Prasad B.,University of Washington |
Johnson K.,University of Washington |
Billington S.,University of Washington |
Lee C.,Ardea Biosciences |
And 5 more authors.
Drug Metabolism and Disposition | Year: 2016
Protein expression of renal uptake and efflux transporters was quantified by quantitative targeted proteomics using the surrogate peptide approach. Renal uptake transporters assessed in this study included organic anion transporters (OAT1-OAT4), organic cation transporter 2 (OCT2), organic/carnitine cation transporters (OCTN1 and OCTN2), and sodium-glucose transporter 2 (SGLT2); efflux transporters included P-glycoprotein, breast cancer resistance protein, multidrug resistance proteins (MRP2 and MRP4), and multidrug and toxin extrusion proteins (MATE1 andMATE2-K). Totalmembranewas isolated from the cortex of human kidneys (N = 41). The isolated membranes were digested by trypsin and the digest was subjected to liquid chromatography-tandem mass spectrometry analysis. The mean expression of surrogate peptideswas as follows (given with the standard deviation, in picomoles per milligram of total membrane protein): OAT1 (5.3 ± 1.9), OAT2 (0.9 ± 0.3), OAT3 (3.5 ± 1.6), OAT4 (0.5 ± 0.2), OCT2 (7.4 ± 2.8), OCTN1 (1.3 ± 0.6), OCTN2 (0.6 ± 0.2), P-glycoprotein (2.1 ± 0.8), MRP2 (1.4 ± 0.6), MRP4 (0.9 ± 0.6), MATE1 (5.1 ± 2.3), and SGLT2 (3.7 ± 1.8). Breast cancer resistance protein (BCRP) and MATE2-K proteins were detectable but were below the lower limit of quantification. Interestingly, the protein expression of OAT1 and OAT3 was significantly correlated (r > 0.8). A significant correlation was also observed between expression of multiple other drug transporters, such as OATs/OCT2 or OCTN1/OCTN2, and SGLT2/OCTNs, OCT, OATs, and MRP2. These renal transporter data should be useful in deriving in vitro to in vivo scaling factors to accurately predict renal clearance and kidney epithelial cell exposure to drugs or their metabolites. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
News Article | November 1, 2016
SAN DIEGO, Nov. 01, 2016 (GLOBE NEWSWIRE) -- Organovo Holdings, Inc. (NASDAQ:ONVO) (“Organovo”), a three-dimensional biology company focused on delivering scientific and medical breakthroughs using its 3D bioprinting technology, today announced that it has received a strong customer response for its second tissue service, the ExViveTM Human Kidney Tissue. This kidney proximal tubule model was launched in September, and is a natural expansion of the Company’s preclinical product and service portfolio. Customers use Organovo’s 3D bioprinted kidney tissue to study the effects of drug exposure through toxicology panels and transporter studies. The Company already has multiple commercial orders from several customers, including with two, global, top 25 pharmaceutical companies. “Nephrotoxicity is a key concern in drug development and the proximal tubule is the primary site of renal toxicity,” said Dr. Caroline Lee, senior director, Ardea Biosciences, Inc. “Specifically, transporters in the proximal tubule play a crucial role in the distribution and accumulation of drugs in the kidney. The ExVive Human Kidney Tissue provides an ideal means to study the impact of renal transporters on the disposition of drugs because it closely resembles native human kidney proximal tubule, with its polarized renal epithelial cells and tubulointerstitial interface and in particular its native expression level of transporters enabling formation of the transport network.” Ardea Biosciences, Inc. is a wholly-owned subsidiary of AstraZeneca PLC. "At La Jolla Pharmaceutical Company, we incorporate in vitro models to assess nephrotoxicity in the preclinical stage of drug development,” said Dr. Andrew Seacat, director, preclinical development, La Jolla Pharmaceutical Company. “Early safety prediction of compounds is challenging and many drugs fail in the clinic because of renal toxicity. Organovo has developed an in vitro human kidney tissue model that allows for study of renal toxicity, biomarker expression, and overall cellular and tissue health following compound exposure. La Jolla currently utilizes the ExVive Human Kidney Tissue model to assess the renal impact of our compounds during development.” About Organovo Holdings, Inc. Organovo designs and creates functional, three-dimensional human tissues for use in medical research and therapeutic applications. The Company develops 3D human tissue models through internal development and in collaboration with pharmaceutical, academic and other partners. Organovo's 3D human tissues have the potential to accelerate the drug discovery process, enabling treatments to be developed faster and at lower cost. The Company’s ExVive Human Liver and Kidney Tissues are used in toxicology and other preclinical drug testing. The Company also actively conducts early research on specific tissues for therapeutic use in direct surgical applications. In addition to numerous scientific publications, the Company's technology has been featured in The Wall Street Journal, Time Magazine, The Economist, Forbes, and numerous other media outlets. Organovo is changing the shape of life science research and transforming medical care. Learn more at www.organovo.com. Any statements contained in this press release that do not describe historical facts constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations, but are subject to a number of risks and uncertainties. The factors that could cause the Company’s actual future results to differ materially from current expectations include, but are not limited to, risks and uncertainties relating to the Company’s ability to develop, market and sell products and services based on its technology; the expected benefits and efficacy of the Company’s products, services and technology; the market acceptance of the Company’s products and services; the Company’s business, research, product