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GlaxoSmithKline plc is a British multinational pharmaceutical, biologics, vaccines and consumer healthcare company which has its headquarters in Brentford, London. As of March 2014, it was the world's sixth-largest pharmaceutical company after Johnson & Johnson, Novartis, Hoffmann-La Roche, Pfizer, and Sanofi, measured by 2013 revenue. The company was established in 2000 by the merger of Glaxo Wellcome and SmithKline Beecham plc .The company has a primary listing on the London Stock Exchange and is a constituent of the FTSE 100 Index. As of 2 May 2014 it had a market capitalisation of £79 billion, the fourth-largest of any company listed on the London Stock Exchange. It has a secondary listing on the New York Stock Exchange. Andrew Witty has been the chief executive officer since May 2008.GSK manufactures drugs and vaccines for major disease areas such as asthma, cancer, infections, diabetes, digestive and mental health conditions, the biggest selling of which were Advair, Avodart, Flovent, Augmentin, Lovaza, and Lamictal in 2013. Many medicines were historically discovered or developed at GSK and its predecessor companies and are now sold as generics. Its drugs and vaccines earned £21.3 billion in 2013. Its consumer healthcare division, which earned £5.2 billion in 2013, sells oral healthcare and nutritional products, drinks and over-the-counter medicines, including Sensodyne, Boost and Horlicks.In July 2012 GSK pleaded guilty to criminal charges and agreed to a pay $3 billion to settle the criminal charges as well as civil qui tam lawsuits in the largest settlement paid by a drug company at the time. The criminal charges were for promoting Paxil and Wellbutrin for unapproved uses and failing to report safety data about Avandia; GSK paid $1 billion to settle the criminal charges. The remaining $2 billion were part of the civil settlement over unapproved promotion and paying kickbacks, making false statements concerning the safety of Avandia; and reporting false prices to Medicaid. GSK also signed an agreement which obligated it to make major changes to the way it did business.On December 17, 2013, GSK announced that it would stop paying professionals for speaking at medical conferences. The company stated that it would still pay fees to doctors for functions it regards as critical to obtaining insights into specific diseases, including performing company sponsored clinical trials, scientific advisory services, and market research.GlaxoSmithKline received top ranking among international pharmaceutical companies in the Access to Medicines Index in 2010, 2012 and 2014. In 2014 the company applied for regulatory approval for the first vaccine against malaria. The vaccine was developed as a joint project with the PATH vaccines initiative and the Bill and Melinda Gates Foundation. The company has committed to make the vaccine available in developing countries for a price set at 5% above the cost of production. Wikipedia.

Kenakin T.,Glaxosmithkline
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

With the emergence of information describing functional selectivity and biased agonists and antagonists has come a lack of confidence in "one size fits all" assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such "biased" ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as "pluridimensional efficacy"), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

Ulloa-Montoya F.,Glaxosmithkline
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

To detect a pretreatment gene expression signature (GS) predictive of response to MAGE-A3 immunotherapeutic in patients with metastatic melanoma and to investigate its applicability in a different cancer setting (adjuvant therapy of resected early-stage non-small-cell lung cancer [NSCLC]). Patients were participants in two phase II studies of the recombinant MAGE-A3 antigen combined with an immunostimulant (AS15 or AS02B). mRNA from melanoma biopsies was analyzed by microarray analysis and quantitative polymerase chain reaction. These results were used to identify and cross-validate the GS, which was then applied to the NSCLC data. In the patients with melanoma, 84 genes were identified whose expression was potentially associated with clinical benefit. This effect was strongest when the immunostimulant AS15 was included in the immunotherapy (hazard ratio [HR] for overall survival, 0.37; 95% CI, 0.13 to 1.05; P = .06) and was less strong with the other immunostimulant AS02B (HR, 0.84; 95% CI, 0.36 to 1.97; P = .70). The same GS was then used to predict the outcome for patients with resected NSCLC treated with MAGE-A3 plus AS02B; actively treated GS-positive patients showed a favorable disease-free interval compared with placebo-treated GS-positive patients (HR, 0.42; 95% CI, 0.17 to 1.03; P = .06), whereas among GS-negative patients, no such difference was found (HR, 1.17; 95% CI, 0.59 to 2.31; P = .65). The genes identified were mainly immune related, involving interferon gamma pathways and specific chemokines, suggesting that their pretreatment expression influences the tumor's immune microenvironment and the patient's clinical response. An 84-gene GS associated with clinical response for MAGE-A3 immunotherapeutic was identified in metastatic melanoma and confirmed in resected NSCLC.

Clark M.A.,Glaxosmithkline
Current Opinion in Chemical Biology | Year: 2010

Over the past 10 years, a handful of academic and industrial research groups have developed strategies for the synthesis and interrogation of DNA-encoded small-molecule libraries. These strategies can be divided into those in which DNA directs small-molecule synthesis and those in which it records the synthesis. These libraries have started to yield novel modulators of biological targets, including: SH3-domain-binding peptoids, macrocyclic peptide-based Bcl-XL/BH3 interaction disruptors, ligands for TNF, albumin, streptavidin and others, and small-molecule kinase inhibitors. The DNA-encoded library field holds the potential to address the general problem of biological ligand discovery, including pharmaceutical lead generation. © 2010 Elsevier Ltd. All rights reserved.

Lane P.W.,Glaxosmithkline
Statistical Methods in Medical Research | Year: 2013

This is a review of methods for the meta-analysis of incidence of rare events using summary-level data. It is motivated and illustrated by the dataset used in a published analysis of cardiovascular safety in rosiglitazone trials. This review compares available methods for binary data, considering risk-difference, relative-risk and odds-ratio scales, fixed-effect and random-effects models, and frequentist and Bayesian approaches. Particular issues in this dataset include low incidence rates, the occurrence of studies with no events under one or all treatments, and discrepancy among results achieved using different statistical methodologies. The common method of adding a correction factor to handle zeroes may introduce bias where the incidence of events is small, as in this case. Alternative analyses on the log-odds scale are shown to give similar results, but the choice between them is less important than the potential sources of bias in any meta-analysis arising from limitations in the underlying dataset. It is important to present results carefully, including numerical and graphical summaries on the natural scale of risk when the analysis is on a statistically appropriate scale such as log-odds: the incidence rates should accompany an estimated ratio (of odds or risk) to put the analysis into the proper context. Beyond the statistical methodologies which are the focus of this paper, this dataset highlights the importance of understanding the limitations of the data being combined. Because the rosiglitazone dataset contains clinically heterogeneous trials with low event rates that were not designed or intended to assess cardiovascular outcomes, the findings of any meta-analysis of such trials should be considered hypothesis-generating. © The Author(s) 2011 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Tough D.F.,Glaxosmithkline
Immunology and Cell Biology | Year: 2012

Production of type I interferon (IFN-α/β) is a common cellular response to virus infection. IFN-α/β has a dual role in combating infection, triggering innate antiviral mechanisms and stimulating the generation of an adaptive immune response. This review focuses on the effects of IFN-α/β on one particular immune cell type, the T cell, and the impact of IFN-α/β-mediated signalling in T cells on the immune response. The critical role of T-cell responsiveness to IFN-α/β for the generation of productive T-cell responses after infections with certain viruses in vivo is discussed in the context of in vitro experiments investigating the mechanisms by which IFN-α/β modifies T-cell function. These studies reveal complex effects of IFN-α/β on T cells, with the consequences of exposure to IFN-α/β depending on the context of other signals received by the T cell. © 2012 Australasian Society for Immunology Inc. All rights reserved.

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