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Targeting Diabetes With Novel Therapeutics - Day 1


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7:00am – 6:00pm Registration Open


2:00pm Chairperson’s Remarks 
Jesper Gromada, Ph.D., Head of Discovery Biology, Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Inc. 

2:10 FGF-21 for the Treatment of Type 2 Diabetes 
Jesper Gromada, Ph.D., Head of Discovery Biology, Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Inc.
Fibroblast growth factor 21 (FGF-21) is a recently discovered metabolic regulator. FGF21 activity depends on beta-klotho, a single-pass transmembrane protein. Beta-klotho physically interacts with FGF receptors 1c and 4. FGF-21 stimulates glucose uptake in adipocytes, reduces glucagon secretion and lowers blood glucose and triglyceride levels when administrated to diabetic rodents and monkeys. FGF-21 also preserves pancreatic insulin content and beta cell mass when administered to diabetic mice. Finally, FGF-21 protects animals from diet-induced obesity when overexpressed in transgenic mice. These data suggest that FGF-21 might offer a promising new therapeutic approach to treat type 2 diabetes.

2:40 11beta-HSD1 Inhibition as an Entrée to Cardio-Metabolic Benefit in Type 2 Diabetes
Reid Huber, Ph.D., Senior Director, Metabolic Endocrine Drug Development, Incyte Corporation
Excess cortisol action has been proposed to underlie several cardiovascular risk factors observed in type 2 diabetes, namely insulin resistance, hyperlipidemia, hypertension, and abdominal obesity.  The enzyme 11beta-HSD1 catalyzes the tissue-specific, intracellular conversion of biologically inactive cortisone to biologically active cortisol.  Emerging preclinical and clinical data indicate that 11beta-HSD1 inhibitors may provide a means to achieve both microvascular and macrovascular benefit in patients with type 2 diabetes.

3:10 Antidiabetic Effects of Glucokinase Activators: From Benchside to Bedside
Joseph Grimsby, Ph.D., Senior Research Leader, Metabolic Diseases, F. Hoffmann-La Roche Inc.
Glucokinase (GK) plays a key role in glucose homeostasis by controlling the rate of glucose metabolism in many tissues.  In pancreatic b-cells GK acts as a molecular sensor for glucose stimulated insulin release (GSIR) and in hepatocytes it catalyzes the first step of glucose metabolism.  The relationship between changes in GK activity and fasting plasma glucose in humans with GK diseases has been well established for both loss and gain of function mutations.  Such strong biological rationale for targeting GK as a potential antidiabetic therapy led to the discovery of small molecule allosteric GK activators (GKAs).  GKAs bind to an allosteric site 20 Å away from the bound glucose site and act as non-essential mixed-type enzyme activators.  GKAs that increase Vmax and decrease [S]0.5 augment glucose metabolism and lower the threshold of GSIR in normal and T2D human islets.  Animals treated acutely and chronically with GKAs show improvements in basal and post-prandial glucose levels.  Evidence suggests that the glucose lowering effects in rodents are mediated by dual effects on increasing plasma insulin levels and suppression of hepatic glucose levels as assessed by a pancreatic clamp.  Early data in humans will be presented. GKAs offer a promising new therapeutic approach to treat T2D. 

3:40 Networking Refreshment Break in the Exhibit Hall

4:20 Discovery of a Second Generation FBPase Inhibitor, MB07803, with Reduced Metabolism, Improved Oral Bioavailability, and Clinical POC in Type 2 Diabetic Patients
Max Dang, Ph.D., Director, Medicinal Chemistry, Metabasis Therapeutics, Inc.
MB07803 is the first FBPase inhibitor achieving clinical POC in type 2 diabetic patients. Inhibition of FBPase led to direct control of the overactive gluconeogenesis in type 2 diabetic patients, therefore representing a promising new treatment.

4:50 Technology Watch (Sponsorship Available) 

5:20 SGLT2 Inhibition:  A Novel Approach to the Treatment of Type 2 Diabetes
Jean Whaley, Ph.D., Director, Diabetes Drug Discovery, Bristol-Myers Squibb Co.

The inhibition of renal sodium-glucose cotransport via inhibition of SGLT2 promotes the excretion of glucose into the urine and represents a new therapeutic approach to treat hyperglycemia. Relatively nonselective SGLT inhibitors such as phlorizin have beendemonstrated to improve insulin sensitivity and reduce elevated endogenous glucose production in diabetic animal models by the correction of glucotoxicity. Dapagliflozin, a novel SGLT2 inhibitor under clinical investigation, was identified in a drug discovery program which focused on the identification of stable, potent inhibitors of SGLT2 that were selective vs. SGLT1 and major GLUT isoforms. Dapagliflozin produces robust glucosuria in both rodents and humans, and has been shown to reduce fasting and postprandial glucose levels in type 2 diabetic patients. The preclinical and emerging clinical profile of dapagliflozin will be discussed.

5:50 Managing Diabetes with an Amylin Mimetic: A Step Closer to Restoring Normal Physiology
Elaine Chiquette, Pharm.D., BCPS, Senior Medical Science Liaison, Medical Affairs, Amylin Pharmaceuticals Inc.
Despite its potency, insulin replacement therapy still fails to normalize glucose control in the majority of patients with diabetes. Furthermore, it is associated with increased risk of hypoglycemia, weight gain, and excessive diurnal glucose fluctuations. Amylin is the other b-cell hormone, co-secreted with insulin in response to meals, and is deficient in patients with type 1 and late-stage type 2 diabetes. Amylin replacement with pramlintide, as an adjunctive therapy to insulin, is an approach that fulfills some of the unmet clinical needs of insulin-using patients with type 1 and type 2 diabetes.

6:20pm End of Day


Click the links below to
view Discovery On Target 2008
Targeting RB