Targeting Metabolic Disorders 
Event Information
Document Title
Agenda
| Day One Monday, March 17, 2008 | DAY ONE | DAY TWO | DAY THREE | | ||||
| 12:00 | Registration Opens | |||
| 1:20 | Chairperson's Opening Remarks Margaret S. Lee, Ph.D., Vice President, Therapeutic Area Research, CombinatoRx, Incorporated | |||
| Lessons Learned from Challenging Targets | ||||
| Keynote Presentation | ||||
| 1:30 | The TZDs: Lessons Learned in Metabolic and Skeletal Homeostasis TZDs, as a class of drugs that target the nuclear receptor PPAR gamma, entered the market around the turn of the century accompanied by huge expectations. However, over the last three years, both observational and longer-term studies revealed an alarming increase in risk for congestive heart failure, cardiovascular events, and peripheral fractures. What lessons have we learned about drug discovery, and do the benefits of the applied research that came from these agents outweigh the potential harm inherent in the clinical use of these drugs? Clifford J. Rosen, M.D., Senior Scientist, St. Joseph Hospital, Member, FDA Endocrine Advisory Board | |||
| 2:15 | Do Insulin Sensitizers Have a Future? The glitazone insulin sensitizers were the first treatment for diabetes to directly target insulin sensitization. They were discovered as a result of toxicological observation followed by in vivo screening. Early findings showed two potential side effects - water retention and adipogenesis. Despite a massive research effort, no second-generation compound with improved properties has come forward. This talk will focus on the prospects of identifying second-generation compounds that have an enhanced therapeutic index. Michael Cawthorne, Ph.D., Director of Metabolic Research, Clore Laboratory, University of Buckingham, United Kingdom | |||
| 2:45 | The CETP Target - Challenges and Future Progress Abstract to come. Carl Sparrow, Ph.D., Director, Lipid Biochemistry, Merck Research Laboratories | |||
| 3:15 | Structure-Activity Relationship of 5,6-Diaryl-pyrazine-2-amides, A Novel Class of CB1 Receptor Antagonists To further explore the clinical use of CB1 inhibition, we developed 5,6-diaryl-pyrazine-2-amides as a novel class of CB1 antagonists. A scaffold hopping approach has been employed and Structure-Activity Relationships on CB1 potency, selectivity over CB2 have been generated. There are major differences on SARs between 6 and 5 membered scaffolds. Optimal substitution pattern for pyrazine will be discussed. Leifeng Cheng, Ph.D., Principal Scientist, Medicinal Chemistry, AstraZeneca R&D, Sweden | |||
| 3:45 | Networking Refreshment Break | |||
| 4:15 | Resolving Side Effect Problems with PPAR Targets: Case Study of Chiglitazar, A Configuration-Restricted PPAR Pan-Agonist for T2D Now in Human Trials Although edema is believed to be associated with PPARgamma activation, the design of a configuration-restricted PPAR pan agonist with gamma activity may still reduce such side effects while maintaining efficacy on glucose modulation. Similar rational that a configuration-restricted PPAR agonist with alpha and delta activities to benefit lipid modulation in T2D patient can also be separated from potential cardiovascular side effects associated with Avandia. A randomized clinical study in 240 patients demonstrated the safety profile associated with Chiglitazar while demonstrating improvement in efficacy-related endpoints. Xian-Ping Lu, Ph.D., President, and Chief Scientific Officer, Shenzhen Chipscreen Biosciences, Inc., China | |||
| Improving the Efficacy of Metabolic Disease Therapeutics with Drug Combinations | ||||
| 4:45 | CRx-401, a Novel Insulin Sensitizer Discovered Using a Systems Biology Approach Using a systems biology approach to diabetes drug discovery, CombinatoRx has identified a pool of novel synergistic combinations that increase glucose uptake in cellular assays. One combination, CRx-401, has demonstrated preclinical efficacy in decreasing fasting blood glucose and insulin resistance without promoting weight gain. A phase 2a clinical trial of CRx-401 in Type 2 diabetes began in 2007 and this will be discussed in the context of combination clinical trial design. Margaret S. Lee, Ph.D., Executive Director, Therapeutic Area Research, CombinatoRx, Incorporated | |||
| 5:15 | Metformin as a Platform for Combination Drug Therapy of Metabolic Diseases Metformin is an effective first-line treatment for type-2 diabetes without the weight gain and hypoglycemia seen with insulin and some oral glucose-lowering agents. The progression of type-2 diabetes usually requires an add-on therapy approach to maintain glucose control over time. As a first-line therapy with a different mechanism of action from sulfonylureas, thiazolidinediones, and DPP-4 inhibitors, metformin may provide an excellent platform to which antihyperglycemic, antilipedemic, or antihypertensive drugs might be added. Carl A. Pelzel, President and Chief Executive Officer, Depomed, Inc. | |||
