14 Howard Haimes

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This presentation is copyright Ó2007 by Alteon Inc. Any duplication, use or distribution of this presentation is strictly prohibited without prior written authorization from Alteon Inc. ALTEON Protein Glycation and the Cardiovascular System Edmonton Aging Symposium Howard B. Haimes, Ph.D. Executive Director, Preclinical Sciences March 30-31, 2007 Breakthrough Medicines For Cardiovascular Aging and Complications of Diabetes

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General Introduction to The “A.G.E. Pathway”

A.G.E.s Form and….: 

A.G.E.s Form and…. Amino Acids Sugar Lipid Schiff Base Amadori Product (e.g. HbAlc) Serum and Tissue AGEs Dicarbonyl Intermediates + Polyol Pathway [ox] [ox] glu glu [ox]

….Induce Inflammation: 

….Induce Inflammation  IL-1  TNF  TGFβ  NFκβ  eNOS Pathologies: Vascular Stiffening Chronic Heart Failure Nephropathy Source: Diabetes, Brownlee, Vol. 54, June 2005 Intracellular protein glycation AGE precursors Glucose Matrix Intracellular transducers Transcription factors Glucose DNA Transcription AGE receptor AGE plasma proteins AGE receptor ROS NF-β Macrophage mesangial cell mRNA Proteins Integrins Endothelial cell RNA 

The Role of A.G.E.s in Ventricular Remodeling: 

The Role of A.G.E.s in Ventricular Remodeling A variety of factors including diabetes, hypertension and aging lead to cardiac hypertrophy This hypertrophy is primarily due to enhanced deposition of type I and III collagens in the myocardium Glycation causes an upregulation of sclerotic cytokines such as CTGF and TGFß Glycation of Extracellular matrix molecules restricts normal turnover

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Cardiovascular Studies with Alagebrium in Rodents

Alagebrium Reduces LV Mass: 

Alagebrium Reduces LV Mass Aged SHR Rats (45 Weeks) 0.01, 0.1, 1.0 and 10mg/kg daily for 20 weeks Confirmed 1 mg/kg/day as optimal dose Susic, D et al Cardiovascular and Renal Effects of a Collagen Cross-Link Breaker (ALT 711) in Adult and Aged Spontaneously Hypertensive Rats. AJH 2004; 17:328-333

Left Ventricular Mass Reduction: 

Left Ventricular Mass Reduction * p<0.05 when compared to controls Adapted from: Susic, D et al Cardiovascular and Renal Effects of a Collagen Cross-Link Breaker (ALT 711) in Adult and Aged Spontaneously Hypertensive Rats. AJH 2004; 17:328-333

Alagebrium Attenuates Diabetic Cardiomyopathy: 

Alagebrium Attenuates Diabetic Cardiomyopathy STZ Induced Diabetes in Sprague Dawley Rats for 32 weeks Treatment with alagebrium (10 mg/kg) beginning at week 16 for 16 weeks Candido R et al A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes Circ Res 2003; 92:785-792

Alagebrium Attenuates Diabetic Cardiomyopathy: 

Alagebrium Attenuates Diabetic Cardiomyopathy

Alagebrium Restores Collagen Solubility: 

Alagebrium Restores Collagen Solubility % LV Collagen Solubility Adapted from: Candido R et al A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes Circ Res 2003; 92:785-792

Alagebrium Attenuates mRNA RAGE Expression: 

Alagebrium Attenuates mRNA RAGE Expression Adapted from: Candido R et al A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes, Circ Res 2003; 92:785-792

Intervention with Alagebrium Reverses Glycation Induced Deficits in Structure and Function: 

Intervention with Alagebrium Reverses Glycation Induced Deficits in Structure and Function Decrease in LV mass over time Return of collagen solubility by MMPs Decreased expression of types I & III collagens Decrease in sclerotic cytokines Decrease in inflammatory stimulus

Alagebrium Decreases Myocardial Fibrosis and Improves Endothelial Function: 

Alagebrium Decreases Myocardial Fibrosis and Improves Endothelial Function DAHL salt sensitive rat Alagebrium treatment for 4 weeks at 10 mg/kg/day PO Veronesi, M et al ALT-711, A Collagen Cross-Link Breaker, Decreases Myocardial Fibrosis and Improves Endothelial Dysfunction in Hypertensive DAHL Salt Rats 2001 AHA Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research

Alagebrium Decreases Myocardial Fibrosis and Improves Endothelial Function: 

Alagebrium Decreases Myocardial Fibrosis and Improves Endothelial Function

Intervention with Alagebrium: 

Intervention with Alagebrium Reduces tissue and serum A.G.E.s Reverses collagen solubility Reduces urinary albumin excretion Reduces inflammatory and cytokine expression

Alagebrium Restores Diastolic, Systolic and Endothelial Function : 

Alagebrium Restores Diastolic, Systolic and Endothelial Function Aging Rat Study conducted at Johns Hopkins School of Medicine (unpublished results) Evaluated effects of exercise +/- treatment with alagebrium Hemodynamic evaluations

The Effect of Aminoguanidine and Alagebrium on AGE and RAGE Expression in Atherosclerotic Plaque: 

The Effect of Aminoguanidine and Alagebrium on AGE and RAGE Expression in Atherosclerotic Plaque

The Effect of Alagebrium on Urinary Protein Excretion: 

The Effect of Alagebrium on Urinary Protein Excretion

Pressure-Volume Loops in Young and Old Rats: 

