Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation

Frank J. Accurso, Steven M. Rowe, J. P. Clancy, Michael P. Boyle, Jordan M. Dunitz, Peter R. Durie, Scott D. Sagel, Douglas B. Hornick, Michael W. Konstan, Scott H. Donaldson, Richard B. Moss, Joseph M. Pilewski, Ronald C. Rubenstein, Ahmet Z. Uluer, Moira L. Aitken, Steven D. Freedman, Lynn M. Rose, Nicole Mayer-Hamblett, Qunming Dong, Jiuhong ZhaAnne J. Stone, Eric R. Olson, Claudia L. Ordoñez, Preston W. Campbell, Melissa A. Ashlock, Bonnie W. Ramsey

Research output: Contribution to journalArticle

Abstract

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 cellsurface 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. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.)

Original languageEnglish (US)
Pages (from-to)1991-2003
Number of pages13
JournalNew England Journal of Medicine
Volume363
Issue number21
DOIs
StatePublished - Nov 18 2010

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Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis
Mutation
Placebos
Chlorides
Sweat
Forced Expiratory Volume
ivacaftor
Exanthema
Isoproterenol
Nose
Blood Glucose
Alleles
Urine
Safety
Lung
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Accurso, F. J., Rowe, S. M., Clancy, J. P., Boyle, M. P., Dunitz, J. M., Durie, P. R., ... Ramsey, B. W. (2010). Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. New England Journal of Medicine, 363(21), 1991-2003. https://doi.org/10.1056/NEJMoa0909825

Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. / Accurso, Frank J.; Rowe, Steven M.; Clancy, J. P.; Boyle, Michael P.; Dunitz, Jordan M.; Durie, Peter R.; Sagel, Scott D.; Hornick, Douglas B.; Konstan, Michael W.; Donaldson, Scott H.; Moss, Richard B.; Pilewski, Joseph M.; Rubenstein, Ronald C.; Uluer, Ahmet Z.; Aitken, Moira L.; Freedman, Steven D.; Rose, Lynn M.; Mayer-Hamblett, Nicole; Dong, Qunming; Zha, Jiuhong; Stone, Anne J.; Olson, Eric R.; Ordoñez, Claudia L.; Campbell, Preston W.; Ashlock, Melissa A.; Ramsey, Bonnie W.

In: New England Journal of Medicine, Vol. 363, No. 21, 18.11.2010, p. 1991-2003.

Research output: Contribution to journalArticle

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, Ordoñez, CL, Campbell, PW, Ashlock, MA & Ramsey, BW 2010, 'Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation', New England Journal of Medicine, vol. 363, no. 21, pp. 1991-2003. https://doi.org/10.1056/NEJMoa0909825
Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. New England Journal of Medicine. 2010 Nov 18;363(21):1991-2003. https://doi.org/10.1056/NEJMoa0909825
Accurso, Frank J. ; Rowe, Steven M. ; Clancy, J. P. ; Boyle, Michael P. ; Dunitz, Jordan M. ; Durie, Peter R. ; Sagel, Scott D. ; Hornick, Douglas B. ; Konstan, Michael W. ; Donaldson, Scott H. ; Moss, Richard B. ; Pilewski, Joseph M. ; Rubenstein, Ronald C. ; Uluer, Ahmet Z. ; Aitken, Moira L. ; Freedman, Steven D. ; Rose, Lynn M. ; Mayer-Hamblett, Nicole ; Dong, Qunming ; Zha, Jiuhong ; Stone, Anne J. ; Olson, Eric R. ; Ordoñez, Claudia L. ; Campbell, Preston W. ; Ashlock, Melissa A. ; Ramsey, Bonnie W. / Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. In: New England Journal of Medicine. 2010 ; Vol. 363, No. 21. pp. 1991-2003.
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T1 - Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation

AU - Accurso, Frank J.

AU - Rowe, Steven M.

AU - Clancy, J. P.

AU - Boyle, Michael P.

AU - Dunitz, Jordan M.

AU - Durie, Peter R.

AU - Sagel, Scott D.

AU - Hornick, Douglas B.

AU - Konstan, Michael W.

AU - Donaldson, Scott H.

AU - Moss, Richard B.

AU - Pilewski, Joseph M.

AU - Rubenstein, Ronald C.

AU - Uluer, Ahmet Z.

AU - Aitken, Moira L.

AU - Freedman, Steven D.

AU - Rose, Lynn M.

AU - Mayer-Hamblett, Nicole

AU - Dong, Qunming

AU - Zha, Jiuhong

AU - Stone, Anne J.

AU - Olson, Eric R.

AU - Ordoñez, Claudia L.

AU - Campbell, Preston W.

AU - Ashlock, Melissa A.

AU - Ramsey, Bonnie W.

PY - 2010/11/18

Y1 - 2010/11/18

N2 - 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 cellsurface 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. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.)

AB - 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 cellsurface 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. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.)

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