title: Development, clinical utility, and place of ivacaftor in the treatment of cystic fibrosis.
abstract: Cystic fibrosis (CF) is a life-limiting, multisystem disease characterized by thick viscous secretions leading to recurrent lung infections, bronchiectasis, and progressive deterioration in lung function. CF is caused by loss or dysfunction of the CF transmembrane conductance regulator (CFTR) protein which is responsible for transepithelial chloride and water transport. Improved understanding of CFTR protein dysfunction has allowed the development of mutation-specific small-molecule compounds which directly target the underlying CFTR defect. Ivacaftor is the first licensed small-molecule compound for CF patients which targets the CFTR gating mutation Gly551Asp (previously termed G551D) and has the potential to be truly disease-modifying. Ivacaftor is an oral medication given twice daily and has shown benefit in terms of an increase in lung function, decreased sweat chloride, weight gain, improvement in patient-reported quality of life, and reduction in number of respiratory exacerbations in clinical trials. Although ivacaftor is currently only licensed for use in approximately 5% of the CF population (those who have at least one Gly551Asp mutation), the developmental pathway established by ivacaftor paves the way for other CFTR modulators that may benefit many more patients. In particular, a CFTR modulator for those with the Phe508del deletion (previously ∆F508) would allow 90% of the CF population to benefit from disease-modifying treatment.
authors.affiliation: Sheffield Children's Hospital, Western Bank, Sheffield, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: O'Reilly
authors.forename: Heather E
authors.initials: HE
authors.lastname: Elphick
mesh_terms: D000627:Aminophenols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D011788:Quality of Life; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000627:Aminophenols; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor
keywords: cystic fibrosis; cystic fibrosis transmembrane conductance regulator; ivacaftor
references.citation: Science. 1989 Sep 8;245(4922):1066-73
references.pmid: 2475911
references.citation: N Engl J Med. 1994 Sep 8;331(10):637-42
references.pmid: 7503821
references.citation: J Biol Chem. 2012 Oct 26;287(44):36639-49
references.pmid: 22942289
references.citation: Am J Physiol Cell Physiol. 2001 Nov;281(5):C1734-42
references.pmid: 11600438
references.citation: Chest. 2006 Nov;130(5):1441-7
references.pmid: 17099022
references.citation: Thorax. 2012 May;67(5):382-4
references.pmid: 22407889
references.citation: Genet Test. 1997;1(1):35-9
references.pmid: 10464623
references.citation: J Cyst Fibros. 2008 Sep;7(5):450-3
references.pmid: 18442953
references.citation: Am J Respir Crit Care Med. 2011 Jun 1;183(11):1463-71
references.pmid: 21330455
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18843-8
references.pmid: 21976485
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1117-30
references.pmid: 16443646
references.citation: Chest. 2012 Sep;142(3):718-724
references.pmid: 22383668
references.citation: Med Lett Drugs Ther. 2012 Apr 16;54(1388):29-30
references.pmid: 22499233
references.citation: N Engl J Med. 1981 Dec 17;305(25):1489-95
references.pmid: 7300874
references.citation: Pediatr Pulmonol. 2004 Sep;38(3):204-9
references.pmid: 15274098
references.citation: Chembiochem. 2007 Jun 18;8(9):1012-20
references.pmid: 17497613
references.citation: Am J Respir Cell Mol Biol. 2007 Jul;37(1):57-66
references.pmid: 17347447
references.citation: Am J Hum Genet. 1992 Jan;50(1):222-8
references.pmid: 1370365
references.citation: N Engl J Med. 1994 Oct 13;331(15):974-80
references.pmid: 7521937
references.citation: Am J Hum Genet. 1992 Aug;51(2):245-50
references.pmid: 1379413
references.citation: Nat Rev Drug Discov. 2012 Apr 30;11(5):349-50
references.pmid: 22543461
references.citation: Chest. 2013 Jan;143(1):14-18
references.pmid: 23276841
references.citation: J Cyst Fibros. 2012 May;11(3):237-45
references.pmid: 22293084
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30
references.pmid: 19846789
references.citation: Lancet. 2002 Sep 28;360(9338):978-84
references.pmid: 12383667
references.citation: Cell. 2006 Nov 17;127(4):803-15
references.pmid: 17110338
references.citation: Mol Ther. 2012 Jun;20(6):1108-15
references.pmid: 22371844
references.citation: N Engl J Med. 2011 Nov 3;365(18):1663-72
references.pmid: 22047557
references.citation: Eur Respir J. 2013 Jan;41(1):203-16
references.pmid: 22878883
references.citation: Lancet. 2008 Aug 30;372(9640):719-27
references.pmid: 18722008
references.citation: Science. 1989 Sep 8;245(4922):1059-65
references.pmid: 2772657
references.citation: Ann Hum Genet. 2003 Sep;67(Pt 5):471-85
references.pmid: 12940920
references.citation: Thorax. 2006 Feb;61(2):155-7
references.pmid: 16384880
references.citation: Nature. 2007 May 3;447(7140):87-91
references.pmid: 17450125
references.citation: Am J Med Genet A. 2003 Jan 30;116A(3):262-7
references.pmid: 12503104
references.citation: J Cyst Fibros. 2010 Sep;9(5):332-8
references.pmid: 20646968
references.citation: J Pediatr. 2008 Aug;153(2):S4-S14
references.pmid: 18639722
references.citation: Neurosci Lett. 2012 Oct 11;527(2):90-9
references.pmid: 22609847
references.citation: PLoS Biol. 2009 Jul;7(7):e1000155
references.pmid: 19621064
references.citation: Thorax. 2012 Jan;67(1):12-8
references.pmid: 21825083
references.citation: Cell. 1992 Feb 21;68(4):809-18
references.pmid: 1371239
references.citation: Nat Med. 2004 May;10(5):487-93
references.pmid: 15077107
references.citation: Nature. 2006 Mar 23;440(7083):477-83
references.pmid: 16554808
references.citation: Nat Chem Biol. 2010 Jan;6(1):25-33
references.pmid: 19966789
references.citation: Science. 1989 Sep 8;245(4922):1073-80
references.pmid: 2570460
references.citation: Lancet. 2003 May 17;361(9370):1671-6
references.pmid: 12767731
references.citation: Thorax. 2005 Jul;60(7):558-63
references.pmid: 15994263