Treating Tobacco Addiction in a Subject concerned about Weight Gain – What is the role of the

1. 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. Support Disclosures • Sanofi Synthelabo • I am not a consultant or paid speaker for any pharmaceutical companies.

3. 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, andeconomic costs-United States-1995-1999. MMWR 2002;51(14):300-3

4. 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. 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. 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. 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. Subject Presentation • 42 year old WF • Employed as an artist • Married, husband is smoker • Some college • Motivated to quit (8/10 scale)

9. 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. Medical History • No significant comorbidities • No concomitant medications

11. 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. 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. Stratus WW Study (CTRI) Subject Presentation - currently • 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

14. 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 Rimonabant 20 mg n=261 Placebo n=261 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

15. 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. 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. STRATUS-US Study 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%

18. 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. STRATUS-US Conclusions • 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

20. 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. RIO Lipids Study Weight Loss 10% * p < 0.001 for high-dose vs placebo Weight Loss 5% * p < 0.001 for high-dose vs placebo * Subjects at end of 1-yr treatment

22. 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. 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. 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. 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. RIO Lipids Conclusions • 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

27. Conclusions • 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)