1. Rimonabant: New therapeutic option for managing cardiometabolic risk

2. Unmet needs in obesity and the metabolic syndrome Obesity, metabolic syndrome, and diabetes have reached epidemic proportions Increased prevalence of these conditions is projected to have a major impact on CV disease and associated costs of care Even modest weight loss (5%–10%) can reduce cardiometabolic risk factors Current behavioral and dietary approaches to weight loss have limited success New approaches to weight loss are urgently needed Gelfand EV, Cannon CP. J Am Coll Cardiol. 2006;47:1919-26. NIH Expert Panel. Obes Res. 1998;6(suppl 2):51S-209S.

3. Endocannabinoid system (ECS): Overview Gelfand EV, Cannon CP. J Am Coll Cardiol. 2006;47:1919-26. Pagotto U et al. Ann Med. 2005;37:270-5. Endocannabinoid ligands Produced on demand Act locally Inactivated rapidly Bind to transmembrane G-protein receptors, principally inhibiting neurotransmitter release Cannabinoid receptor type 1 (CB 1 ) Cannabinoid receptor type 2 (CB 2 ) Cannabinoid receptor type 1 (CB 1 ) Immune cellsMost widespread CB receptor (brain, spinal cord; peripheral nervous system, organs, tissues)

4. Implications of CB 1 receptor activation Central nervous systemPeripheral tissue  Appetite  Motivation to eat/smoke Gelfand EV, Cannon CP. J Am Coll Cardiol. 2006;47:1919-26. Pagotto U et al. Ann Med. 2005;37:270-5.  Lipogenesis Altered glucose metabolism Adipose tissue LiverGI tract Skeletal muscle HypothalamusLimbic system

5. Overview of rimonabant clinical trial programs for the treatment of multiple cardiometabolic risk factors Rimonabant In Obesity (RIO) –RIO-Europe –RIO-Lipids –RIO-North America (NA) –RIO-Diabetes Studies with Rimonabant and Tobacco Use (STRATUS) –STRATUS-United States –STRATUS-Europe –STRATUS-Worldwide Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study (STRADIVARIUS) Gelfand EV, Cannon CP. J Am Coll Cardiol. 2006;47:1919-26.

6. Rimonabant In Obesity (RIO) program RIO-EuropeRIO-LipidsRIO-NARIO-Diabetes N = 1507 BMI ≥30 kg/m 2 or >27 kg/m 2 with comorbidity* N = 1033 BMI 27–40 kg/m 2 and dyslipidemia N = 3045 BMI ≥30 kg/m 2 or >27 kg/m 2 with comorbidity* N = 1045 BMI 27–40 kg/m 2 and type 2 diabetes 1 year 2 years1 year Randomized, double-blind, placebo-controlled evaluations of rimonabant 5 mg or 20 mg qd added to hypocaloric diet (600 kcal/day deficit) † Weight, waist circumference, metabolic syndrome, and cardiometabolic risk factors assessed Potential CNS effects assessed via Hospital Anxiety and Depression scale (HAD) * Hypertension and/or dyslipidemia † RIO-NA: Rimonabant patients re-randomized at 1 year to placebo or continued rimonabant Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006. Gelfand EV et al. J Am Coll Cardiol. 2006.

7. RIO clinical trial program: Efficacy overview Rimonabant 5 mg (range) Rimonabant 20 mg (range) Weight (lbs)↓2.9–3.6*↓10.4–12.0* Waist (in)↓0.2–0.6↓1.4–1.9* HDL-C (%)↑2.3–3.2↑7.2–8.7* TG (%)↓4.2–↑1.4↓12.4–13.2* Insulin resistance (%) (RIO-Europe & NA only) ↓0.4–0.6↓0.7–0.8* CRP (mg/L) (RIO-Lipids only) ↑0.2↓0.5 † Adiponectin (μg/mL) (RIO-Lipids only) ↑0.3↑1.5* RIO-Europe, RIO-Lipids, RIO-NA; Placebo-corrected change from baseline at 1 year Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006. *P ≤ 0.002 vs placebo † P = 0.02 vs placebo

8. ↓54% 42.2 52.9 34.8 * 21.2 * 25.8 * 19.6 0 10 20 30 40 50 60 RIO-EuropeRIO-LipidsRIO-NA Patients (%) Baseline1 year Significant decrease in metabolic syndrome Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006. Rimonabant 20 mg ↓51% ↓39% (n = 599)(n = 346)(n = 1222) ATP III criteria *P < 0.001 vs placebo

9. RIO clinical trial program: Safety and tolerability overview Most common drug-related adverse event was mild nausea –Rimonabant 5 mg (5.1%–7.2%); 20 mg (11.2%–12.9%) Adverse event-related discontinuation rate was similar or slightly higher vs placebo –Rimonabant 5 mg (8.3%–9.4%); 20 mg (12.8%–15.0%); placebo (7.0%–9.2%) Changes in anxiety and depression scores (HAD scale) were similar across treatment and placebo groups Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006. HAD = Hospital Anxiety and Depression

10. Rimonabant: No significant effect on mood Placebo Rimonabant 5 mg Rimonabant 20 mg RIO-Europe Anxiety Depression 4.4 2.7 4.5 2.7 5.6 3.4 RIO-Lipids Anxiety Depression 5.2 3.2 5.5 3.0 5.6 3.1 RIO-NA Anxiety Depression 5.2 3.1 5.3 3.0 5.6 3.0 HAD scale: Scores at 1 year Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006.

11. Rimonabant: RIO program summary Over 1 year, rimonabant 20 mg combined with diet demonstrated: –Significant decreases in weight and waist circumference –Weight loss: 14.0–15.3 lbs absolute change, 10.4–12.0 lbs placebo-corrected change –Favorable changes in cardiometabolic risk factor profile Van Gaal LF et al. Lancet. 2005;365:1389-97. Després J-P et al. N Engl J Med. 2005;353:2121-34. Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

12. Rimonabant: Therapeutic potential Cannabinoid receptor blockade is a novel approach to treatment of cardiometabolic risk factors Any degree of weight loss can impact metabolic syndrome and diabetes, ultimately reducing CV risk Moderate weight loss encourages continued health- promoting behaviors and adherence to medical therapy Gelfand EV, Cannon CP. J Am Coll Cardiol. 2006;47:1919-26.