Pimagedine: A Drug for Renal Disease
Pimagedine, and orally active inhibitor of A.G.E. formation, is being developed as a treatment for diabetic nephropathy.

The A.G.E. Pathway and the Development of Diabetic Nephropathy
Nephropathy is one of the most common complications of diabetes mellitus. The disease is characterized by increased glomerular basement membrane thickness, decreased glomerular filtration rate, and expansion of mesangial volume. Diabetes-induced changes in physical and biochemical properties of the glomerular basement membrane can result in proteinuria.

A.G.E.s and A.G.E. Crosslinks have been proposed as significant contributing factors in the development and progression of nephropathy. Studies have shown that A.G.E. modification of extracellular matrix components of the kidney results in an increase in the number of large openings in the meshwork of the membrane, which further leads to an impairment of function. The presence of A.G.E.s has been demonstrated in the mesangial matrix of diabetic patients, using immunohistochemical techniques and high resolution scanning electron microscopy to detect ultrastructural changes. This supports the role that A.G.E.s are likely to play in the progression of diabetic nephropathy through impairment of the assembly of matrix proteins.

How Pimagedine Slows the Progression of Nephropathy
Damage to glomerular basement membranes by A.G.E.s initially is manifested by loss of microvascular integrity, due to increased permeability of the glomerular basement membrane to blood proteins. This results clinically in proteinuria, which is a direct marker for damage to the glomerular basement membrane. Over time, formation of A.G.E.s in these microvascular beds contributes to development of chronic complications of diabetes, including nephropathy, retinopathy and neuropathy.

Pimagedine inhibits the formation of A.G.E.s by irreversibly binding to an A.G.E. moiety on the surface of structural proteins. This binding step prevents further protein-to-protein complexing, which in turn results in a slowing of crosslink formation along proteins. By its unique mechanism of action, pimagedine is able to have a widespread beneficial impact on one of the earliest steps in the pathophysiologic process of nephropathy in diabetic patients. Also, because pimagedine exerts its activity by a mechanism uniquely different from currently available therapies, its benefits are additive to current treatment.

The ACTION Clinical Program at Alteon
The ACTION clinical program, (A Clinical Trial In Overt Nephropathy) was initiated in 1993 as a Phase II/III program with the objective of evaluating the impact of pimagedine on the progression of diabetic overt nephropathy.

Two trials were designed to demonstrate a treatment effect over and above optimal medical therapy for diabetic populations, including the use of ACE-inhibitors. The results for the primary endpoint, Adjudicated Time to Doubling of Serum Creatinine, as well as secondary endpoints for ACTION I and ACTION II are briefly reviewed below:

ACTION I

A reduction in the risk of death over the course of the clinical trial. A strong trend for reduction in the risk for a doubling of serum creatinine. A strong trend in a secondary analysis of the primary endpoint when the risk of doubling of serum creatinine was stratified for baseline serum creatinine. A statistically significant impact for the composite endpoint of doubling of serum creatinine or mortality in patients with a baseline serum creatinine of less than 1.5. A highly statistically significant impact on the prospectively defined secondary endpoint, urinary protein excretion (p <0.001), which meets the National Kidney Foundation's recommended therapeutic range of efficacy for this disease. A statistically significant impact on reducing the progression of retinopathy. A statistically significant positive impact on lipid parameters.

ACTION II

A statistically significant reduction in urinary protein excretion in a sub-population of patients with moderate renal impairment. A statistically significant positive impact of pimagedine on triglycerides.

In summary, the strong and consistent findings with regards to both primary and secondary endpoints provides a significant body of evidence with which to position pimagedine as a unique and clinically relevant therapeutic agent. Alteon believes that pimagedine has the potential to offer much needed benefit to a patient population not well treated by current optimal medical therapy.

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