The A.G.E. Pathway A.G.E. Formation on Proteins Leads to Pathologies in Critical Organs and Tissues There is substantial evidence that many of the complications of diabetes and aging are a direct consequence of the formation of glucose-protein crosslinks through the A.G.E. Pathway. These complications result from increased stiffness of tissues, abnormal protein accumulation, membrane leakiness and dysfunction, and eventual damage to cells, tissues and organs. Key examples of serious pathophysiologic consequences that result from compromised physiologic functions are: the loss in elasticity of the left ventricle leads to decreased cardiac output and excessive workload on the heart; the progressive loss in elasticity of the aorta similarly results in excessive workload for the heart; the progressive membrane thickening of the glomerulus of the kidney and the resulting glomerular damage leads to the progressive development of diabetic nephropathy and end stage renal disease. In the absence of strict glycemic control, it is unlikely that a significant slowing of the progression of diabetic complications can be achieved through conventional therapies for the general population. While the Diabetes Complications and Control Trial (DCCT) proved that chronically elevated glucose is pathological and responsible for the development of diabetic complications, the rigid daily regimens employed within this trial could not be achieved outside the controlled clinical setting. Although the restoration of insulin sensitivity and the clearance of excess glucose after a meal is an ideal property of a therapeutic agent for the treatment of diabetes, no pharmaceuticals exist today with such an absolute beneficial profile of activity. The formation of A.G.E.s and their subsequent crosslinks between proteins continues on an ongoing basis regardless of the degree of diabetes. Biochemical evidence demonstrates that reactive A.G.E. intermediates that were formed during typical periods of hyperglycemia, such as after a meal, will continue to mature to highly reactive A.G.E.s even after glucose levels return to normal. Once formed, the A.G.E. is committed to remain in a covalent state on a protein or to form a covalent crosslink with another protein. About Synvista Synvista was incorporated in 1986 to apply its expertise and detailed understanding of the A.G.E. Pathway to the discovery and development of pharmaceuticals designed to interfere with the pathological consequences of A.G.E. formation and crosslinking. With little competition in the A.G.E. technology arena, Synvista has built an important pipeline and has extensive patent coverage surrounding its scientific discoveries. Figure II. Synvista's Platform Technology and Product Pipeline (click on graphic to enlarge) Synvista is developing several new classes of compounds and “First-in-Class” drugs that reverse or slow down diseases of aging and complications of diabetes. These compounds are designed to to inhibit or reverse the formation or crosslinking of A.G.E.s and may provide relief for many medical conditions where A.G.E. crosslinking has contributed to a loss of normal function, elasticity and/or flexibility. Synvista has created a library of novel classes of compounds targeting the A.G.E. Pathway. These include A.G.E. Crosslink Breakers, A.G.E. Formation Inhibitors and Glucose Lowering Agents. Synvista’s lead compound alagebrium, the only A.G.E. Crosslink Breaker in advanced human testing, has demonstrated safety and efficacy in several Phase 2 trials and is actively being developed for systolic hypertension and heart failure. Previous