| Technology Workshop | ||||
| 5:45 |  High-Throughput Multiplex Biomarker Assays for Obesity, Diabetes and Metabolic SyndromeMeso Scale Discovery has released new assays for metabolic biomarkers. These assays offer superior sensitivity, broad dynamic range and easy workflows that afford high throughput with minimal “hands-on” time. The assays are available as single analyte and multiplex assays and allow one to survey up to 10 biomarkers with as little as 25 microliters of sample. Active GLP-1, total ghrelin, and adiponectin have been added to the existing offering of insulin, glucagon, leptin, and resistin. Robert Umek, Ph.D., Director, Research, Meso Scale Discovery | |||
| 6:15 | Opening of Poster and Exhibit Hall | |||
| Day Two Tuesday, March 18, 2008 | DAY ONE | DAY TWO | DAY THREE | | ||||
| 7:30 | Morning Coffee, Registration Opens | |||
| 8:40 | Morning Chairperson's Opening Remarks Karin Conde-Knape, Ph.D., Research Leader, Metabolic and Vascular Diseases, Roche | |||
| Next Generation Obesity Strategies | ||||
| Keynote Presentation | ||||
| 8:45 | Strategies for the Discovery of Anti-Obesity Drugs: Balancing Risk with Hope Current drugs for obesity fail to fulfill medical need. The least risky route for drug discovery is to seek better drugs that act through similar mechanisms, but we must hope that novel approaches will bring a leap forward in efficacy. The risks and hopes for novel drugs that act through central, gut hormone and peripheral targets are discussed. Michael Cawthorne, Ph.D., Director of Metabolic Research, Clore Laboratory, University of Buckingham, United Kingdom (giving presentation of Jon Arch, Ph.D., Deputy Director of Metabolic Research, Clore Laboratory, University of Buckingham, United Kingdom) | |||
| 9:30 | Targets Affecting Lipid Metabolism as Potential Treatments for Obesity and its Complications Pharmaceutical companies have the challenge to come up with new treatments that will provide a benefit to obese patients not only for weight loss but also for diabetes and dyslipidemia. Targets that affect lipid metabolism have the potential to become the "goldmine" if efficacy and safety parameters are appropriate. This talk reviews some of the challenging targets in terms of efficacy and safety obtained with small molecules. Karin Conde-Knape, Ph.D., Research Leader, Metabolic and Vascular Diseases, Roche | |||
| 10:00 | Ghrelin Receptor Antagonists: Therapeutic Value for Obesity and Diabetes Ghrelin, through action on its receptor GHS-R1a, exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. Piperidine-substituted quinazolinone derivatives were recently identified as a new class of small-molecule GHS-R1a antagonists. These compounds were found to block the inhibitory effects of ghrelin on insulin secretion in vitro and improve glucose tolerance and promote weight loss in vivo in rodent models. William P. Esler, Ph.D., Principal Research Scientist, Diabetes Translational Pharmacology, Cardiovascular, Metabolic and Endocrine Disorders, Global Research & Development, Pfizer Inc. | |||
| 10:30 | Networking Refreshment Break, Exhibit and Poster Viewing | |||
| 11:15 |
Intranasal (IN) delivery of macromolecules has the potential to overcome challenges associated with conventional administration, i.e., injections and oral delivery. To this end, Nastech is developing IN dosages of a variety of therapeutic peptides, including PYY3-36. The PYY3-36 Nasal Spray program will be discussed as an important case study illustrating the challenges and benefits of this delivery strategy. Henry R. Costantino, Ph.D., Chief Scientific Officer, Delivery, Nastech Pharmaceutical Company Inc. | |||
| 11:45 | Gut Hormones and Metabolic Disease New targets for pharmacotherapy in the metabolic disease area include the various regulatory gut peptides. These peptide hormones are some of the most important factors controlling appetite and satiety regulating a complex interplay between energy balance and metabolic derangement. Modulation of these pathways by small molecule ligands holds promise in the treatment of obesity and diabetes. Mausumee Guha, Ph.D., Principal Scientist, Kalypsys Inc. | |||
| 12:15 | Networking Luncheon, Exhibit and Poster Viewing | |||
| 1:40 | Afternoon Chairperson's Opening Remarks Reid Huber, Ph.D., Senior Director, Metabolic Endocrine Drug Development, Incyte Corporation | |||
| Inflammation Targets and Effects | ||||
