The Metabolic Diseases World Summit is a conference that strives to bring together experts from academia, clinical practice and the pharmaceutical industry in an atmosphere with a free flow of information. The Conference also emphasizes the real world realities of drug development and features discussions by professionals in the regulatory and marketing areas of pharmaceutical companies.
Marc Rendell, the Chairperson of the Conference, introduced the keynote speaker, Paul Chew, Vice President of Development of Sanofi Aventis. Chew discussed the characteristics of metabolic syndrome and introduced the role of endocannabinoid receptors in feeding behavior. He explained the efficacy of inhibition of the cannabinoid receptor (CB)1 in reducing caloric intake in rodent models of insulin resistance, including obese (ob/ob) and diabetic (db/db) mice. He showed that rimonabant has been effective in inducing weight loss in obese and diabetic patients. The degree of weight loss is modest, but is associated with improvements in hemaglobin (Hb)A1C and insulin sensitivity, which are greater than expected by weight loss alone. These findings suggest that rimonabant may act at CB1 receptors at multiple tissues to achieve improvements in metabolic syndrome risk factors. Several new long-term studies have started to investigate rimonabant in patients at high risk of cardiovascular disease to see if there are eventual benefits in reduction of serious events.
Peer Jacobson of Abbott Pharmaceuticals discussed several candidate drugs for the treatment of metabolic syndrome. These include acetyl CoA carboxylase inhibitors, Jun-N-terminal kinase and 11β-hydroxysteroid dehydrogenase (HSD) inhibitors. Each of these agents have promising theoretical benefits but have not proven successful in animal models of insulin resistance.
Joseph Grimsby from Hoffman LaRoche reviewed the discovery of glucokinase activators, showing that these agents have been successful in animal models in lowering glucose levels, largely by stimulating insulin release. The glucokinase activators are now in clinical trials.
Robert Mashall from Alinea Pharmaceuticals described the protein tyrosine phosphatase (PTP)1B receptor. This phosphatase is the primary mechanism for downregulating the insulin and leptin signaling systems. Several compounds that inhibit PTP1B have improved glucose and lipid levels and reduced weight gain in animal models.
Jonathan Zalevsky from Xencor described the production of adiponectin analoes. Richard Ho from Johnson and Johnson reviewed biosimulation techniques to model complex physiological models of glucose and insulin dynamics. Harold Wright from the CytRx Corporation explained the new technology of small interfering RNA-mediated gene silencing to identify new target genes in metabolic end points to assess new agents.
There was considerable interest in the possible benefit of suppression of glucocorticoid excess in patients with metabolic syndrome. 11β-HSD1 knockout mice show improved glucose tolerance, decreased triglycerides, decreased weight gain and lower blood pressure. Rolf Thieringer from Merck Laboratories presented several compounds that inhibit adipocyte activity of 11β-HSD1. These agents lowered body weight, improved insulin sensitivity and lowered glucose and triglyceride levels in obese and diabetic mouse models. In addition, he showed reduced atherogenesis in the apoE knockout mouse model and suggested nervous system benefits of 11β-HSD inhibition. Ming Wang from the Amgen Corporation provided similar data showing modest reduction in glucose levels and marked reduction of insulin levels in animals treated with a candidate compound. She provided further information on the structure and mechanism of action of 11β-HSD. Bernice Welles from the DiObex Corporation presented data on the use of ketoconazole to inhibit cortisol production. DiObex is pursuing clinical trials with an enantiomer of ketoconazole to treat diabetes. The potential advantage of the enantiomer is absence of liver toxicity of the enantiomer, which does not interact with the cytochrome P7A system in the liver.
John Mayer presented research at Lilly Laboratories on β-melanocyte-stimulating hormone peptides as agents for weight loss. Several compounds have been chosen for Phase I clinical studies.
There was a focus on the peroxisome proliferator-activated receptor (PPAR) system to develop new agents for the treatment of the metabolic syndrome. David Erbe discussed the theoretical basis for the proven benefits of renin–angiotensin inhibition in improvement of glucose metabolism. He showed data to suggest that the angiotensin II type 1 receptor antagonists telmisartan and candesartan activated PPAR-γ. Anne Reifel-Miller, Chief Scientific Officer at Eli Lilly, discussed the many options for modulation of the PPAR isoforms to develop therapeutic agents. Grant Barish from the Salk Institute presented his research on the PPAR-δ isoform. PPAR-δ agonists show a beneficial effect on atherosclerosis and reduced levels of obesity.
