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Lorenzo Guerra, Susanna D'Oria, Maria Favia, Stefano Castellani, Teresa Santostasi, Angela M Polizzi, Maria A Mariggiò, Crescenzio Gallo, Valeria Casavola, Pasqualina Montemurro, Giuseppina Leonetti, Antonio Manca, Massimo Conese
AIM: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well. METHODS: Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR...
April 26, 2017: Pediatric Pulmonology
Jessica E Char, Colleen Dunn, Zoe Davies, Carlos Milla, Richard B Moss, Jeffrey J Wine
We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent 'C-sweat' and methacholine to stimulate 'M-sweat', which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor's effect on the open probability (PO) of R117H-CFTR...
2017: PloS One
Jean-Louis Delaunay, Alix Bruneau, Brice Hoffmann, Anne-Marie Durand-Schneider, Véronique Barbu, Emmanuel Jacquemin, Michèle Maurice, Chantal Housset, Isabelle Callebaut, Tounsia Aït-Slimane
ABCB4 (MDR3) is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding...
February 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Elena K Schneider, Felisa Reyes-Ortega, John W Wilson, Tom Kotsimbos, Dominic Keating, Jian Li, Tony Velkov
ORKAMBI (ivacaftor-lumacaftor [LUMA]) and KALYDECO (ivacaftor; IVA) are two new breakthrough cystic fibrosis (CF) drugs that directly modulate the activity and trafficking of the defective CFTR underlying the CF disease state. Currently, no therapeutic drug monitoring assays exist for these very expensive, albeit, important drugs. In this study, for the first time HPLC and LC-MS methods were developed and validated for rapid detection and quantification of IVA and its major metabolites hydroxymethyl-IVA M1 (active) and IVA-carboxylate M6 (inactive); and LUMA in the plasma and sputum of CF patients...
December 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Béla Z Schmidt, Jérémy B Haaf, Teresinha Leal, Sabrina Noel
Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients...
2016: Clinical Pharmacology: Advances and Applications
Elena K Schneider, Mohammad A K Azad, Mei-Ling Han, Qi Tony Zhou, Jiping Wang, Johnny X Huang, Matthew A Cooper, Yohei Doi, Mark A Baker, Phillip J Bergen, Mark T Muller, Jian Li, Tony Velkov
Novel combination therapies are desperately needed for combating lung infections caused by bacterial "superbugs". This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P...
July 8, 2016: ACS Infectious Diseases
Johanna F Dekkers, Gitte Berkers, Evelien Kruisselbrink, Annelotte Vonk, Hugo R de Jonge, Hettie M Janssens, Inez Bronsveld, Eduard A van de Graaf, Edward E S Nieuwenhuis, Roderick H J Houwen, Frank P Vleggaar, Johanna C Escher, Yolanda B de Rijke, Christof J Majoor, Harry G M Heijerman, Karin M de Winter-de Groot, Hans Clevers, Cornelis K van der Ent, Jeffrey M Beekman
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations...
June 22, 2016: Science Translational Medicine
Caroline Rung Elsas, Elinor Langfelder Schwind, Laura Hercher, Michael J Smith, Kara Gardner Young
This project aimed to explore the attitudes of prenatal genetic counselors toward discussion of novel approved and experimental CF treatments in the prenatal setting, and to assess how knowledge of genotype-specific, targeted treatments may influence their current practices. Targeted treatments have the potential to impact the health-related quality of life of individuals affected with CF and therefore, knowledge of the availability of such treatments may influence the decision-making process of parents who receive a fetal diagnosis of CF...
June 9, 2016: Journal of Genetic Counseling
Johanna F Dekkers, Peter Van Mourik, Annelotte M Vonk, Evelien Kruisselbrink, Gitte Berkers, Karin M de Winter-de Groot, Hettie M Janssens, Inez Bronsveld, Cornelis K van der Ent, Hugo R de Jonge, Jeffrey M Beekman
The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities...
September 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Christen Rachul, Maeghan Toews, Timothy Caulfield
BACKGROUND: The cystic fibrosis drug, Kalydeco, has attracted attention both for its effectiveness in particular CF patients and its substantial price tag. An analysis of newspaper portrayals of Kalydeco provides an opportunity to examine how policy issues associated with rare diseases and orphan drugs are being represented in the popular press. METHODS: We conducted a content analysis of 203 newspaper articles in Canada and the U.S. that mention Kalydeco. Articles were analyzed for their main frame, discussion of Kalydeco, including issues of drug development, patient access, and reimbursement, and overall tone...
September 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Isha Dey, Kalpit Shah, Neil A Bradbury
The recent FDA approval of two drugs to treat the basic defect in cystic fibrosis has given hope to patients and their families battling this devastating disease. Over many years, with heavy financial investment from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, pre-clinical evaluation of thousands of synthetic drugs resulted in the production of Kalydeco and Orkambi. Yet, despite the success of this endeavor, many other compounds have been proposed as therapeutic agents in the treatment of CF...
