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THURSDAY, OCTOBER 23
NOVEL APPROACHES FOR NEW THERAPIES
7:30am Morning Coffee
8:35 Chairperson’s Remarks
Peter J. Oates, Ph.D., Research Fellow, CVMED Translational Pharmacology, Diabetes and Diabetic Complications, Pfizer Global Research and Development
8:40 A Systems Biology Approach to Dissecting the Topology of the Insulin Signaling Network
Norbert Perrimon, Ph.D., Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School
Our studies illustrate how we are combining RNA-interference, Mass-Spectrometry, time course gene expression and phosphorylation profiling, and computational analyses to generate a comprehensive network of the Drosophila insulin signaling network.
9:10 Chemical Screening for Modulators of Beta Cell Differentiation and Proliferation
Julia Lamenzo Ph. D., Research Associate, Stem Cell and Regenerative Biology, Harvard University
There are two potential sources of insulin producing beta cells which could potentially be used in transplant therapies similar to the Edmonton protocol: beta cells derived through the differentiation of embryonic stem cells, and beta cells derived through expansion of an existing beta cell population. We have discovered small molecule modulators of beta cell differentiation and proliferation in high-throughput screens with embryonic stem cells and primary beta cells.
9:40 Modeling Complex Mechanisms of Action in Diabetes Therapy
Richard Ho, M.D., Ph.D., Principal, Rosa & Co. LLC
Many therapies in development for diabetes, such as glucokinase modulators, exhibit multiple tissues of action, complex feedback loops in response to therapy, and strong drug interactions with disease pathophysiology. Species-specific metabolic constraints also make extrapolation from animal studies misleading and risky, thus it can be extremely difficult for researchers to understand the dynamic response to such therapies sufficiently well for successful drug development. Quantitative physiological modeling and simulation can be a much cheaper and faster method to explore the key dynamics involved in the mechanism of action for these therapies. Such dynamics play a crucial role in determining dose ranges, responder patient populations, and selection of backup compounds. We find that there are more than enough public data available, especially in metabolism, to develop quantitative models capable of quickly, inexpensively, and reliably yielding valuable insights for diabetes drug development projects.
10:10 Networking Coffee Break in the Exhibit Hall
10:55 Diabetic Complications and the Polyol Pathway: Lessons Learned and a New Paradigm
Peter J. Oates, Ph.D., Research Fellow, CVMED Translational Pharmacology, Diabetes and Diabetic Complications, Pfizer Global Research and Development
Driven by a simple paradigm, the “Osmotic Hypothesis,” and armed with positive pre-clinical results on prototype aldose reductase (AR) inhibitors (ARIs), researchers worldwide have targeted diabetic complications with ARIs for four decades. However, the outcomes of most double-blind placebo-controlled ARI clinical trial have been disappointing. Ironically, the scientific evidence including new human genetic data that AR plays a key pathogenic role in diabetic complications has continued to mount. Evidence is now strong that the Osmotic Hypothesis and the widely employed sorbitol biomarker were misleading and caused underestimation of doses needed for clinical efficacy and overestimation of drug safety margins. Moreover, current recognition of the pathogenic importance of oxidative stress and its strong link to metabolic flux through AR has led to the "Metabolic Flux Hypothesis," which emphasizes the importance of cofactor turnover rather than polyol accumulation. Hopefully, these new insights will lead to novel ARIs that will effectively and safely slow the progression of diabetic complications.
11:25 GPR40 Agonists for the Treatment of Type 2 Diabetes
Daniel Lin, Ph.D., Principal Scientist, Metabolic Disorders, Amgen Inc.
GPR40 is a G-protein coupled receptor that has been shown to be expressed in pancreatic -cells and enteroendocrine cells. Small molecule agonists of GPR40 will be described that improve insulin secretion and post-prandial glucose control and may be useful in the treatment of type 2 diabetes.
11:55 GPR119 Agonists Mediate Glycemic Control via a Glucose Dependent Insulinotropic and Incretinotropic Action
Rob Jones Ph.D., Director, Medicinal Chemistry, Arena Pharmaceuticals
Pancreatic b-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the GLP-1 receptor have shown significant promise as anti-diabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic b-cell mass. These effects are mediated via stimulation of cyclic AMP through b-cell GLP-1 receptors. Here we report that the Gas-coupled receptor GPR119 is largely restricted to insulin-producing b-cells of pancreatic islets together with L-cells of the GI tract, stimulation of GPR119 under hyperglycemic conditions leads to a dual nutrient dependent insulinotropic and incretinotropic effect to maintain glucose homeostasis. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 has proven amenable to the development of potent, orally active, small-molecule agonists. Specific orally active GPR119 agonists may offer significant promise as novel anti-diabetics acting in a glucose-dependent fashion.
12:25pm Luncheon Technology Workshop (Sponsorship Available) or Lunch on Your Own
12:55 Session Break
A CLOSER LOOK AT INCRETINS
1:55 Chairperson’s Remarks
Richard E. Pratley, M.D., Professor of Medicine and Director, Diabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine
2:00 Incretins
Michael R. Hanley, Ph.D., Chief Scientific Officer, Amylin Pharmaceuticals, Inc.
Incretins are glucose-dependent insulinotropes that have emerged as potentially the most powerful class of Type II diabetes therapeutics. Three structural families of incretins will be compared and contrasted: GLP-1, exendin-4, and GIP. Each class has a distinctive pharmacological profile, with varying degrees of additional health benefits, such as weight loss. The future promise of a portfolio of incretin drugs, used as monotherapies or in combination, is compelling.
2:30 Incretin Mimetics: Clinical Perspective and Position in the T2DM Treatment Algorithm
Richard E. Pratley, M.D., Professor of Medicine and Director, Diabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine
This talk will review the clinical data for incretin mimetics on the market or in late-stage development and the evolving role for these agents in the management of type 2 diabetes.
3:00 Networking Ice Cream Refreshment Break in the Exhibit Hall (Last Chance for Viewing)
3:40 GLP-1: Physiology and Therapeutic Potential
Rachele Berria, M.D., M.S.C.I., U.S. Medical Director, Diabetes franchise, Roche Laboratories
The prevalence of type 2 diabetes, as well as obesity, is increasing worldwide. The physiology of GLP-1 and its potential as part of a pharmacological intervention have drawn considerable interest over the most recent years. The known glucoregulatory actions of GLP-1 include enhancement of glucose-dependent insulin secretion, suppression of unsuitably elevated glucagon secretion, slowing of gastric emptying and appetite reduction. Furthermore, weight loss has been a consistent finding both in animal and human studies and makes incretin mimetics a valuable option in the treatment of type 2 diabetes and fighting of obesity.
4:10 PANEL DISCUSSION
The Future of Incretins as a Target for Diabetes
Moderator: Richard E. Pratley, M.D., Professor of Medicine and Director, Diabetes and Metabolism Translational Medicine Unit, University of Vermont College of Medicine
5:10pm Close of Targeting Diabetes with Novel Therapeutics Conference