development, regulatory approval, marketing and distribution plans and strategies; the Company’s ability to successfully complete the contracts and recognize the revenue represented by the contracts included in its previously reported total contract bookings and secure additional contracted collaborative relationships; the final results of the Company’s preclinical studies may be different from the Company’s studies or interim preclinical data results and may not support further clinical development of its therapeutic tissues; the Company may not successfully complete the required preclinical and clinical trials required to obtain regulatory approval for its therapeutic tissues on a timely basis or at all; the risk of further adjustments to the Company’s select preliminary financial results for the second quarter of fiscal 2016; and the Company’s ability to meet its fiscal year 2017 outlook and/or its long-range outlook. These and other factors are identified and described in more detail in the Company’s filings with the SEC, including its Annual Report on Form 10-K filed with the SEC on June 9, 2016, its Quarterly Report on Form 10-Q filed with the SEC on August 4, 2016 and other filings with the SEC. You should not place undue reliance on these forward-looking statements, which speak only as of the date that they were made. These cautionary statements should be considered with any written or oral forward-looking statements that the Company may issue in the future. Except as required by applicable law, including the securities laws of the United States, the Company does not intend to update any of the forward-looking statements to conform these statements to reflect actual results, later events or circumstances or to reflect the occurrence of unanticipated events.
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.
News Article | November 7, 2016
There are many reasons why promising drug compounds fail in the early stages of development, but many see inefficiency as a culprit. In fact, the Obama administration’s FY 2017 budget proposes to give the Secretary of HHS authority to require drug manufacturers to publicly disclose certain information, including research and development costs. Presumably this is intended to root out inefficiency, putting added pressure on manufacturers. R&D labs should and do feel the pressure too. Laboratory efficiency will be scrutinized even more in the coming months and years, creating an unprecedented sense of urgency. But the question is where to start. To help labs get started, we’ve identified five problem areas that, when addressed, will have an immediate impact on efficiency and productivity. Sample management procedures are critical to good laboratory practices (GLP) compliance and must be enforced. Audit trails must be documented, and even sample storage conditions must be monitored. Future defensibility is nearly impossible without this. And, finally, where defensibility is slow or unreliable, efficient drug development is at risk. Laboratory information management systems (LIMS) that are unfit for sample management simply cannot provide answers reliably or rapidly. Fortunately, LIMS have evolved from their roots as basic sample management and data reporting tools. Today, LIMS are capable of continuously and purposefully organizing everything required for traceability and for rapid retrieval, analysis and reporting. San Diego-based Ardea Biosciences adopted Thermo Fisher’s LIMS software as the biotechnology company underwent its transition from a preclinical development team, where only handfuls of samples are analyzed, to a translational science group, responsible for analyzing thousands of samples from very large clinical programs. “Management of samples was the primary reason we adopted a LIMS,” said Senior Director David M. Wilson, Ph.D. “The ability to adequately inventory, track and report our results from many late-stage studies, some with more than 10,000 samples, was critical and not something that could be accomplished using basic spreadsheets or paper-based methods.” Measurement traceability is hard. A single laboratory is responsible for hundreds of tests each week, and adhering to GLP and Standard Operating Procedures requires discipline that goes beyond a single test. To defend results, technicians must painstakingly retrace all steps aligned with a test, and many of these are deeply embedded in the fabric of the lab – they are now routine for technicians. When defense is necessary, however, technicians can spend a quarter of their productive time sifting through these steps to defend results. When traceability steps take place in the background, however, labs can dramatically reduce the time and expense of defensibility. “Watson reports enable us to ensure that samples are analyzed within proven stability and to determine gaps before quality inspections by tracking sample freeze-thaws, time on the bench and storage duration,” says Wilson. Too many labs focus on solving errors retrospectively. But this is far less effective than predicting and preventing errors – even small ones. Errors that mask QA/QC problems, for example, can mushroom into larger and systemic quality issues or create productivity gaps that eventually require costly method rework. But knowing whether an experiment is failing – or soon will be – is challenging. Ardea’s Wilson recognizes the need for statistical quality control (SQC) to discern trends in GC data before they reach pre-defined thresholds. “The use of standard working solutions over and over is prone to evaporation and concentration effects. In situations where a set of working solutions might be used over a long period of time, but in serially-conducted studies, tracking standard slopes from individual study start to study end doesn’t tell the whole story,” he says. “Using SQC over multiple studies can easily provide the opportunity