Hayward, Calif., Jan. 24 /PRNewswire/ -- Metabolex, Inc. today announced findings showing the molecular and cellular differences between metaglidasen, a novel oral insulin sensitizer in clinical development for the treatment of type 2 diabetes, and rosiglitazone and pioglitazone, currently marketed insulin sensitizers of the TZD (thiazolidinedione) class. These preclinical findings demonstrated that metaglidasen provided glycemic control and lipid-lowering activity equivalent to the TZDs with a significantly improved side effect profile, including less weight gain and edema (fluid retention). The data will be presented today in Vancouver at Keystone Symposia's Scientific Conference on Diabetes Mellitus and the Control of Cellular Energy Metabolism during the Poster Session (poster #342).
"These data support the clear mechanistic differentiation between metaglidasen, a selective PPAR-gamma modulator, and the full PPAR-gamma agonists, and demonstrate that this translates into fewer side effects," said Harold E. Van Wart, Ph.D., president and CEO of Metabolex. "The results of this preclinical study are fully consistent with other preclinical studies of metaglidasen and with the results of our Phase 2 clinical trial -- all of which support the profile of equivalent anti-diabetic efficacy without the safety and tolerability issues associated with currently marketed insulin sensitizers. We are excited about the promise of metaglidasen because it represents the first of a new generation of PPARs that has an improved side effect profile."
Study Results
Metaglidasen was compared to rosiglitazone and pioglitazone using a variety of in vitro and in vivo model systems. Key findings included:
-- Metaglidasen was shown to act as a selective PPAR-gamma partial agonist and antagonist. It did not have activity against either PPAR-alpha or PPAR-delta. -- For the first time, metaglidasen was found to bind directly to PPAR-gamma and to recruit cofactors in a manner distinct from rosiglitazone. (Cofactors are proteins that interact with PPAR-gamma and cause genes to turn on or off.) These findings may explain the differences in gene expression observed with metaglidasen versus the TZDs and, consequently, the difference in side effect profiles. For example, metaglidasen was found to regulate genes involved in fatty acid uptake and storage differently than rosiglitazone. Metaglidasen is less likely than rosiglitazone to enlarge existing adipocyte (fat) cells and recruit additional fat cells from pre-adipocyte cells. This increase in adipocyte cell size and number may partially explain the weight gain associated with rosiglitazone and pioglitazone. -- In both diabetic and insulin-resistant animal models, metaglidasen provided glycemic control and lipid-lowering activity equivalent to rosiglitazone and pioglitazone with less body weight gain and cardiac hypertrophy (increase in heart weight), the latter of which is believed to be a result of increased edema. -- The differential gene expression between metaglidasen and rosiglitazone observed in the cell-based models was reconfirmed in the animal models. Metaglidasen: Novel Approach to Insulin Sensitizers
The only insulin sensitizers on the market today are from the TZD class, with worldwide sales of nearly $4 billion. These represent an attractive treatment option for type 2 diabetes because they target insulin resistance, the underlying cause of the disease, and may preserve the function of pancreatic beta-cells (the source of insulin). However, these drugs can cause significant weight gain, compromising patient compliance. Furthermore, currently marketed insulin sensitizers carry a warning of increased risk of congestive heart failure due to fluid retention.
Metaglidasen (formerly MBX-102), the lead candidate in Metabolex's clinical development program, has a chemical structure and method of action that differentiates it from the TZD insulin sensitizers. Metaglidasen modulates the genes needed for insulin sensitization but not those responsible for edema and weight gain. This difference in target profile compared to the marketed TZDs was confirmed in a three-month Phase 2 clinical trial in diabetic patients taking insulin. Results were presented at the American Diabetes Association's 65th Scientific Sessions in June 2005.
About Keystone Symposia
Keystone Symposia, a non-profit organization, has a 35-year history of organizing high quality scientific conferences to connect the scientific community and accelerate discoveries that benefit society.
About Metabolex
Metabolex is a privately held biotechnology company dedicated to the discovery and development of novel therapeutics to transform the treatment of diabetes and related metabolic disorders. Metabolex has drawn on its deep understanding of diabetes to create the largest database of genes involved in diabetes and to build a rich pipeline of product candidates and drug discovery targets. The company's clinical program is focused on developing next-generation insulin sensitizers that lower blood glucose without the serious safety and tolerability issues associated with currently marketed products. For additional information about Metabolex and its development pipeline, visit www.metabolex.com.
Metabolex, Inc.CONTACT: Mark Bagnall of Metabolex, +1-510-293-8800, ormbagnall@metabolex.com; or media, Daryl Messinger of WeissComm Partners,+1-415-999-2361, or daryl@weisscommpartners.com, for Metabolex
Web site: http://www.metabolex.com//
