Reporter: Aviva Lev-Ari, PhD, RN
Diabetes Drug Discovery and Beyond
October 1-3, 2012
The Diabetes Drug Discovery and Beyond meeting will cover progress on promising pre-clinical and early clinical phase diabetes drug candidates. But this year, we will also highlight emerging therapeutic targets that probe how the underlying defects in metabolic diseases are connected. Some presentations will cover obesity, other metabolic disorders and cardiovascular disease in the context of diabetes and energy homeostasis.
TUESDAY, OCTOBER 2
TARGETS FOR NEW DIABETES THERAPIES
1:30 pm Chairperson’s Remarks
Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer
| 1:40 FEATURED SPEAKER
Targeting Diabetes via Glucocorticoid Modulation: The Identification of Advanced 11b-HSD-1 Inhibitors
Preventing excess glucocorticoid tone in metabolically active tissues such as the liver and adipose may be beneficial in addressing glucose homeostasis and hyperglycemia in patients with type 2 diabetes. We have optimized a series of triazolopyridine based inhibitors resulting in the advancement of BMS-770767 to phase 2 clinical trials. The discovery of BMS-770767 will be presented as well as a description of its development properties, pharmacokinetics, and pre-clinical pharmacology profile. |
Jeffrey A. Robl, Ph.D., Executive Director, 2:10 Dyslipidemia Targets and Diabetes
Rebecca Taub, M.D., CEO, Madrigal Pharmaceuticals
This talk will defining diabetic dyslipidemia and discuss how elevated VLDL, triglycerides and fatty liver might contribute to diabetic CV disease. Novel dyslipidemia mechanisms to treat diabetic dyslipidemia including THRbeta agonists will also be covered.
2:40 Effects of PF-04620110, a Novel Diacylglycerol Acyl-Transferase 1 (DGAT1) Inhibitor on Healthy-Obese Volunteers and Type 2 Diabetic Subjects
Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer
Inhibition of DGAT1, the terminal enzyme in the synthesis of triglycerides (TG), has been proposed for the treatment of type 2 diabetes (T2DM). We sought to examine the effects of a potent and selective DGAT1 inhibitor, PF-04620110, on vitamin A absorption, TG, glucose, insulin and total amide glucagon like peptide-1 (GLP-1) levels in both healthy-obese volunteers and Type 2 Diabetic subjects. The results of these studies will be presented.
3:10 Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 Pharmacological Manipulation of Diacyl Glycerol Acyl Transferase 1 Using Pre-Clinical Models
Shirly Pinto, Ph.D., CVD – Atherosclerosis Team Lead, Merck Research Laboratories
4:15 Sponsored Presentations (Opportunities Available)
4:45 Beneficial and Adverse Effects of Glucokinase Activators on Glucose Metabolism in Rat Liver Cells
Gabriel Baverel, Ph.D., CEO and CSO, Metabolomics, Metabolys, Inc.
Using a metabolic flux approach, we show the potential beneficial and adverse effects of three gluco-kinase activator drug candidates for type2 diabetes. We report the gluco-kinase activators’ effects on glucose utilization and production, glycogen synthesis and degradation, lactic acid and triglyceride accumulation and on the citric acid cycle during glucose metabolism in rat liver cells. Our work illustrates the advantage of metabolic flux analysis for predicting early during the drug development process, both the efficacy and safety of very small amounts of antidiabetic drug candidates.
5:15 Connecting Mitochondrial Dysfunction and Diabetes
James Dykens, CEO, Eyecyte Therapeutics
Mitochondrial dysfunction contributes via bioenergetic and oxidative mechanisms to a host of degenerative and metabolic diseases, including diabetes. Mitochondrial Ca2+ dynamics alter insulin release, while production of free radicals yields dysregulation of glycolysis. Importantly, xenobiotic therapies for diabetes, e.g., biguanides and thiazolidinediones, directly undermine mitochondrial function thereby lowering blood glucose, albeit via an untoward mechanism. The latter results from cell culture conditions that model diabetes and anaerobic poise, not normal aerobic physiology.
5:45 End of Day
WEDNESDAY, OCTOBER 3
| 8:00 am Interactive Breakfast Breakout Discussion Groups
Targeting GPCRs Moderator: Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.
Cardiovascular Challenges Moderator: Rebecca Taub, CEO, Madrigal Pharmaceuticals
Better Diabetes Models and Markers Moderator: Jerome J. Schentag, PharmD, Professor of Pharmaceutical Sciences, University at Buffalo
|
TARGETING MEMBRANE PROTEINS FOR TYPE2 DIABETES
9:05 Chairperson’s Remarks
Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.
| 9:10 FEATURED PRESENTATION
Discovery of Ertugliflozin: An Anti-Diabetic Agent from a New Class of SGLT2 Inhibitors
Inhibition of sodium-dependent glucose co-transporter 2 (SGLT2), located in the kidney, promotes reduction of plasma glucose concentration. The medicinal and synthetic organic chemistry rationale that led to the rapid identification of Ertugliflozin (PF-04971729), an anti-diabetic agent currently in development and belonging to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane bridged ketal motif, will be presented. |
Vincent Mascitti, Ph.D., Senior Director, Pfizer Global R&D9:40 Targeting FGF21 for Type 2 Diabetes
Andrew C. Adams, Ph.D., Post-Doctoral Research Fellow, Diabetes Research, Lilly Research Laboratories
10:10 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 Update on the Clinical Candidate ARRY-981: A GPR119 Agonist
Brad Fell, Senior Research Investigator, Medicinal Chemistry, Array BioPharma
GPR119 is a promising new target for the treatment of type 2 diabetes. Agonists of this GPCR, which promote insulin secretion from pancreatic ß-cells and GLP-1 release from enteroendocrine L-cells, provide a unique opportunity for a single drug to elicit insulin secretion via two distinct pathways. However, several GPR119 agonists have recently demonstrated poor clinical efficacy. We will discuss our novel GPR119 clinical candidate, ARRY-981, that has shown meaningful and durable glucose control in preclinical models of diabetes.
