Effect of VX-770 in Persons with Cystic Fibrosis and the G551D-CFTR Mutation
By F. Accurso, S. Rowe, J. Clancy, M. Boyle, J. Dunitz, P. Durie, S. Sagel, D. Hornick, M. Konstan, S. Donaldson and 16 more. New England Journal of Medicine, 2010
732 citations recorded by the source corpus.
BACKGROUND A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro. 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). RESULTS At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was −3.5 mV (range, −8.3 to 0.5; P = 0.02 for the within-subject comparison, P = 0.13 vs. placebo), and the median change in the level of sweat chloride was −59.5 mmol per liter (range, −66.0 to −19.0; P = 0.008 within-subject, P = 0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 for the within-subject comparison, P = 0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. CONCLUSIONS This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.
Subfields: Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/bd21d23a00a8bc8292501d79ad0beb11d4f13d28
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Citations in the corpus
- European Position Paper on Rhinosinusitis and Nasal Polyps 2020. (2020, methodology): “were identified in 14% CRS patients by conventional techniques (culture and histology)((138)).”
- Handbook of ion channels (2015, background): “Soon after the discovery of VX-770 on the bench, encouraging results were reported from clinical trials (Accurso et al., 2010; Ramsey et al., 2011), followed without delay by the approval of VX-770 for CF treatment by the FDA.”
- Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 (2011, background): “In support of this approach, the CFTR potentiator VX-770 (9) improved in vivo measures of chloride transport and lung function in patients with CF with the G551D CFTR channel gating mutation (10).”
- A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation (2011, background): “This finding confirms the observation from an early-phase trial that ivacaftor improved CFTR-mediated iontransport function.(11) The mechanisms by which changes in CFTR function may lead to pulmonary and weight changes are incompletely understood and probably multifactorial.”