1. Rimonabant: A new approach to multiple cardiometabolic risk factors Version 1.1 29 April 2005

2. RIO programme RIO: Rimonabant In Overweight/Obesity RIO-North America: 2-year treatment RIO-Europe: 2-year treatment RIO-Lipids: 1-year treatment RIO-Diabetes: 1-year treatment (>6600 patients enrolled)

3. Study Population Design Obese or overweight with/without comorbidities (excluding diabetes) 3040 1+1 year Re-randomized Obese or overweight with/without comorbidities (excluding diabetes) 15072 years Obese or overweight with untreated dyslipidaemia (excluding diabetes) 1033 1 year Obese or overweight with type 2 diabetes To be released at the ADA 2005 1047 1 year Rimonabant In Overweight/Obesity N=6627 Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27

4. RIO programme study design Rimonabant 20 mg Rimonabant 5 mg Placebo Week 104 Week 52 Inclusion Randomization Week 0 Inclusion Randomization Week - 4Week - 6 Mild hypocaloric diet, reduced by 600 kcal/day Screening Placebo run-in Single-blind Treatment period: 1 or 2 years double-blind Re-randomization: RIO-NA Rimonabant 20 mg Rimonabant 5 mg Placebo Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27

5. RIO programme study populations Ratio women/men (%):  80/20 (RIO-North America & RIO-Europe)  ~50/50 (RIO-Lipids & RIO-Diabetes) 80–95% of patients had a waist circumference >88 cm (women) or 102 cm (men) Mean body weight: 94–104 kg Mean BMI: 33–38 kg/m2  >1300 patients with BMI >40 (RIO-North America & RIO-Europe) 50–70% completed 12 months Data on file

6. Associated medical conditions indicated at baseline or screening Dyslipidaemia (%)*62.760.8100 Metabolic syndrome (%) ATP III 34.741.454.0 Hypertension (%)**30.440.927.2 Smoking (%)9.319.816.7 *Patients treated for dyslipidaemia or untreated patients with LDL-C ≥3.36 mmol/L and/or HDL-C<1.03 mmol/L and/or TG ≥1.69 mmol/L ** Patients treated for hypertension or untreated patients with supine SBP ≥140 mmHg and/or DBP ≥90 mmHg N.B.Patients with type 1 or type 2 diabetes were not included in these trials Pi-Sunyer X.,2004, IASO, Sun City, South Africa, 28  31 October

7. Rimonabant induces consistent changes in: Waist circumference Weight change

8. Consistent Changes in Waist Circumference Completers -10 -8 -6 -4 -2 0 0481216202428323640444852 LOCF Waist circumference change (cm) Weeks Placebo R 20 mg Placebo R 20 mg Placebo R 20 mg -4.5cm* -8.5cm* L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727Circulation 2005, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005

9. Consistent weight change at 1 year Completers Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727Circulation 2005, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005

10. Changes in weight & waist circumference at 1-year: RIO-Europe PlaceboRimonabant 5 mgRimonabant 20 mg Completers Waist circumference change (cm) - 4.5 - 5.3 - 8.5 p<0.001 Weeks ITT LOCF placebo: - 2.4 cm 5 mg: - 3.9 cm (p=0.002 vs placebo) 20 mg: - 6.5 cm (p<0.001 vs placebo) Waist (cm) Weight change (kg) Weight (kg) - 3.6 - 4.8 p=0.042 - 8.6 p<0.001 Weeks ITT LOCF placebo: - 1.8 kg 5 mg: - 3.4 kg (p=0.002 vs placebo) 20 mg: - 6.6 kg (p<0.001 vs placebo) L.Van Gaal, Lancet 2005; 365: 1389-97

11. Weight loss ≥ 10% at 1-year Completers Placebo Rimonabant 20 mg 12.4% 10.3% 39.0% 44.3% 0 5 10 15 20 25 30 35 40 45 50 RIO~Europe RIO~Lipids Percent (%) p<0.001 13.6% 38.2% p<0.001 L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727, N. Finer, Poster presented at IASO congress 2004

12. Rimonabant produces consistent change in metabolic parameters: 1 year results Lipids (triglycerides, HDL) Insulin resistance (HOMA)

