Effect of VX-770 in Persons with Cystic Fibrosis and the G551D-<i>CFTR</i>Mutation

Accurso, Frank J.; Rowe, Steven M.; Clancy, John; Boyle, Michael; 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; 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.

doi:10.1056/nejmoa0909825

Cited by 741 publications

(574 citation statements)

References 18 publications

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“…Ivacaftor has been tested in clinical studies only in patients with the G551D mutation and in those homozygous for F508del (24); in the latter, as expected, there was no beneficial effect. Several ongoing studies are underway to explore response in patients with mutations beyond G551D and F508del.…”

Section: Discussionmentioning

confidence: 83%

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

Davies

Wainwright

Canny

et al. 2013

Am J Respir Crit Care Med

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464

386

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Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation. Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele. Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n ¼ 26) or placebo (n ¼ 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies. Measurements and Main Results: Despite near-normal mean baseline values in FEV 1 , patients receiving ivacaftor had a significant increase in percent predicted FEV 1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P , 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P , 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was 253.5 mmol/L (P , 0.001) versus placebo. The incidence of adverse events was similar in the two groups. Conclusions: In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).

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Section: Discussionmentioning

confidence: 83%

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

Davies

Wainwright

Canny

et al. 2013

Am J Respir Crit Care Med

Self Cite

464

386

View full text Add to dashboard Cite

show abstract

“…In addition, identification and characterization of the mutations in CFTR has aided the diagnosis of CF, facilitated genetic counseling for families, and screening of newborns and carriers in the general population. Last but not least, it becomes more evident that the precise knowledge of the CFTR mutations will be a prerequisite for the rationale basis for mutation-specific therapies that are now imminent (Accurso et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Assessing the Disease-Liability of Mutations in CFTR

Férec

Cutting

2012

Cold Spring Harbor Perspectives in Medicine

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“…It is thus safe to say that new approaches are needed to tackle this coupling mechanism that bears ramifications not only on CFTR, but also on ABC proteins at large. In addition, we foresee that understanding CFTR gating at a molecular level will shed light on the mechanism of action for therapeutic reagents such as Vx-770 (Kalydeco or ivacaftor), a recently FDA-approved CFTR potentiator for treating CF patients carrying the G551D mutation (Van Goor et al 2009;Accurso et al 2010;Ramsey et al 2011).…”

Section: Future Perspectives Regarding Atp-dependent Channel Gatingmentioning

confidence: 99%

The CFTR Ion Channel: Gating, Regulation, and Anion Permeation

Hwang

Kirk

2013

Cold Spring Harbor Perspectives in Medicine

106

110

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Effect of VX-770 in Persons with Cystic Fibrosis and the G551D-CFTRMutation

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 cell-surface CFTR in vitro.

Cited by 741 publications

References 18 publications

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

Assessing the Disease-Liability of Mutations in CFTR

The CFTR Ion Channel: Gating, Regulation, and Anion Permeation

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