| 1:45 | From Discovery to the Clinic with XOMA 052: A Novel Anti-IL1β Antibody XOMA designs customized therapeutic monoclonal antibody discovery programs tailored to the specific target biology and guided by the desired product profile. Our success is founded on our antibody technology platform which includes hybridoma technology, proprietary Human Engineering™ technology, antibody optimization technologies, and manufacturing. These unique capabilities create unprecedented opportunities to navigate technical/business considerations. XOMA 052 is a 300fM, high potency anti-IL-1β mAb entering Phase I clinical testing in Type 2 diabetes, whose story will be presented to illustrate the success of this approach from the clinical development perspective. Alan M. Solinger, M.D., FACP FACR, Vice President, Clinical Immunology, XOMA (US) LLC | |||
| 2:15 | Role of Inflammation in Insulin Resistance and Diabetic Heart Increasing evidence indicates the role of chronic inflammation in the etiology of diabetes and its complications. Diet-induced obesity increases macrophages and cytokines and causes insulin resistance in skeletal muscle. Inflammation also affects cardiac insulin action and glucose metabolism that may characterize diabetic heart. Anti-inflammatory strategies may have a beneficial role in treating diabetes and cardiovascular complications. Jason K. Kim, Ph.D., Associate Professor, Department of Cellular & Molecular Physiology, Pennsylvania State University College of Medicine | |||
| Next-Generation Diabetes Targets | ||||
| 2:45 | Mechanisms of SIRT1 Activation for Treating Diabetes These beneficial effects of calorie restriction are likely mediated through activation of the sirtuin, SIRT1. Multiple novel and potent NCEs were identified from several distinct chemical scaffolds that activate SIRT1. These small molecule compounds are currently being investigated as novel treatments for diabetes using in vitro and in vivo models with a goal to initiate additional clinical testing in the near future. A lead molecule, SRT501, is currently being evaluated for safety and PK in Phase I clinical trials. Philip D. Lambert Ph.D., Senior Director, Pharmacology, Sirtris Pharmaceuticals | |||
| 3:15 | Networking Refreshment Break, Last Chance for Exhibit and Poster Viewing | |||
| 3:45 | Proof-of-Concept for 11beta-HSD1 Inhibition in Man: Evidence for Metabolic Improvements in Type 2 Diabetic Subjects after Short-Term INCB013739 Therapy Abstract to come. Reid Huber, Ph.D., Senior Director, Metabolic Endocrine Drug Development, Incyte Corporation | |||
| 4:15 | From Selective PPAR Ligands to PPAR Pan-agonists The PPARs (PPARα, PPARγ and PPARδ) comprise a family of ligand-activated transcription factors belonging to the nuclear receptor gene superfamily. Starting with GW501516, a known PPARδ-selective agonist, and guided by structural studies, a PPAR Pan-agonist series was achieved. The synthetic design, SAR, and in vivo studies for this series are presented, with the in vivo data suggesting that PPAR Pan-agonist treatment may offer distinct advantages over selective traditional PPAR therapy. Stephen W. Rafferty, Ph.D., Principal Scientist, MDR Exploratory Chemistry, GlaxoSmithKline | |||
| 4:45 | A Synthetic Adrenal Androstene with Glucose Lowering and Insulin Sensitizing Properties Diabetic db/db mice given oral TRIOLEX decreased hyperglycemia. In younger animals, it abrogated progression towards hyperglycemia. OGTT showed amelioration of glucose intolerance. Clamp studies showed whole body glucose disposal. DIO mice showed reduced glucose intolerance. Macrophage studies in vitro revealed a partial block of NF-κB translocation with no PPAR transactivation. Clinical trials reveal a promising PK and safety profile. Jaime Flores-Riveros, Ph.D., Vice President, Endocrinology & Metabolism, Hollis-Eden Pharmaceuticals, Inc. | |||
| 5:15 | Close of Day Two | |||
| Day Three Wednesday, March 19, 2008 | DAY ONE | DAY TWO | DAY THREE | | ||||
| 7:30 | Morning Coffee, Registration Opens | |||
| 7:55 | Chairperson's Opening Remarks H. James Harwood Jr., Ph.D., Chief Consultant, Delphi BioMedical Consultants | |||
| Metabolomics and Systems Biology for Metabolic Disease Research | ||||
| Keynote Presentation | ||||
| 8:00 | Comprehensive Metabolic Analysis for Understanding of Chronic Disease Mechanisms Tools for static profiling of intermediary metabolites and measurement of flux in pathways in which the metabolites participate have advanced significantly in recent years. This affords an unprecedented opportunity to define alterations in metabolism that contribute to development of chronic diseases and conditions such as obesity, diabetes, cardiovascular disease (CVD), and cancer. Specific examples of the utility of modern metabolic analysis tools will be provided in the areas of obesity and type 2 diabetes. Christopher B. Newgard, Ph.D., Director, Sarah W. Stedman Nutrition and Metabolism Center, W. David and Sarah W. Stedman Distinguished Professor, Duke University Medical Center | |||
