ABCMdb

PMID: 21825083

Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordonez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW
Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.
Thorax. 2012 Jan;67(1):12-8. Epub 2011 Aug 8., [PubMed]

Sentences

No. Mutations Sentence Comment

108 ABCC7 p.Gly551Asp Using this paradigm, the treatment effects on sweat chloride reported with the CFTR potentiator VX-770 in patients with CF with the G551D-CFTR mutation were successfully used to power the current study to detect improvements in sweat chloride (within-group comparisons and with placebo). Login to comment 119 ABCC7 p.Gly551Asp To minimise a Type 2 error and attain an 80% power to detect a chloride-free isoproterenol response approximating 30% of that seen with VX-770 in patients with CF with the G551D-CFTR mutation, the current study would have required >50 subjects per study group undergoing the NPD.17 22 In vitro studies also suggest that measurement of the effect of VX-809 on CFTR may be below the lower limits of sensitivity of immunoblot assays performed on small biopsy samples.17 Pretrial studies indicated that the assay developed here was capable of detecting w10% of C-Band CFTR relative to wild-type levels (ex vivo dilution experiments using human rectal biopsy specimens obtained from non-CF study subjects; see online supplement, figure 2B). Login to comment 124 ABCC7 p.Tyr122* For example, PTC124 has been shown to have detectable bioactivity by NPD over 2 weeks of treatment in patients with CF possessing premature termination codons in CFTR, while sweat chloride measurements remained unchanged.24 Improvements in lung function and cough frequency were not observed until months of treatment were completed.25 Systemic gentamicin has also been shown to suppress PTCs26 and improve NPD parameters in two pilot studies, but effects on sweat chloride were predominantly limited to a subset of patients with the Y122X mutation.27 28 Using a separate CFTR modulator strategy, Rubenstein and colleagues treated F508del-CFTR homozygous patients with CF with the F508del-CFTR modulator 4-phenyl butyrate. Login to comment