11:25 Inflammation, Obesity and Diabetes: Pre-Clinical Investigations of a CCR2 Antagonist
Dana Johnson, Ph.D., Senior Scientific Director, Drug Discovery, Janssen Pharmaceuticals, Johnson & Johnson
With the growing idea of insulin resistance due, in part, to low grade systemic inflammation, mechanistic investigations aimed at altering inflammatory tone have been undertaken by us as well as others. Recruitment of the macrophage and continued activity in the adipose tissue appears to drive insulin resistance, in part, via the secretion of Moncocyte Chemoattractant Protein 1 (MCP-1) and its cognate receptor C-C Chemokine Receptor-2 (CCR2). Our efforts in disrupting the macrophage recruitment via the use of CCR2 antagonists will be presented.
11:55 Monoclonal Antibody Antagonists of the Glucagon Receptor as Therapeutic Agents
Bernard B. Allan, Ph.D., Scientist, Department of Molecular Biology, Genentech, Inc.
Excess glucagon signaling plays a key role in the development of hyperglycemia in type 1 and type 2 diabetic patients. We have generated potent anti-glucagon receptor antagonist antibodies and will present the mechanisms underlying their anti-diabetic activities in pre-clinical models, including their direct effects on hepatic glucose metabolism and indirect effects on beta-cell mass.
12:25 pm Sponsored Presentation (Opportunity Available)
12:40 Luncheon Workshop (Sponsorship Opportunity Available) or Lunch on Your Own
NEW THERAPEUTIC APPROACHES
1:55 Chairperson’s Remarks
Jesper Gromada, Ph.D., Executive Director, Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research
2:00 XMetA, an Allosteric Agonist Antibody to the Insulin Receptor that Selectively Activates Insulin Receptor Metabolic Signaling and Restores Glycemic Control in Mouse Models of Diabetes
John Corbin, Ph.D., Associate Director, Molecular Interactions and Biophysics, Preclinical Research, XOMA
The XMetA antibody represents novel drug class for the treatment of diabetes. XMetA has unique properties including selective partial agonism of insulin receptor metabolic signaling resulting in improvements in the disease state of both hyperinsulinemic insulin resistant and insulinopenic diabetic animals. The in vitro and in vivo data to be presented for XMetA will provide a clear demonstration of how allosteric modulation of the insulin receptor with a monoclonal antibody can translate to improvements in disease.
2:30 Phenotype-Driven Approaches towards Novel Beta-Cell Proliferative and Protective Therapies
Bryan Laffitte, Ph.D., Associate Director, Genomics Institute of the Novartis Research Foundation
Type 1 and type 2 diabetes are characterized by a loss of beta cell mass. However, therapeutic options aimed at preservation or restoration of endogenous beta cell mass, are not currently available. We used phenotypic screening approaches for both small molecule and biologic agents to identify regulators of beta cell survival and beta cell proliferation. We report on several series of small molecules that induce beta cell proliferation and/or protect beta cells from various forms of stress and have potential as therapeutic options for both type 1 and type 2 diabetes.
3:00 Refreshment Break in the Exhibit Hall with Poster Viewing
3:40 Gastric Bypass in Mice as a Model for Target Identification
Vincent Aguirre, M.D., Ph.D., Assistant Professor, Internal Medicine, University of Texas Southwestern Medical Center
We will discuss a mouse model of gastric bypass, which recapitulates effects of this procedure on body weight, body composition, glucose homeostasis, and stool energy observed in humans. The reproducibility of this model allows high-resolution comparison of effects of gastric bypass across genetic models using advanced methodologies, such as MRS metabolic flux, proteo metabolomics, and deep sequencing. As such, it enables targeted investigation of bypass-induced biological pathways and refined identification of novel pharmaceutical targets capable of mimicking beneficial effects of bariatric surgery.
4:10 Cell-Based Therapies to Treat Diabetes
Norma Kenyon, Ph.D., Professor of Surgery, Microbiology and Immunology and Biomedical Engineering; Executive Director of the Wallace H. Coulter Center for Translational Research; School of Medicine, University of Miami
This presentation will focus on the role of stem cell-based therapies to treat diabetes, highlighting the therapeutic potential of mesenchymal stem cells in diabetes. Our research group’s focus is on ways to transplant islet cells without the need for anti-rejection drugs, including the incorporation of stem cells into transplant protocols.
4:40 Discovery of Lorcaserin: A Selective 5-HT2C Agonist for Weight Management
Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals, Inc.
Compelling evidence suggests that drugs which activate the 5-HT2C receptor cause weight loss and thus have potential for use as weight management agents. Because serotonin elicits a number of biological responses through modulation of other 5HTrelated proteins, selectivity was a critical challenge particularly with respect to the closely related 5-HT2A and 5-HT2B receptors. This presentation outlines some of events, challenges and achievements that led to the discovery and development of lorcaserin.
2012pharmaceutical
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