ABCMdb

PMID: 21083385

Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW
Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
N Engl J Med. 2010 Nov 18;363(21):1991-2003., 2010-11-18 [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Gly551Asp Methods We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). Login to comment 8 ABCC7 p.Gly551Asp Methods We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). Login to comment 18 ABCC7 p.Gly551Asp A strategy with potential advantages over current regimens involves improving defective CFTR function systemically; this strategy aims to slow lung damage and reduce the manifestations of extrapulmonary disease and the treatment burden.6 Some mutations permit CFTR protein to reach the epithelial-cell surface, but the protein is defective in chloride transport.7 The most prevalent mutation of this type in patients with cystic fibrosis causes a substitution of glycine for aspartic acid at amino acid 551 (G551D-CFTR); this mutation occurs in approximately 4 to 5% of persons with cystic fibrosis.4 Agents that increase the ion-channel function of activated cell-surface CFTR are referred to as "potentiators." Login to comment 19 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp A strategy with potential advantages over current regimens involves improving defective CFTR function systemically; this strategy aims to slow lung damage and reduce the manifestations of extrapulmonary disease and the treatment burden.6 Some mutations permit CFTR protein to reach the epithelial-cell surface, but the protein is defective in chloride transport.7 The most prevalent mutation of this type in patients with cystic fibrosis causes a substitution of glycine for aspartic acid at amino acid 551 (G551D-CFTR); this mutation occurs in approximately 4 to 5% of persons with cystic fibrosis.4 Agents that increase the ion-channel function of activated cell-surface CFTR are referred to as "potentiators." Login to comment 20 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp VX-770 is an investigational, orally bioavailable CFTR potentiator that has been shown to increase the activity of wild-type and defective cell-surface CFTR protein in vitro.8 The greatest effect of VX-770 was on cells with G551D-CFTR. Login to comment 21 ABCC7 p.Gly551Asp The primary end points of this randomized, placebo-controlled trial involving subjects with the G551D-CFTR mutation were the safety and adverse-event profile of VX-770. Login to comment 24 ABCC7 p.Gly551Asp Subjects had to be 18 years of age or older and have cystic fibrosis,9 a G551D mutation on at least one CFTR allele, and a forced expiratory volume in 1 second (FEV1) of 40% or more of the predicted value for age, sex, and height.10 The first author wrote the first draft of the manuscript and made the decision to submit the article for publication after consultation with the other authors. Login to comment 25 ABCC7 p.Gly551Asp Subjects had to be 18 years of age or older and have cystic fibrosis,9 a G551D mutation on at least one CFTR allele, and a forced expiratory volume in 1 second (FEV1) of 40% or more of the predicted value for age, sex, and height.10 The first author wrote the first draft of the manuscript and made the decision to submit the article for publication after consultation with the other authors. Login to comment 65 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* (%)‡4(100)4(100)4(100)4(100)4(100)20(100)4(100)8(100)7(100)19(100) Age-yr Median36314126213024232121 Range19to4822to5122to5019to3419to3319to5118to4218to4020to3818to42 Body-massindex Median23232420212322222322 Range22to2920to2419to2719to2417to2617to2921to2320to2320to2520to25 CFTRgenotype G551D/F508del3(75)4(100)4(100)2(50)3(75)16(80)4(100)7(88)5(71)16(84) G551D/1078delT1(25)----1(5)---- G551D/G551D----1(25)1(5)---- G551D/N1303K---1(25)-1(5)---- G551D/R553X---1(25)-1(5)---- G551D/3849+10kbC→T--------1(14)1(5) G551D/621+1G→T-------1(12)-1(5) G551D/G542X--------1(14)1(5) FEV1 Median%ofpredictedvalue57665663495677657669 Range%ofpredictedvalue48to9744to10942to6546to10242to5842to10953to11242to12240to10640to122 40to<70%ofpredictedvalue -no. Login to comment 70 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* (%)‡4(100)4(100)4(100)4(100)4(100)20(100)4(100)8(100)7(100)19(100) Age-yr Median36314126213024232121 Range19to4822to5122to5019to3419to3319to5118to4218to4020to3818to42 Body-massindex Median23232420212322222322 Range22to2920to2419to2719to2417to2617to2921to2320to2320to2520to25 CFTRgenotype G551D/F508del3(75)4(100)4(100)2(50)3(75)16(80)4(100)7(88)5(71)16(84) G551D/1078delT1(25)----1(5)---- G551D/G551D----1(25)1(5)---- G551D/N1303K---1(25)-1(5)---- G551D/R553X---1(25)-1(5)---- G551D/3849+10kbC→T--------1(14)1(5) G551D/621+1G→T-------1(12)-1(5) G551D/G542X--------1(14)1(5) FEV1 Median%ofpredictedvalue57665663495677657669 Range%ofpredictedvalue48to9744to10942to6546to10242to5842to10953to11242to12240to10640to122 40to<70%ofpredictedvalue -no. Login to comment 139 ABCC7 p.Gly551Asp Discussion This randomized, double-blind, placebo-controlled, multicenter trial of oral VX-770 involved subjects with cystic fibrosis and the G551D mutation on at least one allele. Login to comment 156 ABCC7 p.Gly551Asp Discussion This randomized, double-blind, placebo-controlled, multicenter trial of oral VX-770 involved subjects with cystic fibrosis and the G551D mutation on at least one allele. Login to comment