WS23.6 Ivacaftor treatment in patients with cystic fibrosis who have an R117H-CFTR mutation, the KONDUCT study

Moss, Richard B.; Flume, Patrick A.; Elborn, J.S.; Cooke, Jennifer; Rowe, Steven M.; McColley, Susanna A.; Rubenstein, Ronald C.; Higgins, M.

doi:10.1016/s1569-1993(14)60137-5

Cited by 9 publications

(8 citation statements)

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“…Subject 1's baseline sweat chloride concentration was 134 mmol/L, as is seen in some CF patients, and it is not known if even with a 40 mmol/L decrease whether ivacaftor would confer a long‐term clinical benefit. The sweat chloride concentration decrease in Subjects 2 and 3 (−19.3 and −14.8 mmol/L) was slightly less than the mean decrease observed in trials of ivacaftor in R117H mutations . All three subjects had a sweat chloride concentration decrease that was greater than that observed in trials of lumacaftor–ivacaftor in patients with F508del/F508del …”

Section: Discussionmentioning

confidence: 66%

“…Ivacaftor and ivacaftor combined with lumacaftor result in decreased sweat chloride concentration, improved pulmonary function, fewer pulmonary exacerbations, and improved mortality, but were tested and FDA‐approved for only a few CFTR mutations. Ivacaftor is approved for R117H and nine CFTR class III mutations, which encompasses 6% of CF patients in the US . Lumacaftor is approved only for F508del homozygotes, which is 46% of CF patients in the US .…”

Section: Introductionmentioning

confidence: 99%

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In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

McGarry

Illek²,

et al. 2017

Pediatric Pulmonology

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Summary Rationale: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown. Methods: This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT). Human nasal epithelium (HNE) was obtained via nasal brushing and cultured. Sweat chloride concentration change was the in vivo outcome. Chloride current change in HNE cultures with ivacaftor was the in vitro outcome. Results: Three subjects had decreased sweat chloride concentration (−14.8 to −40.8 mmol/L, P<0.01). Two subjects had unchanged sweat chloride concentration. Two subjects had increased sweat chloride concentration (+23.8 and +27.3 mmol/L, P<0.001); both were heterozygous for A455E and pancreatic sufficient. Only subjects with decreased sweat chloride concentration had increased chloride current in HNE cultures. Conclusions: Some CF patients with residual CFTR function have decreased sweat chloride concentration with ivacaftor. Increased chloride current in HNE cultures among subjects with decreased sweat chloride concentrations may predict clinical response to ivacaftor. Ivacaftor can increase sweat chloride concentration in certain mutations with unclear clinical effect.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

McGarry

Illek²,

et al. 2017

Pediatric Pulmonology

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“…34 The efficacy of ivacaftor in class IV mutations has been examined in clinical trials including the KONDUCT and KON-TINUE studies, and the recently presented N-of-1 studies. 35,36 KONDUCT and KONTINUE evaluated the effects of ivacaftor in patients carrying the R117H mutation, which is notable for a heterogeneous phenotype. KONDUCT was a 24-week phase double-blind, placebo-controlled trial involved 69 patients !…”

Section: Cftr Potentiators In Other Mutationsmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator Modulators: The End of the Beginning

Barry

Ronan

Plant

2015

Semin Respir Crit Care Med

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Cystic fibrosis (CF) represents one of the success stories of modern medicine with sustained incremental increases in the survival from one of childhood death to one of adult survival into the middle decades over the past 30 years. Improving survival has focused on multidisciplinary management centered on treating the consequences of this genetic disease. It has been firmly established for more than 20 years that mutations in the CF transmembrane conductance regulator (CFTR) gene result in a defective protein that normally functions as a chloride channel on epithelial cell surfaces. Until recently, modulating CFTR dysfunction was only a research aspiration, however, greater focus placed upon addressing the primary defect of CF has developed several clinical therapeutic strategies in this area. This review highlights the evidence to date on efforts to modulate CFTR and restore robust functional protein to the cell surface. This approach has now led to the licensing of one CFTR potentiator, which has been shown to have significant clinical improvements in a subset of CF patients. This success represents the beginning for CFTR modulation and further research is ongoing which aims to broaden the applicability of these techniques.

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“…Part of this qualitative defect in the mutation R117H has been attributed to 'gating' problems similar to class III mutations, and highlighting the complexities of classifying individual mutations. KONDUCT was a randomised double-blind, placebo-controlled trial of ivacaftor therapy in patients expressing the R117H mutation [26]. This study failed to reach its primary efficacy endpoint of improvement in lung function but did show significant decreases in sweat chloride concentration.…”

Section: Cftr Potentiatorsmentioning

confidence: 99%

New and Emerging Treatments for Cystic Fibrosis

Barry¹,

Jones²

2015

Drugs

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Recently, a significant number of additional key medications have become licensed in Europe for the treatment of patients with cystic fibrosis (CF), including a number of inhaled antibiotics, such as nebulised aztreonam and dry powder versions of colistin and tobramycin for inhalation; dry powder inhaled mannitol, an agent to improve airway hydration and aid airway clearance; and ivacaftor, an oral therapy that directly acts on dysfunctional CFTR to correct the basic defect encountered in CF patients with the G551D CF gene mutation. The marked success of ivacaftor both in clinical trials and in post-licensing evaluation studies in treating patients with G551D and other gating mutations has greatly encouraged the ongoing development of similar therapies that can directly target the underlying cause of CF. Other therapies, including a number of anti-infectives, anti-inflammatories and replacement pancreatic enzymes, are currently undergoing clinical studies. This article reviews those treatments that have been recently licensed for CF and highlights some of the exciting emerging therapies presently under evaluation in clinical trials. In addition, it discusses some of the potential challenges being encountered by research and clinical teams in developing and delivering treatments for this condition.

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WS23.6 Ivacaftor treatment in patients with cystic fibrosis who have an R117H-CFTR mutation, the KONDUCT study

Cited by 9 publications

References 0 publications

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

Cystic Fibrosis Transmembrane Conductance Regulator Modulators: The End of the Beginning

New and Emerging Treatments for Cystic Fibrosis

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