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Chapman M.S.,Biogen Idec | Miner J.N.,Ardea Biosciences
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: The development of new drugs over the last few decades has targeted specific proteins thought to be a key to the disease state. MAPK kinases 1 and 2 (commonly known as MEK1â€"2) represent such proteins as they lie downstream of important drug targets for oncology, such as EGFR, RAS and RAF. Several MEK1â€"2 inhibitors are currently in Phase I and II clinical trials in oncology. Areas covered: This review of current literature and recent conferences provides a background on the RAS-RAF-MEK-ERK signaling pathway and a discussion of early MEK inhibitors. The potential of MEK1â€"2 inhibitors for the treatment of inflammation is briefly presented. Preclinical and early clinical results are discussed for MEK inhibitors currently in development. Completed clinical trials of MEK inhibitors in oncology include some disappointments as well as some promising signs of the value of these compounds and we discuss the potential for MEK inhibitors as monotherapy and their use in drug combinations. Expert opinion: The utility of MEK inhibitors as anticancer agents will depend on careful patient selection based on the presence of mutations in genes such as KRAS and BRAF, the identification of additional predictive biomarkers, and an improved understanding of the benefit of drug combinations utilizing both established and emerging therapeutics. © 2011 Informa UK, Ltd. Source


Wertheimer A.,Temple University | Morlock R.,Ardea Biosciences | Becker M.A.,University of Chicago
Current Therapeutic Research - Clinical and Experimental | Year: 2013

Background: Gout is a chronic, inflammatory arthritis characterized by painful and debilitating acute/episodic flares. Until recently, gout has been regarded as a minor medical problem, in part because the associated economic burden has not been appreciated. Previous literature on this subject focused on the costs associated with acute episodes of gout rather than on the long-term medical and economic implications of this chronic disorder. Objective: Our aim was to estimate the current impact of gout in the United States with respect to disability and economic costs. Methods: The following data sources were used: published data on the incremental economic burden of gout; statistics from the US Census Bureau and the US Bureau of Labor Statistics; and recent epidemiological and clinical literature concerning the course, treatment, and outcomes of the disease. Disability is expressed as days of lost productivity. Charges for gout-related treatments were used as direct cost inputs. Results: Gout affects an estimated 8 million Americans, among whom those working have an average of almost 5 more absence days annually than workers without gout. On average, the incremental annual cost of care for a gout patient is estimated at >$3000 compared with a nongouty individual. Even though comorbidities common in gout patients account for a portion of this increased economic burden, the total annual cost attributable to gout patients in the United States is likely in the tens of billions of dollars and comparable to those of other major chronic disorders, such as migraine and Parkinson's disease. Conclusions: The economic burden of gout is most readily assessable in patients whose acute arthritic flares result in emergency department visits, bedridden days, and episodic loss of productivity. Chronic progression of the disease can also result in long-term impairment of function and health-related quality of life, but the contribution of chronic gout to the economic burden is more difficult to quantitate because gout is frequently associated with serious cardiovascular, metabolic, and renal comorbidities. Recent demonstration that successful gout management can reverse functional deficits in many chronic gout patients, however, supports the views that chronic gout contributes substantially to the medical and thus economic costs of these patients and that early and aggressive efforts to improve gout outcomes are likely to reduce the associated economic burden. © 2013 The Authors. Source


Ives A.,University of Lausanne | Nomura J.,University of Lausanne | Nomura J.,Bio-Medical Research Limited | Martinon F.,University of Lausanne | And 6 more authors.
Nature Communications | Year: 2015

Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1β upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1β release and that XO blockade results in impaired IL1β and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K-AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Patent
Ardea Biosciences | Date: 2014-09-05

This invention concerns N-(2-arylamino)aryl sulfonamides, which are inhibitors of MEK and are useful in treatment of cancer and other hyperproliferative diseases.


Perez-Ruiz F.,Hospital Universitario Cruces | Sundy J.S.,Gilead Sciences | Miner J.N.,Ardea Biosciences | Cravets M.,Receptos | Storgard C.,Ardea Biosciences
Annals of the Rheumatic Diseases | Year: 2016

Objectives To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol. Methods Patients (N = 227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200-600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout. Results Patients (n = 208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p < 0.0001, all doses vs placebo). Similar results were observed in patients with mild or moderate renal insufficiency (estimated creatinine clearance 30 to < 90 mL/min). The incidence of ≥ 1 treatment-emergent adverse event was 46%, 48% and 54% with lesinurad 200, 400 and 600 mg, respectively, and 46% with placebo (most frequent, gout flares, arthralgia, headache and nasopharyngitis), with no deaths or serious adverse events. Conclusions Lesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone. Trial registration number NCT01001338. © 2015 BMJ Publishing Group Ltd & European League Against Rheumatism. Source

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