| 8:45 | Mitochondrial Function and Insulin Action in Skeletal Muscle. Application of targeted metabolic profiling tools has led to our finding that both diet-induced and genetic forms of insulin resistance are accompanied by high rates of "incomplete" fat oxidation, intramuscular accumulation of acylcarnitines (byproducts of incomplete substrate oxidation), impaired switching to carbohydrate substrate during the fasted to fed transition, and moderate depletion of several TCA cycle intermediates. These perturbations and the accompanying glucose intolerance are reversed by exercise training and prevented by pharmacological and genetic maneuvers that limit fatty acid import into mitochondria. The role of lipid-induced mitochondrial stress as a potential cause of insulin resistance is discussed. Deborah M. Muoio, Ph.D., Assistant Professor, Departments of Medicine and Pharmacology & Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center | |||
| 9:15 | Regulation of the MAPK Signaling Network Stress stimuli activate the mitogen-activated protein kinase (MAPK) network, which is ultimately under the control of MAPK kinase kinases, or MAP3Ks. It is the MAP3Ks that coordinate the localization, duration and magnitude of MAPK activation in response to cell stress. The integrated activation of the MAPK network to stressors will be presented, with an emphasis on how the balance of signaling through MAP3Ks controls the MAPK response for determination of cell fate. Gary L. Johnson, Ph.D., Professor & Chairman, Department of Pharmacology, University of North Carolina | |||
| Strategies for Reducing Cardiovascular Risks in Cardiometabolic Syndrome | ||||
| 9:45 | Cardiac Dysfunction in Prediabetic Metabolic Syndrome; Is JTV519 (K201) Future Therapy? Obesity and the metabolic syndrome can cause a variety of cardiac and hemodynamic alterations. Hyperphosphorylation of RyR2 contributes to impaired contraction, generation of ventricular arrhythmias and the development of heart failure. Cardio selective beta-adrenoceptor blockers and/or calcium release channel stabilizer JTV519 (K201) treatment would appear to be most effective in not only preventing but also in reversing the myocardial alterations in the metabolic syndrome. U. Deniz Dincer, M.D., Ph.D., Assistant Research Professor, Cellular & Integrative Physiology, Indiana University School of Medicine | |||
| 10:15 | Networking Refreshment Break | |||
| 10:45 | Role of Vasodilating Beta-Adrenoceptor Blockers Beta-adrenoceptor blockers have been shown to achieve and maintain adequate blood pressure control in patients with hypertension. However, these drugs are underused in patients with type 2 diabetes and metabolic syndrome because of possible adverse effects. This discussion will review mechanisms, efficacy and safety of next generation vasodilating beta-adrenoceptor blockers in treatment of hypertension and in reducing cardiovascular risk in the individuals with type 2 diabetes and/or metabolic syndrome. Keshore R.Bidasee, Ph.D., Associate Professor, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center | |||
| Tools to Study and Treat Metabolic Disorders | ||||
| 11:15 | MR Technology to Quantify Body Composition Body composition analysis is important for understanding the pathophysiology of metabolic diseases and the effects of novel drugs. This can now be done with a method based on the nuclear magnetic quantification of proton density in fat and non-fat. The technology (EchoMedical Systems, Houston, TX) is the preclinical gold-standard method for body composition analysis because of its unrivalled precision and accuracy. A scaled-up version is now available for human application that provides body composition measurements in <3min. Derek Nunez, M.A., M.D., FRCP, Director, Metabolic Experimental Medicine, GlaxoSmithKline | |||
| 11:45 | Imaging of Beta Cell Mass Non-invasive assessment of beta cell mass is of great interest to monitor new therapies in the field of diabetes including beta cell proliferation, preservation and transplantation. It may also provide information on beta cells for new therapies in metabolic diseases such as obesity. Examples of PET imaging of beta cell mass will be shown and pros and cons of different methods will be discussed. Lars Johansson, Ph.D., Senior Research Scientist, Discovery Medicine, AstraZeneca R&D, Sweden | |||
| 12:15 | End of Conference | |||
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