Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR

Donaldson, Scott H.; Pilewski, Joseph M.; Griese, Matthias; Cooke, Jonathan; Viswanathan, Lakshmi; Tullis, Elizabeth; Davies, Jane C.; Lekstrom-Himes, Julie; Wang, Linda T.

doi:10.1164/rccm.201704-0717oc

Cited by 156 publications

(157 citation statements)

References 29 publications

(24 reference statements)

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“…In contrast, lumacaftor or tezacaftor combined with ivacaftor in F508del/F508del CF subjects led to modest increases in FEV 1 percent predicted, and moderate reductions in pulmonary exacerbation risk and improvements in weight and pulmonary symptoms compared with placebo . The effects of these therapies on SC were relatively small and not substantially different than results with corrector alone . As lumacaftor/ivacaftor has been studied in younger CF subjects (Ages 6‐11 years), more robust reductions in SC and improvements in lung function (measured by the nitrogen multiple breath washout test and the lung clearance index or LCI) have been observed compared with studies in older populations .…”

Section: Modulating F508del Cftrmentioning

confidence: 98%

Rapid therapeutic advances in CFTR modulator science

Clancy

2018

Pediatric Pulmonology

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Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding the cystic fibrosis transmembrane conduction regulator (CFTR) protein. Loss of CFTR function disrupts chloride, bicarbonate and regulation of sodium transport, producing a cascade of mucus obstruction, inflammation, pulmonary infection, and ultimately damage in numerous organs. Established CF therapies treat the downstream consequences of CFTR dysfunction and have led to steady improvements in patient survival. A class of drugs termed CFTR modulators has recently entered the CF therapeutic landscape. These drugs differ fundamentally from prior therapies in that they aim to improve the function of disease‐causing CFTR variants. This review summarizes the science behind CFTR modulators, including their targets, mechanism of action, clinical benefit, and future directions in the field. CFTR modulators have dramatically changed how CF is treated, validated CFTR as a therapeutic target, and opened the door to truly personalized therapies and treatment regimens.

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Section: Modulating F508del Cftrmentioning

confidence: 98%

Rapid therapeutic advances in CFTR modulator science

Clancy

2018

Pediatric Pulmonology

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“…It was approved by the FDA in February 2018 for the treatment of cystic fibrosis, a disease characterized by mucus buildup in the lungs, reproductive tract, pancreas and gastrointestinal tract . This arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, of which one of the most common is the F508del mutation . Tezacaftor and ivacaftor work synergistically to alleviate the problems associated with this mutation.…”

Section: Aliphatic Substitutionmentioning

confidence: 99%

Fluorine‐Containing Drugs Approved by the FDA in 2018

Mei

Han

Fustero

et al. 2019

Chemistry A European J

374

253

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Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine‐containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3, as well as aliphatic (CF2) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

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“…Using the CF Foundation Patient Registry (CFFPR), the uptake for ivacaftor prescriptions in patients with G551D was 64% within 6 months and 80% within 1 year, while ivacaftor/lumacaftor was prescribed in only 40% and 54% at those time points . The newest modulator combination to be approved for use in F508del homozygous patients over age 12 in 2018 is tezacaftor/ivacaftor . Although regulatory submission dates cannot be predicted at the time of this review, research on “next generation compounds” VX‐445 and VX‐659 in combination with tezacaftor/ivacaftor are underway, with promising early results.…”

Section: Cftr Modulatorsmentioning

confidence: 99%