to identify assay performance changes over time and at a glance.” Standard operating procedures (SOPs) are critical to GLP compliance and other regulatory requirements. Inconsistent application of procedures in clinical and pre-clinical labs can put the company at risk with regulators and jeopardize progress toward development and commercialization. Increasingly, electronic SOPs (ESOPs) are a lab’s defense against staff violating procedures. With SOPs defined in a LIMS, for example, a rigid workflow exists with clearly defined technical corrective actions that ensure consistency and adherence to protocol. If these don’t exist – or the paper SOPs aren’t handy, clear or widely understood – it’s too easy for analysts to err. The good news is that technology, including LIMS, has reached a point where managing SOPs is easier and more efficient than ever. “Standardization and structured workflows driven by Watson have meant that SOPs are more clearly written so ambiguities or individual variances in work streams are no longer considerations,” says Wilson. Drug development is now highly decentralized. Analysis is often spread across different geographies and partners, including contract research organizations that provide industrywide agility. Keeping research on track across complex networks of instruments, SOPs and methods is challenging, if not impossible. Instrument incompatibility, including issues with calibration, maintenance and other factors, can derail development. Costly delays can rapidly escalate into much larger problems that impact drug development. But instrument incompatibility is solvable, especially since the requirements are uniform, regardless of location. Within a LIMS, SOPs can be specified and tracked, throughput can be closely monitored, and instruments can undergo constant and rigid conformance based on predefined maintenance schedules. Doing this will ensure consistency and reliability. If there’s one takeaway from this article, let it be that you should indeed sweat the small stuff because it will compound over time. Or better yet, let your LIMS help you manage everyday problems that cause inefficiencies and lapses in productivity, making your lab a model lab that can easily withstand the increased scrutiny that is sure to come.
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.
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.
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.
Manthripragada A.D.,Amgen Inc. |
O'Malley C.D.,Amgen Inc. |
Gruntmanis U.,University of Texas Southwestern Medical Center |
Hall J.W.,Ardea Biosciences |
And 2 more authors.
Osteoporosis International | Year: 2015
Methods: Using US administrative claims data, we identified 43,813 men ≥30 years old with an osteoporosis diagnosis or use of an osteoporosis medication. Men were followed for a minimum of 12 months after diagnosis or treatment of osteoporosis (index date), until the earliest of fracture (hip, spine, pelvis, distal femur, humerus, wrist, forearm), disenrollment, or study end date.Summary: In this large retrospective study of men with presumed osteoporosis, we estimate the rate of osteoporosis-related fractures in men age ≥30 years. Our results suggest that spine and hip fractures continue to be a considerable disease burden for osteoporotic men of all ages.Introduction: The purposes of this study were to describe a cohort of men with presumed osteoporosis and estimate the incidence rates of fractures by age.Results: During the study period, there were 3834 first fractures following the index date and 3303 fractures in the 6-month period prior to the diagnosis/treatment of osteoporosis. Incidence rates of osteoporosis-related fracture, estimated from the index date onward, increased with age, although did not significantly differ from one another in younger age groups (30–49 and 50–64 years). Spine fractures had the highest incidence rate in men across all age groups, increasing from 10.8 per 100,000 person-years (p-yrs) (95 % confidence interval (CI) 9.1, 12.7), 12.2 per 100,000 p-yrs (95 % CI 11.2, 13.3), and 15.3 per 100,000 p-yrs (95 % CI 13.8, 16.9) in men 30–49, 50–64, and 65–74 years to 33.4 per 100,000 p-yrs (95 % CI 31.5, 35.4) in men ≥75 years. Hip fractures were the second most common, with the incidence rate reaching 16.2 per 100,000 (95 % CI 14.9, 17.6) in the ≥75-year group.Conclusion: These incidence rates suggest that spine and hip fractures are a considerable disease burden for men of all ages diagnosed and/or treated for osteoporosis. © 2015, International Osteoporosis Foundation and National Osteoporosis Foundation.
Girardet J.-L.,Ardea Biosciences |
Miner J.N.,Ardea Biosciences
Annual Reports in Medicinal Chemistry | Year: 2014
Gout is a chronic, inflammatory arthritic condition resulting from monosodium urate crystal deposition in joints and tissues, which develop because of high levels of serum uric acid. Gout treatment includes short-term approaches for acute gout attacks (gout flares) and long-term approaches for treating hyperuricemia. Acute gout therapy focuses on rapid inhibition of pain and inflammation resulting from the inflammatory response to monosodium urate crystal deposition. Most commonly prescribed acute gout therapies in the United States are NSAIDs, colchicine, and corticosteroids. Optimal treatment of gout also includes approaches to address chronically high uric acid levels. Therapeutic approaches to address gout-associated hyperuricemia include inhibiting production of uric acid using xanthine oxidase inhibitors, degrading uric acid with recombinant uricase, and increasing uric acid excretion using older uricosuric agents and newer selective uric acid reabsorption inhibitors. The recent surge of research in this area brings with it the potential for new targets and therapeutic combinations. © 2014 Elsevier Inc.
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.