ECS 2 RIO Europe Lipids

Clinical Evidence: 

Clinical Evidence CB1 receptor blockade with rimonabant improved multiple cardiovascular and metabolic variables HDL-cholesterol, triglycerides, glucose metabolism, CRP and adiponectin Body weight and waist circumference Effects are probably mediated by peripheral and central actions 1

RIO: Rimonabant In Overweight/Obesity: 

RIO: Rimonabant In Overweight/Obesity (>6600 patients enrolled) Pi-Sunyer FX.Obes Res. 2004;12(suppl):08-OR, A27. 1 2

RIO-Europe and RIO-Lipids: Study Design: 

RIO-Europe and RIO-Lipids: Study Design Rimonabant 20 mg Van Gaal et al. The Lancet 2005; 365: 1389-97. Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. 3

RIO-Europe: Baseline Characteristics: 

RIO-Europe: Baseline Characteristics Placebo Rimonabant (n=305) 5 mg (n=603) 20 mg (n=599) Race (white)* 290 (95.1%) 565 (93.7%) 555 (92.7%) Sex (female) 244 (80.0%) 476 (78.9%) 478 (79.8%) Age (years) 45.0 ± 11.6 45.4 ± 11.2 44.6 ± 119 BMI (kg/m2) 35.7 ± 5·9 36.0 ± 5.9 36.2 ± 5.8 Weight (kg) 100.0 ± 20·3 100.9 ±19.8 101.7 ± 19.5 Waist (cm) 107.7 ± 13·8 108.4 14.3 108.8 ± 14.1 TG (mg/dL) [128.3] [129.2] [128.3] HDL (mg/dL) [49.0] [49.0] [49.0] Metabolic 121 (40.6%) 243 (40.8%) 251 (42.4%) Syndrome† * N (%) † Metabolic syndrome present by ATP-III criteria n (%) Van Gaal et al. The Lancet 2005; 365: 1389-97. 4

RIO-Lipids: Baseline Characteristics: 

RIO-Lipids: Baseline Characteristics Placebo Rimonabant (n=342) 5 mg (n=345) 20 mg (n=346) Race (white)* 329 (96.2%) 337 (97.7%) 334 (96.5%) Sex (female) 198 (57.9%) 215 (62.3%) 213 (61.6%) Age (years) 47.0 ± 10.1 48.1 ± 10.2 48.4 ± 10.0 BMI (kg/m2) 34.0 ± 3.5 34.1 ± 3.5 33.9 ± 3.3 Weight (kg) 94.9 ± 15.2 94.2 ± 14.6 93.8 ± 14.8 Waist (cm) 105.6 ± 11.5 104.8 ± 10.9 104.8 ± 11.0 TG (mg/dL) [181.4] [184.1] [187.6] HDL (mg/dL) [42.5] [42.5] [42.9] Metabolic 180 (52.9%) 191 (55.4%) 183 (53.7%) Syndrome† * N (%) † Metabolic syndrome present by ATP-III criteria n (%) Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. 5

RIO-Europe and RIO-Lipids: Weight Change at 1 Year: 

RIO-Europe and RIO-Lipids: Weight Change at 1 Year Completers ITT (LOCF) Placebo Rimonabant 20 mg -10 -8 -6 -4 -2 0 0 16 32 ITT LOCF Weight change (kg) Weeks Van Gaal et al. The Lancet 2005; 365: 1389-97. Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. -1.5 -6.9 -8.6 -2.3 -3.6 -8.6 -1.8 -6.6 6

RIO-Europe : Weight Change at 1 Year: 

RIO-Europe : Weight Change at 1 Year Van Gaal et al. The Lancet 2005; 365: 1389-97. 7 Weight loss ≥ 5% Weight loss ≥ 10% ITT Population Completers Placebo 5 mg 20 mg Rimonabant Rimonabant Placebo 5 mg 20 mg Rimonabant Rimonabant Proportion of Patients (%)

RIO-Europe: Percent Change in HDL-C and TG Levels: 

RIO-Europe: Percent Change in HDL-C and TG Levels Van Gaal, L. et al. The Lancet 2005;365:1389-97 8

RIO-Lipids: Percent Change in HDL-C and TG Levels at 1 Year: 