13. Change in HDL-cholesterol and triglycerides: RIO-Europe Triglycerides Weeks PlaceboRimonabant 5 mgRimonabant 20 mg ITT LOCF Placebo: 8.3% 5 mg : 5.7% (ns vs placebo) 20 mg: - 6.8% (p<0.001 vs placebo) ITT LOCF Placebo: 13.4% 5 mg: 16.2% (p=0.048 vs placebo) 20 mg: 22.3% (p<0.001 vs placebo) Completers 6.6% 4.9% -10.6% p<0.001 HDL-cholesterol Weeks 0 5 10 15 20 25 30 0481214202428323640444852 27.0% 19.0% 17.3% p<0.001 % change L.Van Gaal, Lancet 2005; 365: 1389-97

14. Improvements in lipids adjusted for weight loss: RIO-North America 20 mg vs placebo p=0.008 20 mg vs placebo p<0.001 TG Weight-independent effect 47% Weight-dependent effect 53% Overall effect: - 13.2 % 44% Weight-dependent effect HDL-C 56% Weight-independent effect Overall effect: + 7.2% % change -10 0 5 10 -5 -15 X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

15. 0.0 Improvement in fasting insulin and insulin resistance adjusted for weight loss: RIO-North America Overall effect - 0.80* - 0.8 - 0.6 - 0.4 - 0.2 2 50% Weight- dependent effect 50% Weight- independent effect - 3.0 - 2.5 - 2.0 - 1.5 - 1.0 - 0.5 0.0 FASTING INSULIN 20 mg vs Placebo *p<0.001 HOMA-IR 20 mg vs Placebo *p<0.001 Change in HOMA (%) Change in fasting insulin (µU/mL) 51% Weight- independent effect 49% Weight- dependent effect Overall effect - 2.8* 1 Year Analysis X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

16. Insulin during OGTT among patients with/without metabolic syndrome (MS) at baseline: RIO-Lipids ITT-LOCF 0 10 Time 20 30 40 50 60 70 80 90 100 110 0 mn30 mn60 mn90 mn120 mn ulU/mL Placebo 0 Rimonabant 20mg 10 20 30 40 50 60 70 80 90 100 110 0 mn30 mn60 mn90 mn120 mn Time ulU/mL AUC ulU/mL*min With MS Without MS AUC ulU/mL*min With MS Without MS Year 1 with MS Year 1 without MS Baseline with MS Baseline without MS R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409- 1

17. Effect on HOMA-derived insulin resistance: RIO-Europe ITT LOCF 5 mg vs placebo: ns 20 mg vs placebo: p=0.003 Baseline 1 year Completers  - 0.7  0.3 p=0.005 2.4 2.6 2.8 3.0 3.2 HOMA (%) 2.8 3.1 3.0 3.1 2.6 Placebo Rimonabant 20 mg Rimonabant 5 mg L.Van Gaal, Lancet 2005; 365: 1389-97

18. Changes in leptin and adiponectin: RIO-Lipids Leptin levels (ng/mL)  - 3.8 ng/mL p<0.001  1.6  g/mL p=0.001 Adiponectin levels (  g/mL) ITT-LOCF PlaceboRimonabant 20 mgPlaceboRimonabant 20 mg 18 14 5.9 6.7 5.8 8.2 10 12 14 16 18 20 22 0 2 4 6 8 10 Baseline1 Year  41% LeptinAdiponectin JP. Després, presented as a poster in ENDO congress 2004, Abst P1-345

19. Metabolic syndrome NCEP-ATP III Criteria Abdominal obesity: men: waist circumference >102 cm, women: waist circumference >88 cm Hypertension:  130/  85 mmHg Hypertriglyceridaemia:  150 mg/dl Low HDL-cholesterol: men: <40 mg/dl, women: <50 mg/dl Abnormal fasting glucose:  110 mg/dl To fulfill the diagnostic criteria for the metabolic syndrome patients must meet three of the following criteria: NCEP-ATP-III, JAMA 2001, 285: 2486-2497

20. Reduction in metabolic syndrome Placebo Rimonabant 20 mg ITT - 60 - 50 - 40 - 30 - 20 - 10 0 - 21% - 53% p<0.001 - 21% - 51% p<0.001 Reduction in metabolic syndrome (%) - 8% - 39% p<0.001 1 year L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005

