1. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Treating Tobacco Addiction in a Subject concerned about Weight Gain – What is the role of the investigational drug: Rimonabant. Daniel Lawrence, Ph.D. Dan Nalepinski, BS O8 October 2004

2. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Support Disclosures Sanofi Synthelabo I am not a consultant or paid speaker for any pharmaceutical companies.

3. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Tobacco Addiction Chronic, relapsing and potentially life threatening condition Contributing to increases in the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer 440,000 smoking-attributable deaths per year $157 billion in annual health-related economic losses in the United States alone Source: CDC. Annual smoking-attributable mortality, years of potential life lost, and economic costs-United States-1995-1999. MMWR 2002;51(14):300-3

4. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Smoking Statistics (USA) Adult female smokers (%): 20% Motivated to quit (%): 75% Weight gain associated with quitting: - Female quitters at 12 months: + 3.2 to 5.5 kg (13% have up to 11 kg gain) Abstinence rates (male & females): - Cold Turkey at approximately 10 weeks (%): 11% - Clinical trials data – 9 week on Zyban Zyban 58% ( 1.8 magnitude of difference) Placebo 33% Source: CDC. MMWR 2002;51(14):300-3, NEJM 1999;340:685-691

5. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Objectives Introduce Rimonabant, a drug in a new class of therapeutics called Selective CB1 Blockers. Present some preliminary results from two phase 3 clinical trials.

6. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Rimonabant A new chemical entity, which is the first potent and selective antagonist of the CB1 cannabinoid receptor. CB1 receptors are found in the brain and other human tissue, including adipocytes. CB1 receptors are part of the endocannabinoid system

7. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Rimonabant cont. Endocannabinoid system is involved in the regulation of body mass and weight, lipid metabolism, insulin resistance, and sensitivity to positive reinforcers such as alcohol, nicotine and food. Rimonabant is currently being investigated in the treatment of obesity, smoking cessation and alcohol dependence.

8. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Subject Presentation 42 year old WF Employed as an artist Married, husband is smoker Some college Motivated to quit (8/10 scale)

9. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Smoking History 30 year smoking history Smoking 15 cpd CO = 14 ppm No other tobacco use One previous quit attempt (1988) Relapsed 2° to social smoking and weight gain (6.8 kg) at approx. 16 months

10. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Medical History No significant comorbidities No concomitant medications

11. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Stratus WW Study (CTRI) Enrolled over 5,000 subjects who smoked ≥10 cigarettes/day for at least 2 months and were motivated to stop smoking Randomized, double-blind, 5 - arm, multi-country, one year on study medication, one year follow-up UW-CTRI randomized 129 subjects Study Objectives at completion of one year treatment:  Evaluate maintenance of abstinence of re-randomized (RR) subjects  Change in body weight in patients who stopped smoking  Safety and tolerability of treatment over 12 months

12. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Stratus WW Study (CTRI) 5 mg 5 mg Rimonabant Placebo 10 weeks (Abstinent –RR) 42 weeks 1 Year F/U (33%) 20 mg 20 mg Rimonabant 5 mg Placebo

13. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Stratus WW Study (CTRI) Abstinent since quit date, 54+ wks Net weight change: (baseline wt = 68.2 kg) at 10 wks: - 3.9 kg (6% change) at 52 wks: - 1.2 kg (2% change) -previous quit attempt had 6.8 kg gain (68 wks) AEs reported: HA x3 Other information: No major changes in lifestyle with respect to diet or exercise Subject Presentation - currently

14. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention STRATUS- US Study 787 patients who smoked ≥10 cigarettes/day for at least 2 months and were motivated to stop smoking Randomized, double-blind, multi-center Rimonabant 5 mg n=262 Treatment for 10 Wks Study Objectives at completion of treatment:  Prolonged Smoking abstinence (week 7 through week 10)  Change in body weight in patients who stopped smoking Rimonabant 20 mg n=261 Placebo n=261

15. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention STRATUS- US Study Prolonged abstinence rates last 4 wks of treatment (wks 7 to 10) (p < 0.001 for high-dose vs placebo, p = NS for low-dose vs placebo) “ITT” (n=784) “COMPLETERS” (n=557)

16. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention STRATUS- US Study WEIGHT – mean body weight change: baseline to end of treatment (p<0.001 for rimonabant 20 mg vs placebo) Non-obese subjects with prolonged abstinence ITT population (last obs. carried forward)

17. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Safety Data Overall summary of subjects with treatment emergent adverse events. Rimonabant Placebo 5 mg 20 mg (n=261) (n=262) (n=261) Subjects with any AE 78.5% 80.5% 86.2% Subjects with any SAE 2.3% 1.5% 2.7% Subjects d/c due to AE 3.8% 5.7% 6.9% STRATUS- US Study

18. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention STRATUS- US Study Overall, treatment was well tolerated. Most frequent side effects, mild and transient: –Nausea (9.2%, 8.8% and 15.7% for placebo, 5mg, 20mg) –URI (5.7%, 11.1% and 10% for placebo, 5mg, 20mg) No cardiovascular safety concerns (HR, BP, QTcB) and no differences were observed with regard to depression and anxiety scores (HAD scale) No difference in overall drop-out rates (27.9% placebo, 31.2% at 5mg and 28.2% at 20mg)

19. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Rimonabant 20 mg/day –Significantly increased abstinence rate compared to placebo: Prolonged Abstinence, Continuous Abstinence, 7-Day Point Prevalence Abstinence –Controlled weight gain after smoking cessation versus placebo in abstinent subjects: Normal Weight, Overweight, and Obese –Demonstrated good clinical safety profile  No safety issue related to laboratory, vital signs or ECG data STRATUS- US Conclusions

20. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention RIO Lipids Study 1,036 patients with abdominal obesity and abnormal lipid profiles Randomized, double-blind, multi-center, mild hypocaloric diet Rimonabant 5 mg n=345 Rimonabant 20 mg n=346 Placebo n=342 Treatment for 1 Year Study Objectives at completion of treatment:  Weight loss  5% of body weight and  10% of body weight  Change in cardiovascular risk factors

21. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention RIO Lipids Study Weight Loss  5% * p < 0.001 for high-dose vs placebo * Subjects at end of 1-yr treatment Weight Loss  10% * p < 0.001 for high-dose vs placebo

22. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention RIO Lipids Study Relative Reduction in CRP p=0.007 for rimonabant 20 mg vs placebo C-reactive protein reduction greater in rimonabant 20 mg arm compared with placebo (from 3.7 to 2.7 mg/l with rimonabant 20 mg vs. 3.6 to 3.2 mg/l with placebo, p=0.007) HDL increased 23% and triglycerides decreased 15% in rimonabant 20 mg, but no significant difference in LDL levels (Data not shown)

23. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention RIO Lipids Study Percentage of subjects with metabolic syndrome (1) at one year treatment, ITT population (*p<0.0001 vs placebo) * (1) At least 3 among these criteria: - Abdominal obesity - Hypertension - Hypertriglyceridemia - Low HDL cholesterol - Abnormal fasting glucose

24. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention RIO Lipids Study Safety Data Overall summary of subjects with treatment emergent adverse events. Rimonabant Placebo 5 mg 20 mg (n=334) (n=340) (n=344) Subjects with any AE 81.6% 82.3% 86.7% Subjects with any SAE 2.3% 5.2% 4.0% Subjects d/c due to AE 7.0% 8.4% 15.0%

25. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention RIO Lipids Study Overall, treatment was well tolerated. Most frequent side effects, mild and transient: –Nausea (3.2%, 7.2% and 12.7% for placebo, 5mg, 20mg) –Dizziness (6.7%, 8.4% and 10.4% for placebo, 5mg, 20mg) No cardiovascular safety concerns (HR, BP, QTcB) and no differences were observed with regard to depression and anxiety scores (HAD scale) No difference in overall drop-out rates (37.6% placebo, 39.9% at 5mg and 36.3% at 20mg)

26. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Rimonabant 20mg/day –Significant reduction in weight…. and waist circumference / abdominal obesity –Increased HDL-cholesterol and reduced triglycerides –Significantly decreased % of subjects with metabolic syndrome –Demonstrated a good clinical safety profile RIO Lipids Conclusions

27. The University of Wisconsin Medical School The Center for Tobacco Research and Intervention Rimonabant (ACOMPLIA) is the first potent, selective and orally active blocker for the endocannabinoid CB1 receptor Results from two Phase 3 studies support efficacy and safety in two indications: –Smoking cessation (STRATUS-US) –Obesity (RIO-Lipids) Conclusions