Pressure-Volume Loops in Young and Old Rats

The Effect of Alagebrium on Diastolic Function: 

The Effect of Alagebrium on Diastolic Function

The Effect of Alagebrium on Systolic Function: 

The Effect of Alagebrium on Systolic Function

The Effect of Alagebrium on Cardiac Contractility: 

The Effect of Alagebrium on Cardiac Contractility

The Effect of Alagebrium on Endothelial Function: 

The Effect of Alagebrium on Endothelial Function

Intervention with Alagebrium Restores Functional Properties to Tissues and Organs: 

Intervention with Alagebrium Restores Functional Properties to Tissues and Organs Reversal of LV Mass Improvements in systolic and diastolic properties Decreased plaque progression in atherosclerosis Restoration of Nitric Oxide production and bioavailability

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Cardiovascular Studies with Alagebrium in Canines

Alagebrium Treatment Reduces CardiacCollagen and Improves Function: 

Alagebrium Treatment Reduces Cardiac Collagen and Improves Function Male mongrel dogs 9-12 years Induction of diabetes with alloxan monohydrate 25-35 mg/kg Treatment with ALT 711 1mg/kg daily for 1 month Hemodynamic studies by 2-D echo and Millar conductance catheter Liu, J, et al Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. A, J Physiol Heart Circ Physiol. 2003; 285L 2857-2591

Alagebrium Reduces LV Mass: 

Alagebrium Reduces LV Mass LV Mass, g/kg P<0.05 vs. Aging P< 0.05 vs. Aging and Diabetes Liu, J, et al Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. A, J Physiol Heart Circ Physiol. 2003; 285L 2857-2591

Alagebrium Reverses Type I Collagen Deposition: 

Alagebrium Reverses Type I Collagen Deposition

Alagebrium Reverses Type III Collagen Deposition : 

Alagebrium Reverses Type III Collagen Deposition

Alagebrium Restores Collagen Solubility: 

Alagebrium Restores Collagen Solubility

Alagebrium Restores LV Function: 

Alagebrium Restores LV Function P<0.05 vs. Aging P<0.05 vs. Aging and Diabetes Adapted from: Liu, J, et al Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. A, J Physiol Heart Circ Physiol. 2003; 285L 2857-2591 LVEF %

Alagebrium Reverses Functional Deficits in the Heart: 

Alagebrium Reverses Functional Deficits in the Heart Improves vascular compliance Decreases LV mass Improves systolic and diastolic parameters Restores tissues and organs to a more youthful, functional state

Alagebrium Reverses Myocardial Stiffness: 

Alagebrium Reverses Myocardial Stiffness Male mongrel dogs 22-32 kg 1 mg/kg ALT 711 PO daily for one month Baseline and endpoint hemodynamic measurements Asif M. et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. PNAS 2000 97(6); 2809-2913

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(volume loaded) 0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90 100 End-Diastolic Volume Index (ml/m2) End-Diastolic Pressure (mm Hg) Low Volume, High Pressure High Volume, Low Pressure Male mongrel dogs. ALT-711: 1 mg/kg, oral, 4 weeks Adapted from Asif et al, PNAS 2000 Untreated Aged Dogs Young Dogs Control Short-Term Dosing With Alagebrium Restores Flexibility In The Left Ventricle In Aged Dogs

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Cardiovascular Studies with Alagebrium in Primates

Alagebrium Improves Arterial and Ventricular Properties: 

Alagebrium Improves Arterial and Ventricular Properties Male non diabetic Rhesus monkeys 21+/- 3.6 years ALT 711 1.0 mg/kg every other day for 3 weeks (IM) Arterial and ventricular properties measured Vaitekevicius, P et al A cross-link breaker has sustained effects on arterial and ventricular properties in older Rhesus monkeys PNAS 2001; 98(3): 1171-1175

Alagebrium Improves Arterial and Ventricular Structure and Function: 

Alagebrium Improves Arterial and Ventricular Structure and Function

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Cardiovascular Studies with Alagebrium in Humans

Key Clinical Findings for Alagebriumin Heart Failure: 

Key Clinical Findings for Alagebrium in Heart Failure Meaningful reduction in left ventricular mass (p=0.036), in unprecedented timeframe Marked improvement in initial phase of left ventricular diastolic filling (p=0.045) Statistically significant improvements in multiple QOL measurements (p < 0.01) Sickest patient population (class III heart failure) benefited most Source: Kitzman, Zile, et al; Presented as Poster at Society of Geriatric Cardiology Annual Meeting, 2003 *Distensibility Improvement and Remodeling in Diastolic Heart Failure DIAMOND Study Source: Thohan, Koerner, et al; Presented as Poster at the American Heart Association Annual Meeting, 2005 Patients with Impaired Ejection Fraction and Diastolic Dysfunction: Efficacy and Safety Trial of Alagebrium PEDESTAL Study Improvements observed for: Diastolic function (E/A, DT, IVRT) Hemodynamics (LAP, PASP) LV remodeling (LAV, LVEDV, LV mass) NYHA score No alterations in heart rate, blood pressure or physical exam

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ALTEON This presentation is copyright Ó2007 by Alteon Inc. Any duplication, use or distribution of this presentation is strictly prohibited without prior written authorization from Alteon Inc. 6 Campus Drive Parsippany, NJ 07054 Tel: (201) 934-5000 Fax: (201) 934-8880 AMEX: ALT www.alteon.com