A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation

Seattle Children's Hospital and University of Washington School of Medicine, Seattle WA 98105-0371, USA.
New England Journal of Medicine (Impact Factor: 54.42). 11/2011; 365(18):1663-72. DOI: 10.1056/NEJMoa1105185
Source: PubMed

ABSTRACT Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.
We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).
The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).
Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 number, NCT00909532.).

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Available from: Richard B Moss, Jul 28, 2015
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    • "Class VI mutants cause significant plasma membrane instability and include F508del when rescued by most correctors (rF508del) (Amaral & Farinha, 2013). for CFTR-repairing molecules going into clinical trial (Van Goor et al., 2009, 2011) and a good correlation has been found between data collected for VX-770 in HBEs and clinical trial outcomes (Ramsey et al., 2011). Despite this correlation demonstrated for this potentiator compound, it is probably insufficient to prove that primary HBEs are the gold standard for compound validation for all mutations. "
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    ABSTRACT: With the discovery of the CFTR gene in 1989, the search for therapies to improve the basic defects of cystic fibrosis (CF) commenced. Pharmacological manipulation provides the opportunity to enhance CF transmembrane conductance regulator (CFTR) protein synthesis and/or function. CFTR modulators include potentiators to improve channel gating, (class III mutations), correctors to improve abnormal CFTR protein folding and trafficking (class II mutations) and stop codon mutation read-through drugs relevant for patients with premature stop codons (most class I mutations). After several successful clinical trials the potentiator, ivacaftor is now licenced for use in adults and children (>six years), with CF bearing the class III G551D mutation and FDA license was recently expanded to include 8 additional class III mutations. Alternative approaches for class I and class II mutations are currently being studied. Combination drug treatment with correctors and potentiators appear to be required to restore CFTR function of F508del, the most common CFTR mutation. Alternative therapies such as gene therapy or pharmacological modulation of other ion channels may be advantageous because they are mutation-class independent, however progress is less well advanced. Clinical trials for CFTR modulators have been enthusiastically embraced by patients with CF and health care providers. While novel trial end-points are being evaluated allowing CFTR modulators to be efficiently tested, many challenges related to the complexity of CFTR and the biology of the epithelium still need to be overcome.
    Pharmacology [?] Therapeutics 06/2014; 145. DOI:10.1016/j.pharmthera.2014.06.005 · 7.75 Impact Factor
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    • "Efforts have been made to restore cFtr function by gene therapy or by using small organic compounds to ameliorate the disease. to address the reduced activity defect of F508del and of other less frequent mutations, for example G551D, the potentiator VX-770 (Ivacaftor), which improves chloride transport and lung function, in vivo, of patients bearing the G551D mutation (ramsey et al. 2011) has recently been introduced . Attempts to enhance chloride transport by using drugs that increase delivery of functional F508del-cFtr to the cell surface have been less successful, however. "
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    ABSTRACT: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors are new drugs that target the basic CFTR protein defect and are expected to benefit cystic fibrosis patients. To optimize the substances so far proposed for human use, and to minimise unwanted side effects, it is essential to investigate possible interactions between the drugs and cell components. We used small-angle X-ray scattering with synchrotron radiation to analyse the effects of two representative drugs, the potentiator VX-770 (Ivacaftor), approved for human use, and the corrector VX-809 (Lumacaftor), on a model phospholipid membrane. By reconstruction of the electron density profile of unilamellar vesicles treated with VX-770 or VX-809 we found that these drugs penetrate the phospholipid bilayer. VX-809 becomes homogeneously distributed throughout the bilayer whereas VX-770 accumulates predominantly in the internal leaflet, behaviour probably favoured by the asymmetry of the bilayer, because of vesicle curvature. Penetration of the bilayer by these drugs, probably as part of the mechanisms of permeation, causes destabilization of the membrane; this must be taken into account during future drug development.
    Biophysics of Structure and Mechanism 04/2014; 43(6-7). DOI:10.1007/s00249-014-0956-y · 2.47 Impact Factor
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    • "Approximately 4–5% of CF patients carry the G551D mutation, limiting the impact of this oral drug on the global CF population (McKone et al., 2003). Nevertheless, the treatment of G551D patients was associated with rapid and sustained improvement in lung function (FEV 1 ), reduced pulmonary exacerbations and respiratory symptoms, weight gain and increased sweat chloride concentration (Accurso et al., 2010; Ramsey et al., 2011). In addition, remarkable improvements in mucociliary clearance and ventilation defects have been shown during treatment with Ivacaftor , suggesting that restitution of CFTR function is sufficient to normalise the aberrant properties of mucus (Altes et al., 2012; Donaldson et al., 2013). "
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    ABSTRACT: Our current understanding of cystic fibrosis (CF) has revealed that the biophysical properties of mucus play a considerable role in the pathogenesis of the disease in view of the fact that most mucus-producing organs are affected in CF patients. In this review, we discuss the potential causal relationship between altered cystic fibrosis transmembrane conductance regulator (CFTR) function and the production of mucus with abnormal biophysical properties in the intestine and lungs, highlighting what has been learned from cell cultures and animal models that mimic CF pathogenesis. A similar cascade of events, including mucus obstruction, infection and inflammation, is common to all epithelia affected by impaired surface hydration. Hence, the main structural components of mucus, namely the polymeric, gel-forming mucins, are critical to the onset of the disease. Defective CFTR leads to epithelial surface dehydration, altered pH/electrolyte composition and mucin concentration. Further, it can influence mucin transition from the intracellular to extracellular environment, potentially resulting in aberrant mucus gel formation. While defective HCO3(-) production has long been identified as a feature of CF, it has only recently been considered as a key player in the transition phase of mucins. We conclude by examining the influence of mucins on the biophysical properties of CF sputum and discuss existing and novel therapies aimed at removing mucus from the lungs.
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