Ghrelin is a key metabolic regulator that is known to stimulate appetite and food consumption and is believed to play a key role in metabolism and energy storage. Ghrelin is a naturally occurring hormone secreted by the stomach, which acts primarily at the level of the hypothalamus in the brain.
In the first presentation, Elixir scientists explored whether ghrelin exerts a direct effect on adipocytes (fat cells) and if the effect is mediated through ghrelin receptor (GhrR) mRNA expression in these cells. To assess this, the scientists first examined ghrelin signaling by measuring insulin sensitivity in mouse adipocyte cell lines that were treated with ghrelin for four days. Scientists also assessed the expression of GhrR mRNA in adipose tissue, isolated adipocytes from mice, and the mouse adipocyte cell-line. The results showed GhrR was detected in the isolated adipocytes and mouse adipocyte cell lines, suggesting ghrelin acts directly through its receptor on adipocytes to regulate energy homeostasis. Moreover, the reduction of insulin signaling in adipocytes by chronic ghrelin treatment provides a possible mechanism for increased insulin sensitivity in GhrR knockout mice.
In two additional tandem presentations, Elixir scientists showed that, compared to control mice, GhrR knockout mice resisted the development of diabetes and obesity ass ociated with a high-fat diet. The presentations further showed that treatment of wild type diabetic and obese mice with a small molecule ghrelin antagonist recapitulated the effects seen in the knockout mice.
In a first series of experiments, Elixir scientists examined the impact of a high-fat diet on fuel utilization and metabolic flexibility in GhrR knockout mice. Increased metabolic flexibility is associated with increased insulin sensitivity and a resistance to diabetes. As expected, long-term exposure to a high-fat diet caused an overall decrease in metabolic flexibility in the wild type mice; however, this trend was reversed in the GhrR knockout mice fed the same diet.
In another series of experiments, GhrR knockout mice were fed a high-fat diet for 15 weeks, with their body weight and food intake monitored throughout the experiment. The results showed after 15 weeks on the diet, the GhrR knockout mice gained 10 percent less weight than the wild type control mice. Additionally, the knockout mice had lower blood glucose, insulin and HbA1c levels. These results indicate the knockout mice are less prone to the development of diabetes.
The scientists then compared the results of the GhrR knockout mice to those obtained with mice treated twice a day for up to 56 days with one of the Company's potent, small molecule GhrR antagonists. As with the GhrR knockout mice, the antagonist-treated mice showed improved glucose and insulin control compared to the mice treated with vehicle. In addition, the GhrR antagonist treatment resulted in a significant reduction in liver fat content with no evidence of liver toxicity relative to the mice vehicle-treated mice.
"Ghrelin antagonism represents one of the most intriguing new targets for addressing metabolic disorders such as Type 2 diabetes, obesity and other metabolic disorders. Our compilation of preclinical data, including these presentations, has shown it is possible to improve glucose control, d ecrease fat, including in the liver, and to regulate metabolism through the inhibition of ghrelin," stated Peter DiStefano, Ph.D., Chief Scientific Officer. "EX-1350, our small molecule ghrelin antagonist, is currently undergoing IND-enabling studies, with the goal of initiating first-in-man clinical studies in early 2008."
Amongst metabolic diseases, diabetes and obesity are at epidemic proportions in the U.S. and represent an enormous unmet medical need. According to the International Diabetes Federation, Type 2 diabetes affects 195 million people worldwide and the number of sufferers could top 330 million by 2025.
Elixir has filed broad intellectual property protection on all aspects of the ghrelin antagonist program including composition of matter protection covering five novel compound classes and their therapeutic uses.
About Elixir Pharmaceuticals
Elixir is a Cambridge, MA-based biopharmaceutical company focused on developing and commercializing drugs to treat and prevent metabolic disease, prevent age-related diseases, ultimately extending the quality and length of human life.
In addition to its ghrelin antagonist program, the Company has leveraged its knowledge of ghrelin biology and pharmacology by licensing a small molecule ghrelin agonist (designated EX-1314) from Bristol-Myers Squibb Company in April 2005. EX-1314 binds selectively to the ghrelin receptor and mimics the body's naturally occurring ghrelin. In doing so this novel, orally available agent is capable of stimulating appetite, gastric motility and the release of growth hormone. Elixir is currently in IND-enabling studies with EX-1314 targeting a variety of therapeutic indications.
Further, in March 2006, Elixir in-licensed North and South American rights to Glufast(R) (mitiglinide calcium hydrate), an insulin secretagogue, which lowers post-meal glucose levels by improving the body's own ability to produce insulin. Already marketed in Japan, Glufast ha s undergone extensive clinical development demonstrating the product's ability to safely and effectively treat Type 2 diabetes.
Elixir has also developed expertise and a broad IP portfolio of more than twenty patents and patent applications related to the Sirtuin class of proteins, including small molecular weight SIRT1 activators and inhibitors. The Company's own R&D efforts and those of its numerous research partners utilizing modulators of SIRT1 (a human sirtuin) have significantly extended the SIRT knowledge base in recent years. Elixir is also actively pursuing drug discovery efforts focused on other key targets, such as AMP-activated kinase (AMPK) and the INDY gene, both of which have been implicated in the regulation of aging and metabolism in a variety of organisms.
More information about Elixir is available at http://www.elixirpharm.com/
William Heiden, 617-995-7000
Burns McClellan for Elixir Pharmaceuticals, 212-213-0006
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