21. Rimonabant induces improvement in atherogenic parameters

22. LDL peak particle size: RIO-Lipids ITT-LOCF  1.2 Å p<0.001 PlaceboRimonabant 20 mg LDL peak particle size (Å) 259.3 258.4 259.1 259.4 250 252 254 256 258 260 262 Baseline1 Year Data on file

23. Change in proportion of small and large LDL particles: RIO-Lipids Baseline1 Year Proportion of small LDL particles ITT-LOCF PlaceboRimonabant 20 mg  - 4.7% p=0.002 26.2 29.5 25.8 24.4 20 22 24 26 28 30 32 34 % small LDL particles Proportion of large LDL particles PlaceboRimonabant 20 mg  6.3% p<0.001 40.2 35.1 40.0 41.2 20 25 30 35 40 45 % large LDL particles R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409- 1

24. C-reactive protein : RIO-Lipids ITT-LOCF Baseline1 Year CRP levels (mg/L)*  - 0.6 mg/L p=0.007 PlaceboRimonabant 20 mg 3.6 3.2 3.7 2.7 0 1 2 3 4 5  27% * Excluding values>10mg/L R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409- 1

25. Rimonabant maintains metabolic benefits over 2 years

26. Waist circumference maintenance over 2 years in re-randomized patients: RIO-North America ITT-LOCF Weeks Placebo Rimonabant 20 mg/Placebo Rimonabant 20 mg/20 mg X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

27. Prevention of weight regain by chronic therapy: RIO-North America ITT-LOCF Weight (kg) Change from Baseline at 2 Years (Mean + SEM) LOCF - 7.4 ± 0.4 kg - 2.3 ± 0.5 kg - 3.2 ± 0.4 kg - 12 - 9 - 6 - 3 0 526068768492100 Weeks Weight change (kg) Placebo Rimonabant 20 mg/Placebo Rimonabant 20 mg/20 mg X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

28. Consistent Waist Circumference Changes in RIO Studies Van Gaal L.,. Presented at the ACC congress, March 2005, presentation 410-13 20 mg vs. placebo: -4.2cm (p<0.001) RIO~NA ITT (LOCF) 0 -2 -4 -6 -8 -10 -12 041220283644526068768492104LOCF Waist (cm) Weeks Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg 20 mg vs. placebo: -4.1cm (p<0.001) RIO~EU COMPLETERS

29. Weight loss in completers on the same treatment for 2 years: RIO-North America >5% weight loss >10% weight loss ITT LOCF Placebo:19.3% 5 mg: 19.0% (ns vs placebo) 20 mg: 39.7% (p<0.001 vs placebo) ITT LOCF Placebo: 8.3% 5 mg: 8.5% (ns vs placebo) 20 mg: 16.5% (p<0.001 vs placebo) *p<0.001 Placebo Rimonabant 5 mg Rimonabant 20 mg 33.2% 36.7% 62.5%* 0 20 40 60 80 % of patients 32.8%* 20.0% 16.4% 0 20 40 60 80 *p<0.001 Placebo Rimonabant 5 mg Rimonabant 20 mg % of patients X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

30. Change in metabolic syndrome status at 2 years: RIO-North America ITT, LOCF Patients (%) Baseline 2 years of treatment Rimonabant 20 mg Rimonabant 5 mg 0 10 20 30 40 Placebo 31.7% 29.2% 34.7% 29.9% 34.8% 22.5% p<0.001 X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

31. Consistent Reduction in Metabolic Syndrome at 2 Years COMPLETERS Reduction in Metabolic Syndrome (%) PlaceboRimonabant 20 mg PlaceboRimonabant 20 mg -34 % -57 % -28 % -54 % OR= 0.599 (p<0.05) OR= 0.483 (p<0.05) -60 -50 -40 -30 -20 -10 0 -54% -57% Van Gaal L.,. Presented at the ACC congress, March 2005, presentation 410-1 X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

