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Synvista Collaboration Demonstrates in Preclinical Studies the Mechanism for Defective Cholesterol Transport in Patients with Diabetes

MONTVALE, N.J., Nov. 5 /PRNewswire-FirstCall/ -- Synvista Therapeutics, Inc. (Amex: SYI) announced results of a series of preclinical studies designed to explain the mechanism underlying dysfunctional high density lipoprotein (HDL), that creates a defect in reverse cholesterol transport in patients with Diabetes Mellitus (DM). The studies reveal that a common blood protein, Haptoglobin, binds to the core of HDL and that a defective Haptoglobin variant (Hp2-2), found in 40% of the population, may induce dysfunctionality in HDL. Further, the studies report that exposure to Vitamin E can restore HDL functionality and the process of reverse cholesterol transport. The study is being presented today at the American Heart Association's (AHA) Scientific Sessions 2007 in Orlando, Florida.

"We are very pleased with the outcome of these studies, as we believe they provide scientific rationale for our current development platform, including our work developing a diagnostic test for Haptoglobin type, to determine cardiovascular risk and a therapeutic product to decrease HDL oxidation and restore reverse cholesterol transport function," said Noah Berkowitz, M.D., Ph.D., President and Chief Executive Officer of Synvista. "This study further demonstrates that the Hp2-2 phenotype, a risk factor for cardiovascular events in patients with diabetes, may function by interfering with the function of HDL and promoting inflammatory atherosclerosis."

The experiments of Rabea Asleh, M.D., of the Rappaport Faculty of Medicine and Research Institute, at the Technion, Haifa, Israel, who is today's recipient of the AHA's Council on Nutrition, Physical Activity and Metabolism's 2007 New Investigator Award, provided a mechanistic explanation for the defect in reverse cholesterol transport observed in many patients with diabetes mellitus (DM). Reverse cholesterol transport describes the process of moving cholesterol out of the atherosclerotic plaque and into HDL particles ("good cholesterol"). This process is thought to be the mechanism by which high levels of HDL protect patients from atherosclerotic disease. Dr. Asleh reports the presence of Haptoglobin-Hemoglobin (Hp-Hb) complexes in HDL particles and observes that Hp2-2-Hb complexes promote less efficient reverse cholesterol transport in DM, which can be reversed by antioxidants such as vitamin E. He proposes that strategies targeted to decrease oxidation of HDL in Hp2-2 patients may improve HDL function. Synvista has completed enrolling two cohorts of a three cohort Phase 2 clinical trial, evaluating among other endpoints, the impact of the Company's oxidized lipid metabolizing agent, ALT- 2074, on functional reverse cholesterol transport.

Radiolabeled Hp2-2-Hb complexes injected into mice and rats with and without diabetes demonstrated significantly longer half-life then radiolabeled Hp1-1-Hb complexes (e.g. 2-3 fold longer in non-DM animals, p=0001; and doubled in DM mice, p= 0.005). Coimmunoprecipitation studies showed that there is 10-fold more Hp2-2-Hb complex associated with HDL in diabetic mice than Hp1-1-Hb in non-DM mice. This was also shown in human sera where significantly more radioactive hemoglobin is associated with HDL particles in Hp2-2 individuals than Hp1-1 individuals. Reverse cholesterol transport, as measured by radiolabeled cholesterol efflux from pre-loaded macrophages, was significantly impaired (p=0.0001) by incubation with serum from Hp2-2 diabetic mice versus serum from non-DM Hp2-2 mice. This impairment was restored to normal levels when the mice received vitamin E.

About Synvista Therapeutics

Synvista Therapeutics is a biopharmaceutical company developing small molecule drugs to treat and prevent cardiovascular disease and to treat nephropathy in people with diabetes. The Company has identified several product candidates that it believes represent novel approaches to some of the largest pharmaceutical markets. The Company's portfolio includes orally bioavailable, organoselenium mimics of glutathione peroxidase. These compounds metabolize lipid peroxides and have the potential to limit myocardial damage subsequent to a myocardial infarction. The Company is developing a clinical diagnostic test, based on cardiovascular risk assessment, using Haptoglobin characterization, to identify patients at high risk for cardiovascular complications of diabetes.

Synvista Therapeutics also is developing alagebrium, a proposed breaker of AGEs for the treatment of diastolic heart failure. This disease represents a rapidly growing market of unmet medical need, particularly common among diabetic patients. Alagebrium has demonstrated relevant clinical activity in two Phase 2 clinical trials in heart failure, as well as in animal models of heart failure and nephropathy, among others. Alagebrium has been tested in approximately 1,000 patients in multiple Phase 1 and Phase 2 clinical trials, allowing Synvista Therapeutics to assemble a sizeable human safety database. For more information, please visit the Company's website at

Any statements contained in this press release that relate to future plans, events or performance are forward-looking statements that involve risks and uncertainties including, but not limited to, the risks associated with the events described in this press release, future clinical development of Synvista Therapeutics' product candidates, and other risks identified in Synvista Therapeutics' filings with the Securities and Exchange Commission. Further information on risks faced by Synvista are detailed under the caption "Risk Factors" in Synvista Therapeutics' Annual Report on Form 10-K for the year ended December 31, 2006. These filings are available on a website maintained by the Securities and Exchange Commission at The information contained in this press release is accurate as of the date indicated. Actual results, events or performance may differ materially. Synvista Therapeutics undertakes no obligation to publicly release the result of any revision to these forward- looking statements that may be made to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.

SOURCE Synvista Therapeutics, Inc.
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