Change in HDL-C (%) 30 25 20 15 10 5 0 0 12 24 36 52 Week P<0.001 P=0.017 11.8 15.6 22.9 RIO-Lipids: Percent Change in HDL-C and TG Levels at 1 Year Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. Rimonabant 20 mg Rimonabant 5 mg Placebo Placebo : 11. 8% R5 mg : 14.2% (ns v. placebo) R20 mg : 19.1% (p< 0.001 v. placebo) ITT, LOCF Completers Placebo : 0.0. % R5 mg : 1.2% R20 mg :-12.6% (p < 0.001 v. placebo) 10 5 0 -5 -10 -15 -20 0 12 24 36 52 Week Change in TG (%) P<0.001 +0.4 -3.6 -15.7 9

Slide10: 

RIO-Lipids: Effect of Rimonabant on C-Reactive Protein and Adiponectin at 1 Year ITT-LOCF CRP levels (mg/L)*  - 0.6 mg/L P=0.007 Placebo Rimonabant 20 mg 3.6 3.2 3.7 2.7 0 1 2 3 4 5  27% * Excluding values >10 mg/L Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. C-Reactive Protein* Adiponectin D 1.6 m g/mL P=0.001 Adiponectin levels ( m g/mL) Placebo Rimonabant 20 mg 5.9 6.7 5.8 8.2 0 2 4 6 8 10 Baseline 1 Year 41% ITT-LOCF 10

Slide11: 

Prevalence of the Metabolic Syndrome (ATP III Criteria) Rimonabant Placebo RIO-Lipids RIO-Europe 20 mg 5 mg Completers Only Rimonabant Baseline Completion % Change Baseline Completion % Change 38.9 25.7 33.9 42.3 27.6 34.8 44.9 15.8 64.8 Van Gaal et al. The Lancet 2005; 365: 1389-97. Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. 51.9 41.0 21.0 55.9 40.0 28.4 52.9 25.8 51.2 11

Slide12: 

RIO-Europe: Overall Safety Year 1 14.5% 8.3% 9.2% Subjects discontinued due to adverse event Rimonabant Placebo 8.7% 7.5% 7.5% Subjects with any serious adverse event 87.1% 82.6% 84.3% Subjects with any adverse event 39.4% 37.3% 41.6% Overall discontinuations 20 mg n = 599 5 mg n = 603 n = 305 Rimonabant Van Gaal et al. The Lancet 2005; 365: 1389-97. 12

RIO-Europe: Discontinuation Due to Adverse Events in Year 1: 

RIO-Europe: Discontinuation Due to Adverse Events in Year 1 Rimonabant 5 mg n = 603 20 mg n = 599 Psychiatric disorders Depressed mood disorders Anxiety Agitation Sleep disorders 5.2% 3.0% 0.3% 0.7% 0.0 % 3.0% 2.3% 0.0% 0.0% 0.3% 7.0% 3.7% 1.0% 0.5% 0.2% Gastrointestinal disorders Nausea Vomi ting Diarrhea 0.0% 0.0% 0.0% 0.0% 0.8% 0.2% 0.0% 0.0% 3.5% 2.3% 0.7% 0.5% Rimonabant Placebo n = 305 According to MedDRA, in at least 2 patients. One patient may report several events. Van Gaal et al. The Lancet 2005; 365: 1389-97. 13

Slide14: 

RIO-Lipids: Overall Safety Year 1 15.0% 8.4% 7.0% Subjects discontinued due to adverse event Rimonabant Placebo 4.0% 5.2% 2.3% Subjects with any serious adverse event 86.7% 82.3% 81.6% Subjects with any adverse event 36.1% 37.9% 37.4% Overall discontinuations 20 mg n = 344 5 mg n = 340 n = 334 Rimonabant Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. 14

Slide15: 

Despres J-P, et al. N Engl J Med. 2005;353:2121-2134. 15

Slide16: 

The endocannabinoid system is a recently characterized physiologic system It modulates energy balance, feeding behavior, hepatic lipogenesis, and glucose homeostasis It is overactivated in human obesity and in animal models of genetic and diet-induced obesity Overall Summary 16

Slide17: 

Endocannabinoid system stimulation centrally and peripherally favors metabolic processes, which lead to weight gain, lipogenesis, insulin resistance, dyslipidemia, and impaired glucose homeostasis CB1 blockade reverses or ameliorates these effects in non-clinical models CB1 receptor blockade with rimonabant improves multiple cardiovascular and metabolic variables in non-clinical and clinical studies: HDL-cholesterol, triglycerides, glucose, abdominal obesity, CRP, and adiponectin Effects are probably mediated by peripheral and central actions Overall Summary (Cont’d) 17