February 2016: Journal of Genetic Syndrome & Gene Therapy
Steven V Molinski, Saumel Ahmadi, Maurita Hung, Christine E Bear
There are nearly 2000 mutations in the CFTR gene associated with cystic fibrosis disease, and to date, the only approved drug, Kalydeco, has been effective in rescuing the functional expression of a small subset of these mutant proteins with defects in channel activation. However, there is currently an urgent need to assess other mutations for possible rescue by Kalydeco, and further, definition of the binding site of such modulators on CFTR would enhance our understanding of the mechanism of action of such therapeutics...
December 2015: Journal of Biomolecular Screening
Guiying Cui, Nael A McCarty
Development of therapeutic molecules with clinical efficacy as modulators of defective CFTR includes efforts to identify potentiators that can overcome or repair the gating defect in mutant CFTR channels. This has taken a great leap forward with the identification of the potentiator VX-770, now available to patients as "Kalydeco." Other small molecules with different chemical structure also are capable of potentiating the activity of either wild-type or mutant CFTR, suggesting that there are features of the protein that may be targeted to achieve stimulation of channel activity by structurally diverse compounds...
October 1, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Melanie Senior
No abstract text is available yet for this article.
January 2015: Nature Biotechnology
C L Vreede, M C Berkhout, A J Sprij, W J Fokkens, H G M Heijerman
In patients with Cystic Fibrosis and a type III mutation, ivacaftor (Kalydeco(®), Vertex) can increase the opening time of the CFTR channel and improve chloride transport. Research showed significant improvement of lung function and increase in weight following ivacaftor use. However, ivacaftor showed to have adverse events on the sinonasal system as well, such as upper respiratory tract infections, nasal congestion and headaches. This case report showed a positive effect of ivacaftor on the sinonasal pathology in a 17 year old patient with CF...
May 2015: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
C Monneret
Among the new molecular entities approved by the EMEA and the FDA in 2012, four have caught our attention for their significant contribution to the health of patient. First of all, among the notable 2012 approvals, is ivacaftor or Kalydeco®. This is the first treatment that targets one of the gene defects that is underlying cause of cystic fibrosis. This is also an example of the promise of personalized medicine. The benefits with bedaquiline or Sirturo® are its ability to likely provide clinically relevant activity as part of multi-drug regimens against tuberculosis (TB) based on clinical data in multi-drug resistant tuberculosis (MDR TB) patients, who were defined as being at least resistant against the two major tuberculostatic medicines (isaoniazide and rifampicine)...
July 2014: Annales Pharmaceutiques Françaises
Penny Whiting, Maiwenn Al, Laura Burgers, Marie Westwood, Steve Ryder, Martine Hoogendoorn, Nigel Armstrong, Alex Allen, Hans Severens, Jos Kleijnen
BACKGROUND: Ivacaftor (Kalydeco(®), Vertex Pharmaceuticals) is the first of a new class of drugs that target the underlying protein defect in cystic fibrosis (CF). It is aimed at patients with the G551D (glycine to aspartate change in nucleotide 1784 in exon 11) mutation; 5.7% of patients with CF in the UK have this mutation. OBJECTIVES: To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged ≥ 6 years who have the G551D mutation...
March 2014: Health Technology Assessment: HTA
Jessica E Char, Marlene H Wolfe, Hyung-Ju Cho, Il-Ho Park, Jin Hyeok Jeong, Eric Frisbee, Colleen Dunn, Zoe Davies, Carlos Milla, Richard B Moss, Ewart A C Thomas, Jeffrey J Wine
To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (-) ivacaftor, 3 only (+) ivacaftor and 3 (+/-) ivacaftor (1-5 tests per condition). The total number of gland measurements was 852 (-) ivacaftor and 906 (+) ivacaftor...
2014: PloS One
S Durupt, R Nove Josserand, I Durieu
We present the recent therapeutic advances in the cystic fibrosis care. It concerns improvements in symptomatic treatment with the development of dry powder inhaled antibiotics that improved quality of life, and innovative treatments namely the modulators of the cystic fibrosis transmembrane protein conductance regulator (CFTR), molecules which act specifically at the level of the defective mechanisms implied in the disease. The life expectancy of cystic fibrosis patients born after 2000, is estimated now to be about 50 years...
June 2014: La Revue de Médecine Interne
Thida Ong, Bonnie W Ramsey
PURPOSE OF REVIEW: Recent therapies directed at proximal targets within cystic fibrosis (CF) pathophysiology hold potential to modulate disease. This review highlights recent clinical trials and future therapies focused on these early steps of disease. RECENT FINDINGS: Recent approval of a CF transmembrane conductance regulator (CFTR) protein modulator, ivacaftor (Kalydeco), has ignited a wave of investigations for other modulators directed at CFTR mutation classes...
November 2013: Current Opinion in Pulmonary Medicine
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