaftor treatment reduces the frequency of PEx but does not improve on the rate of complete lung function recovery after PEx when compared with placebo.