ABCMdb

PMID: 23922647

Rowe SM, Liu B, Hill A, Hathorne H, Cohen M, Beamer JR, Accurso FJ, Dong Q, Ordonez CL, Stone AJ, Olson ER, Clancy JP
Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation.
PLoS One. 2013 Jul 26;8(7):e66955. doi: 10.1371/journal.pone.0066955. Print 2013., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Gly551Asp Optimizing Nasal Potential Difference Analysis for CFTR Modulator Development: Assessment of Ivacaftor in CF Subjects with the G551D-CFTR Mutation Steven M. Rowe1 , Bo Liu1 , Aubrey Hill1 , Heather Hathorne1 , Morty Cohen2&#a4;a , John R. Beamer2&#a4;b , Frank J. Accurso3 , Qunming Dong4 , Claudia L. Ordon dc; ez4&#a4;c , Anne J. Stone4 , Eric R. Olson4 , John P. Clancy5 *, for the VX06-770-101 Study Group" 1 University of Alabama at Birmingham, Birmingham, Alabama, United States of America, 2 Seattle Children`s Hospital, Seattle, Washington, United States of America, 3 University of Colorado Denver, Aurora, Colorado, United States of America, 4 Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America, 5 Cincinnati Children`s Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio, United States of America Abstract Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. Login to comment 2 ABCC7 p.Gly551Asp Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (KalydecoTM ; also known as VX-770) in four doses or placebo twice daily for at least 14 days. Login to comment 10 ABCC7 p.Gly551Asp Citation: Rowe SM, Liu B, Hill A, Hathorne H, Cohen M, et al. (2013) Optimizing Nasal Potential Difference Analysis for CFTR Modulator Development: Assessment of Ivacaftor in CF Subjects with the G551D-CFTR Mutation. Login to comment 26 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Ivacaftor (KalydecoTM ; also known as VX-770) is a CFTR potentiator approved for the treatment of CF caused by the G551D mutation (in patients $6 years of age) by increasing gating and anion channel activity of G551D-CFTR (found in approximately 4% of patients [25]). Login to comment 27 ABCC7 p.Gly551Asp A Phase II clinical trial of ivacaftor demonstrated dose-dependent improvements in CFTR biomarkers (including NPD and sweat Cl2 along with clinical efficacy measures) in subjects with the G551D-CFTR mutation [22]. Login to comment 32 ABCC7 p.Gly551Asp Institutional review board (IRB) approval at each participating center and written informed consent were obtained for all enrolled study subjects for a two-part, randomized, placebo-controlled trial examining different doses of ivacaftor in subjects with the G551D-CFTR mutation on at least one allele. Login to comment 66 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* Characteristic Part 1 Part 2 Placebo (n = 4) Ivacaftor TOTAL (n = 20) Placebo (n = 4) Ivacaftor TOTAL (n = 19) 25 mg/75 mg (n = 4) 75 mg/25 mg (n = 4) 75 mg/150 mg (n = 4) 150 mg/75 mg (n = 4) 150 mg (n = 8) 250 mg (n = 7) Sex, n (%) Male 2 (50) 1 (25) 4 (100) 1 (25) 1 (25) 9 (45) 3 (75) 3 (38) 4 (57) 10 (53) Female 2 (50) 3 (75) 0 3 (75) 3 (75) 11 (55) 1 (25) 5 (63) 3 (43) 9 (47) Race, n (%) White 4 (100) 4 (100) 4 (100) 4 (100) 4 (100) 20 (100) 4 (100) 8 (100) 7 (100) 19 (100) Age, yr, median (range) 36 (19-48) 31 (22-51) 41 (22-50) 26 (19-34) 21 (19-33) 30 (19-51) 24 (18-42) 23 (18-40) 21 (20-38) 21 (18-42) BMI, kg/m 2 , median (range) 23 (22-29) 23 (20-24) 24 (19-27) 20 (19-24) 21 (17-26) 23 (17-29) 22 (21-23) 22 (20-23) 23 (20-25) 22 (20-25) CFTR genotype G551D/F508del 3 (75) 4 (100) 4 (100) 2 (50) 3 (75) 16 (80) 4 (100) 7 (88) 5 (71) 16 (84) G551D/1078delT 1 (25) - - - - 1 (5) - - - - G551D/G551D - - - - 1 (25) 1 (5) - - - - G551D/N1303K - - - 1 (25) - 1 (5) - - - - G551D/R553X - - - 1 (25) - 1 (5) - - - - G551D/3849+10 kbC - - - - - - - - 1 (14) 1 (5) G551D/6214R1G+7T - - - - - - - 1 (13) - 1 (5) G551D/G542X - - - - - - - - 1 (14) 1 (5) % Predicted FEV 1 , median (range) 40% to ,70%, n (%) 3 (75) 3 (75) 4 (100) 2 (50) 4 (100) 16 (80) 2 (50) 5 (63) 3 (43) 10 (53) 70% to ,90%, n (%) - - - 1 (25) - 1 (5) .90%, n (%) - 1 (25) - 1 (25) - 3 (15) 2 (50) 1 (13) 1 (14) 4 (21) Sweat chloride, mmol/L, median (range) 105.25 (97.00- 112.00) 107.50 (60.00-117.00) 104.50 (102.00-117.00) 97.50 (92.00-102.50) 99.00 (83.00-104.00) 102.00 (60.00-117.00) 93.75 (88.00- 109.50) 100.13 (86.75- 112.50) 97.25 (84.75- 115.75) 95.50 (84.75- 115.75) BMI, body-mass index; CFTR, cystic fibrosis transmembrane conductance regulator; FEV 1 , forced expiratory volume in one second. Login to comment 119 ABCC7 p.Gly551Asp doi:10.1371/journal.pone.0066955.t004 Phase II study of ivacaftor in G551D-CF patients provided a unique opportunity to determine the optimal measures for quantifying CFTR activity and inform future decisions in NPD analysis. Login to comment