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: 55.87). 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, Sep 26, 2015
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    • "Although 90% of CF patients have an in-frame deletion that results in the mislocalization of the CFTR gene product, a small fraction of CF patients (~5%) have a missense mutation G551D-CFTR that has correct CFTR localization but reduced chloride channel activity (Van Goor et al., 2011). Using this allelic information, researchers identified compounds that specifically rectify the perturbation caused by each CFTR allele (Ramsey et al., 2011; Van Goor et al., 2011). For example, the drug Ivacaftor binds the ion channel to promote chloride transport in patients harboring the G551D-CFTR allele (Yu et al., 2012; McPhail and Clancy, 2013). "
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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.
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    • "The genes and pathways discovered can become targets for pharmaceutical intervention, especially when integrated with corroborating studies from disease models, signal transduction experiments, bioinformatics, and protein biochemistry. Examples of using specific genes or their products as pharmaceutical targets have rapidly accumulated over the past decade and include mipomersen, an antisense therapeutic targeting APOB RNA for the treatment of hypercholesterolemia (Raal et al., 2010), ivacaftor which targets the G551D mutation in CFTR found in approximately 4% of individuals with cystic fibrosis (Ramsey et al., 2011), inflammatory cytokines and their receptors (e.g., IL-1β, IL-12/23p40, IL-17A, IL-6R) (e.g., Krueger et al., 2007), other immune cell signaling proteins (e.g., CTLA-4, CD30), a variety of tumorigenesis genes that harbor somatic variants useful for individualized cancer treatment (e.g., BRAF, KRAS, and EGFR), and lipid transfer proteins (e.g., CETP, PCSK9), among many others. As more human genetics studies are conducted, the number of these druggable targets will expand. "
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