32. HDL-cholesterol over 2 years: RIO-North America ITT-LOCF 5 mg vs placebo: ns 20 mg vs placebo: p<0.001 PlaceboRimonabant 5 mg Rimonabant 20 mg 24.5% 15.6% 13.8% 0 5 10 15 20 25 30 012243652647688104 Weeks HDL-C (% change) Completers Data on file

33. Fasting insulin over 2 years by visit: RIO-North America  20 mg vs Placebo: - 1.8 ± 0.7 µIU/ml; p=0.014 PlaceboRimonabant 5 mg Rimonabant 20 mg ITT-LOCF Data on file

34. Rimonabant improves quality of life

35. Improvement in quality-of-life scale - 4 - 2 0 2 4 6 8 10 12 14 16 Physical function Self- esteem Sexual life Public comfort Work Total score Mean Placebo Rimonabant 20 mg Improvement Mean IW-quality of life score change from baseline to year 1 JP. Després, Obes Res 2004, 12 (suppl) 231-P, A 61

36. Safety and tolerability of rimonabant

37. RIO programme pooled 1-year overall safety Pooled year 1 data: RIO-LIPIDS, RIO-EUROPE, RIO-NORTH AMERICA 13.6%8.9%7.7% Subjects discontinued due to adverse event Rimonabant Placebo 5.6%5.0%4.1% Subjects with any serious adverse event 86.1%83.0%82.5% Subjects with any adverse event 20 mg N=2164 5 mg N=2162N=1254 Rimonabant Deathsn=1n=2 n=1 Data on file

38. RIO programme pooled 1-year overall safety: AEs leading to discontinuation PlaceboRimonabant (N=1254) n (%) 5 mg (N=2162) n (%) 20 mg (N=2164) n (%) Psychiatric disorders 40 (3.2)79 (3.7)146 (6.7) Depressed mood disorders19 (1.5)48 (2.2)63 (2.9) Anxiety5 (0.4)8 (0.4)24 (1.1) Irritability2 (0.2)4 (0.2)10 (0.5) Nervous system disorders 14 (1.1)25 (1.2)46 (2.1) Headache5 (0.4)7 (0.3)10 (0.5) Dizziness 1 (<0.1)4 (0.2)14 (0.6) Gastrointestinal disorders 5 (0.4)18 (0.8)49 (2.3) Nausea 1 (<0.1)5 (0.2)29 (1.3) According to MedDRA code, 0.5% in any rimonabant group: in the 3 main system organ class. Data on file

39. RIO programme pooled 1-year cardiovascular safety Placebo Rimonabant 20 mg N subjects Mean (SD) N subjects Mean (SD) Blood pressure (mmHg) (ITT) Supine SBP change Supine DBP change Heart rate change (bpm) Mean QTcB changes 1225 1052 2130 1850 - 0.1 (11.6) - 0.8 (12.3) - 0.2 (8.1) - 0.7 (8.4) - 0.1 (7.9) 0.6 (8.2) - 2.0 (19.7)- 0.6 (19.5) Data on file

40. RIO~Europe Overall Safety Van Gaal L.,. Presented at the ACC congress, March 2005, presentation 410-13 14.5 %8.3 %9.2 % Year 1 18.9 %10.9 %13.1 % Subjects discontinued due to adverse event Yr 1 and Yr 2 Rimonabant 20mg n=599n=305n=603 Rimonabant 5mgPlacebo Year 2 3.9 % 2.6 % 4.4 %

41. Conclusions Consistent results were replicated in 3 large studies Rimonabant 20 mg consistently produced:  Significant reductions in waist circumference and weight  Significant improvement in metabolic profile: Increased HDL-cholesterol and decreased triglyceride levels Improved insulin sensitivity (HOMA)  Significant decrease in % of subjects with metabolic syndrome  Weight-independent effect of rimonabant on several metabolic variables suggestive of a direct pharmacological effect beyond weight loss alone

42. Conclusions II Rimonabant 20 mg: Improved other metabolic and cardiovascular risk factors:  Increased plasma adiponectin and decreased plasma leptin  Decreased CRP, a marker of inflammation  Improved small dense LDL particles profile Achieved efficacy at year 1 which was maintained over year 2 with chronic therapy Improved quality of life Is well tolerated

43. DISCLAIMER Rimonabant is not yet licensed This information is provided for medical information purpose