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

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


Support Disclosures

• Sanofi Synthelabo

• I am not a consultant or paid speaker for any pharmaceutical companies.


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


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


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.


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


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.


Subject Presentation

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


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


Medical History

• No significant comorbidities

• No concomitant medications


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


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


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


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


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


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



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


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)


• 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


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


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%


RIO Lipids StudyRelative Reduction in CRP p=0.007 for rimonabant 20 mg vs placebo

27.0%

11.0%

0%

10%

20%

30%


• 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)


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


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%


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)


• 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


• 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

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