Efficacy Of Ivacaftor Research Articles

Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis

BackgroundIvacaftor (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. MethodsIn 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. ResultsSeven 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. ConclusionsIn 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.

WS05.04 Safety and efficacy of ivacaftor (IVA) in children aged 1 to

Objectives: To assess safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of IVA dosing for 24 weeks in infants with CF aged 1 to <4 months.

EPS6.08 Second-hand smoke exposure reduces the clinical efficacy of ivacaftor in G551D: results from the GOAL study

ePS6.08 Second-hand smoke exposure reduces the clinical efficacy of ivacaftor in G551D: results from the GOAL study

Long-Term Ivacaftor in People Aged 6 Years and Older with Cystic Fibrosis with Ivacaftor-Responsive Mutations.

IntroductionMutations 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.MethodsEfficacy 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.ResultsForty-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.ConclusionsIvacaftor 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 RegistrationNCT01707290Electronic supplementary materialThe online version of this article (10.1007/s41030-020-00129-2) contains supplementary material, which is available to authorized users.

A Review on the Use of Cystic Fibrosis Transmembrane Conductance Regulator Gene Modulators in Pediatric Patients

The literature surrounding the use of cystic fibrosis transmembrane conductance regulator-targeted pharmacotherapies in pediatric patients continues to evolve. These therapies represent a departure from symptom management and infection prevention, which have been the mainstay of cystic fibrosis management in pediatrics, to targeting the genetic defect present within these patients. This article reviews the clinical studies evaluating the safety and efficacy of ivacaftor, ivacaftor/lumacaftor, and ivacaftor/tezacaftor. These medications were initially studied in adults and adolescents but have begun to be studied in younger populations. Further investigation into the use of these drugs with different CFTR mutations and in younger age groups will continue to expand the number of patients who can benefit from these therapies.

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.

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.

Ivacaftor for the p.Ser549Arg (S549R) gating mutation - The Israeli experience.

Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse. Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation. Data obtained from CF patients receiving ivacaftor for one year. Eight CF patients, mean age 21±10 years, received ivacaftor. After one year, significant improvement was found in FEV1, increasing from 74% to 88% (p<0.001), FVC, 89% to 101% (p=0.019), and FEF25-75, 59%-76% (p=0.019). Sweat chloride concentration decreased from 116±8mmol/L to 51±17mmol/L (p<0.001), and BMI increased from 20±3 to 22±4 (p=0.003). Glucose tolerance improved in five patients. There was no significant change in bacterial colonization. Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST)

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION). In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11. Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study. At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study. Vertex Pharmaceuticals Inc.