WS06-4 Ivacaftor (IVA) treatment in patients 6 to &lt;12 months old with cystic fibrosis with a CFTR gating mutation: results of a 2-part, single-arm, phase 3 study

Davies, Jane C.; Wang, L.T.; Panorchan, Paul; Campbell, David; Tian, Simon; Higgins, M.; Egbuna, Ogo; McKee, Charlotte M.; Rosenfeld, M.

doi:10.1016/s1569-1993(19)30151-1

Cited by 5 publications

(4 citation statements)

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“…Small-molecule CFTR modulators include correctors (e.g., lumacaftor, tezacaftor, and elexacaftor) that improve CFTR processing and trafficking [2][3][4] and potentiators (e.g., ivacaftor) that increase CFTR channelopen probability [5]. In studies of participants with CF, clinical benefit was observed with ivacaftor in those 6 months of age and older with CFTR gating mutations [6][7][8][9][10] and in those 12 years of age and older heterozygous for the F508del-CFTR mutation and a residual function CFTR mutation (F/RF) [11]. Clinical benefit was observed with lumacaftor/ivacaftor in studies of participants with CF 2 years of age and older homozygous for the F508del-CFTR mutation (F/ F genotype) [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor

Tsai

Haseltine

et al. 2020

Pulm Ther

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Introduction: The triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF) C 12 years of age with C 1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC. Methods: Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from monoor dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF C 12 years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14 days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14 days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (EC 50) estimated from efficacy endpoint data from clinical studies. Results: In simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90-95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2 weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2 weeks following transition and, at all times, ivacaftor and C 1 CFTR corrector remained above EC 50. Conclusion: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor Digital Features To view digital features for this article go to

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Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor

Tsai

Haseltine

et al. 2020

Pulm Ther

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“…The methodology did not include a multiplicity adjustment, and the p values should therefore be considered nominal. This study focused on pwCF C 6 years of age; future studies should focus on evaluating the long-term impact of ivacaftor in younger age groups in order to demonstrate ivacaftor's ability to modify disease progression and prevent irreversible organ damage [33,34].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Impact of Ivacaftor on Healthcare Resource Utilization Among People with Cystic Fibrosis in the United States

et al. 2021

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Introduction: Ivacaftor was first approved in 2012 for the treatment of a select population of individuals with cystic fibrosis (CF), a rare, lifeshortening genetic disease. Reductions in healthcare resource utilization (HCRU) associated with ivacaftor have been observed during limited follow-up and for selected outcomes in real-world studies. This study aimed to further describe the long-term impact of ivacaftor treatment on multiple measures of HCRU among people with CF (pwCF). Methods: This retrospective study used US commercial and Medicaid claims data from 2011-2018. We included pwCF C 6 years of age with C 1 claim for ivacaftor and 12 months of continuous health plan enrollment before ivacaftor initiation (''pre-ivacaftor'' period) who also had 36 months of continuous enrollment and persistent ivacaftor use (i.e., no gap C 90 days between refills) following initiation (''post-ivacaftor'' period). We compared comorbidities occurring pre-ivacaftor versus the last 12 months post-ivacaftor. HCRU outcomes included medication use, inpatient admissions, and outpatient office visits. We compared medication use pre-ivacaftor versus the last 12 months post-ivacaftor and inpatient admissions and outpatient office visits pre-ivacaftor versus the post-ivacaftor period annualized across 36 months. Results: Seventy-nine pwCF met all criteria, including persistent ivacaftor use during the post-ivacaftor period. Ivacaftor treatment was associated with a significant reduction in pneumonia prevalence (10.1% vs. 26.6%; p \ 0.001) and significantly fewer mean [SD] antibiotics claims (8.0 [7.3] vs. 12.3 [11.1]; p \ 0.001) in the last 12 months post-ivacaftor versus pre-ivacaftor. In comparing the 36-month post-ivacaftor period to the pre-ivacaftor period, we also observed fewer mean [SD] annual inpatient admissions (0.2 [0.4] vs. 0.4 [0.7]), CF-related inpatient admissions (0.1 [0.2] vs. 0.2 [0.5]), and outpatient office visits (8.8 [4.9] vs. 9.9 [5.4]) (all, p \ 0.05). Conclusion: Long-term ivacaftor treatment reduced HCRU, consistent with trends observed in prior real-world studies. Our results support the sustained, long-term value of ivacaftor treatment in reducing CF burden.

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“…It is interesting to speculate how CFTR-modulator therapy may affect male infertility in CF and CBAVD. When starting potentiators early (6-12 months of age), results suggest improved pancreatic function that was previously felt to be irreversible (50). Pancreatic insufficiency is hypothesized to occur in utero due to plugging of pancreatic exocrine ducts and autolysis.…”

Section: Treatments and Impact On Male Infertilitymentioning

confidence: 97%

Genetics of CFTR and male infertility

Bieniek¹,

Lapin²,

Jarvi³

2021

Transl Androl Urol

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Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein.Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications.Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.

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WS06-4 Ivacaftor (IVA) treatment in patients 6 to <12 months old with cystic fibrosis with a CFTR gating mutation: results of a 2-part, single-arm, phase 3 study

Cited by 5 publications

References 0 publications

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor

Long-Term Impact of Ivacaftor on Healthcare Resource Utilization Among People with Cystic Fibrosis in the United States

Genetics of CFTR and male infertility

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