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The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
Treating Tobacco Addiction in aSubject concerned about WeightGain – What is the role of the investigational drug: Rimonabant.
Daniel Lawrence, Ph.D.Dan Nalepinski, BSO8 October 2004
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
Support Disclosures
• Sanofi Synthelabo
• I am not a consultant or paid speaker for any pharmaceutical companies.
The University of Wisconsin Medical SchoolThe 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 aloneSource: CDC. Annual smoking-attributable mortality, years of potential life lost, andeconomic costs-United States-1995-1999. MMWR 2002;51(14):300-3
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe 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.
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe 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.
The University of Wisconsin Medical SchoolThe 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)
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
Medical History
• No significant comorbidities
• No concomitant medications
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
Stratus WW Study (CTRI)
5 mg5 mg Rimonabant
Placebo
10 weeks (Abstinent –RR) 42 weeks 1 Year F/U (33%)
20 mg
20 mg Rimonabant 5 mg
Placebo
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
STRATUS-US StudyProlonged 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)
36.2%
20.2% 20.6%
0%
20%
40%
27.6%
15.6% 16.0%
0%
10%
20%
30%
40% Rimonabant 20 mgRimonabant 5 mgPlacebo
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
STRATUS-US StudyWEIGHT – 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)
0.7
3.0
0
1
2
3
4
kg
Rimonabant 20 mg Placebo
-0.3
1.1
-1
0
1
2
3
4
kg
Rimonabant 20 mg Placebo
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
Safety Data
Overall summary of subjects with treatment emergent adverse events.
RimonabantPlacebo 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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
STRATUS-US StudyOverall, 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)
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
RIO Lipids Study1,036 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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
RIO Lipids StudyWeight 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
72.9%
41.8%
27.6%
0%
20%
40%
60%
80% Rimonabant 20 mgRimonabant 5 mgPlacebo
44.3%
16.3%10.3%
0%
20%
40%
60%
80%
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
RIO Lipids StudyRelative Reduction in CRP p=0.007 for rimonabant 20 mg vs placebo
27.0%
11.0%
0%
10%
20%
30%
Rimonabant 20 mg 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)
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
Placebo 5 mg 20 mg
1 Year TxBaseline
51.9 55.952.9
41.0 40.0
25.820.0
30.0
40.0
50.0
60.0
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
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
RIO Lipids Study Safety Data
Overall summary of subjects with treatment emergent adverse events.
RimonabantPlacebo 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%
The University of Wisconsin Medical SchoolThe Center for Tobacco Research and Intervention
RIO Lipids StudyOverall, 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)
The University of Wisconsin Medical SchoolThe 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
The University of Wisconsin Medical SchoolThe 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