John Rodzvilla of Auxilium Pharmaceuticals highlighted the association between low serum testosterone levels and metabolic syndrome. Hypogonadal men have greater insulin resistance, increased abdominal obesity, higher triglycerides and higher blood pressure than men with normal testosterone levels.
Lori Gowen Morton discussed the use of Regeneron’s Velocigene technology to develop knockout mice models. Using this approach, Morton has analyzed the role of Neuromedin U peptides in the regulation of body weight.
The conference featured state-of-the-art lectures on the clinical management of metabolic syndrome. Rendell introduced the concept of aggressive treatment of postprandial hyperglycemia as the key to improved treatment of hyperglycemia. John Gerich from the University of Rochester School of Medicine reviewed the significance of postprandial hyperglycemia in the genesis of cardiovascular disease and Paresh Dandona from the University of Buffalo discussed the potential mechanisms of vascular damage by glucose elevation following a meal. He demonstrated that ingestion of glucose and lipids upregulates a wide variety of cytokines, thrombotic factors and adhesion molecules. He showed that obesity is characterized by high levels of proinflammatory and prothrombotic factors. Lois Jovanovic from the Sansum Research Insitute explained how the management of diabetic pregnancies is the prototype for the universal management of diabetic glycemia. Dennis Kim and David Parkes from Amylin Pharmaceuticals discussed the use of incretin-like agents to treat postprandial hyperglycemia.
The second day of the conference included a CME Symposium sponsored by Creighton University. Dan Einhorn from the Scripps Whittier Diabetes Institute explained how clinicians today manage metabolic syndrome, given the complexity and controversies of the definition. Jean Claude Desmangles, Assistant Professor of Pediatrics at Creighton University, discussed how metabolic syndrome is affecting children today. He explained that obesity does not have to be present for a diagnosis of metabolic syndrome. The syndrome currently affects 2–4% of children, but the number is increasing dramatically. He suggested that insulin resistance is the cardinal feature of metabolic syndrome in children. He mentioned that puberty is associated with a marked decrease in insulin sensitivity. Jovanovic reviewed her experience in managing pregnant women with metabolic syndrome. She pointed out the importance of exercise in reducing postprandial glucose. John Gerich explained the mechanisms of insulin resistance in metabolic syndrome. He reviewed the benefits of aggressive insulin treatment and presented data showing that hyperinsulinemia lowered the incidence of cardiovascular events, thus rejecting the concept that insulin is atherogenic.
A symposium on the metabolic syndrome and cardiovascular disease followed. Dandona discussed endothelial dysfunction. He showed data demonstrating that insulin is a direct vasodilator acting through nitric oxide, and further showed the benefit of insulin infusion on markers of vascular inflammation. Joel Ray from the University of Toronto presented data on the long-term cardiovascular outcomes of pregnant women with metabolic syndrome. He showed that metabolic syndrome in pregnant women is associated with a high relative risk of later cardiovascular disease. When maternal placental dysfunction is also present, the risk of future heart disease is doubled. Daniel Wilson from Pfizer Inc. suggested that metabolic syndrome is associated with an increased risk of end-stage renal disease, beyond that generated by hypertension alone. Hyperlipidemia may accelerate the progression of renal disease. Hydroxymethyl glutaryl CoA reductase inhibitors may have a protective effect on the kidneys. He explained potential mechanisms for renal protection. Stephen Hong Hsu from Harvard University discussed the public healthcare implications of the metabolic syndrome, as revealed by a study of the population of the Pacific Islands. Ron Grunstein from the University of Sydney described the relationship between metabolic syndrome and the syndrome of obstructive sleep apnea. He presented a study of the benefits of sibutramine-induced weight loss on obstructive sleep apnea.
The final day of the conference was devoted to the approach to the development of new agents. Wick Johnson, Director of Licensing and Development at Pfizer Inc. explained the potential approaches to drugs that will treat multiple components of metabolic syndrome. He explained that obesity and hypertension were the current major concerns for physicians worldwide. He concluded that the major unmet need was to find effective treatments of obesity. Linda Egger from Merck discussed how large pharmaceutical companies pursue licensing opportunities for new agents. She cautioned that there is a declining success rate in new drug development with escalating costs. She explained that there is a focus on building alliances to develop new agents, and illustrated the process with respect to Merck interactions with other companies. Jill Fujisaki from Entelos discussed how important alliances are to developing companies. Ralph Loren, Senior Counsel to Edwards Angell Palmer and Dodge, explained patent considerations for metabolic agents. He reviewed the complexity of developing distinctive definitions.