Rimonabant:

1

• Rimonabant
• A new approach to multiple
• cardiometabolic risk factors

Version 1.1 29 April 2005
2
RIO programme

• RIO Rimonabant In Overweight/Obesity

(gt6600 patients enrolled)
RIO-North America 2-year treatment RIO-Europe
2-year treatment RIO-Lipids 1-year
treatment RIO-Diabetes 1-year treatment
3
Rimonabant In Overweight/Obesity
Study Population Design
Obese or overweight with/without comorbidities (excluding diabetes) 3040 11 year Re-randomized
Obese or overweight with/without comorbidities (excluding diabetes) 1507 2 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
N6627
Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27
4
RIO programme study design
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)
• 8095 of patients had a waist circumference gt88
  cm (women) or 102 cm (men)
• Mean body weight 94104 kg
• Mean BMI 3338 kg/m2
• gt1300 patients with BMI gt40 (RIO-North America
  RIO-Europe)
• 5070 completed 12 months

Data on file
6
Associated medical conditionsindicated at
baseline or screening

Dyslipidaemia () 62.7 60.8 100
Metabolic syndrome () ATP III 34.7 41.4 54.0
Hypertension () 30.4 40.9 27.2
Smoking () 9.3 19.8 16.7
Patients treated for dyslipidaemia or untreated
patients with LDL-C 3.36 mmol/L and/or
HDL-Clt1.03 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

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Consistent Changes in Waist Circumference
Completers
Placebo
R 20 mg
-4.5cm
Waist circumference change (cm)
Placebo
R 20 mg
-8.5cm
Placebo
R 20 mg
Weeks
L.Van Gaal, Lancet 2005 365 1389-97, X.
Pi-Sunyer, Circulation 2005111(13)1727Circulatio
n 2005, JP. Després, Int J. Obes. Relat Metab
Disod 2004, 28 (Suppl1) pS28 T5O2-005
9
Consistent weight change at 1 year
Completers
L.Van Gaal, Lancet 2005 365 1389-97, X.
Pi-Sunyer, Circulation 2005111(13)1727Circulatio
n 2005, JP. Després, Int J. Obes. Relat Metab
Disod 2004, 28 (Suppl1) pS28 T5O2-005
10
Changes in weight waist circumference at
1-year RIO-Europe
Completers
Waist (cm)
Weight (kg)
Waist circumference change (cm)
Weight change (kg)
- 3.6
- 4.5
- 4.8 p0.042
- 5.3
- 8.5 plt0.001
- 8.6 plt0.001
Weeks
Weeks
ITT LOCF placebo - 2.4 cm 5 mg - 3.9
cm (p0.002 vs placebo) 20 mg - 6.5 cm
(plt0.001 vs placebo)
ITT LOCF placebo - 1.8 kg 5 mg - 3.4
kg (p0.002 vs placebo) 20 mg - 6.6 kg
(plt0.001 vs placebo)
L.Van Gaal, Lancet 2005 365 1389-97
11
Weight loss 10 at 1-year
Completers
L.Van Gaal, Lancet 2005 365 1389-97, X.
Pi-Sunyer, Circulation 2005111(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)

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Change in HDL-cholesterol and triglycerides RIO-E
urope
Completers
Triglycerides
HDL-cholesterol
change
Weeks
Weeks
ITT LOCF Placebo
8.3 5 mg 5.7 (ns vs placebo) 20 mg
- 6.8 (plt0.001 vs placebo)
ITT LOCF Placebo
13.4 5 mg 16.2 (p0.048 vs placebo) 20 mg
22.3 (plt0.001 vs placebo)
L.Van Gaal, Lancet 2005 365 1389-97
14
Improvements in lipids adjusted forweight loss
RIO-North America
10
44 Weight-dependent effect
Overall effect 7.2
5
56 Weight-independent effect
TG
0
Weight-independent effect 47
change
HDL-C
-5
Overall effect - 13.2
-10
Weight-dependent effect 53
-15
20 mg vs placebo p0.008
20 mg vs placebo plt0.001
X. Pi-Sunyer, presented at a late breaking
session at the AHA congress 2004
15
Improvement in fasting insulin and insulin
resistance adjusted for weight lossRIO-North
America
1 Year Analysis
0.0
0.0
50 Weight- dependent effect
51 Weight- independent effect
50 Weight- independent effect
2
- 0.5
- 0.2
- 1.0
- 0.4
Change in HOMA ()
Overall effect - 0.80
Change in fasting insulin (µU/mL)
49 Weight-dependent effect
- 1.5
Overall effect - 2.8
- 2.0
- 0.6
- 2.5
- 0.8
HOMA-IR 20 mg vs Placebo plt0.001
FASTING INSULIN 20 mg vs Placebo plt0.001
- 3.0
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
R, Després J-P. Presented at the ACC congress,
March 2004, Abstr. 409-1
17
Effect on HOMA-derived insulin resistance
RIO-Europe
? - 0.7 ? 0.3 p0.005
Completers
1 year
Baseline
ITT LOCF 5 mg vs placebo ns
20 mg vs placebo p0.003
L.Van Gaal, Lancet 2005 365 1389-97
18
Changes in leptin and adiponectin RIO-Lipids
ITT-LOCF
Leptin
Adiponectin
? - 3.8 ng/mL plt0.001
? 1.6 ?g/mL p0.001
10
22
8.2
6.7
20
18
18
18
8
?41
5.9
5.8
18
6
Adiponectin levels (?g/mL)
Leptin levels (ng/mL)
16
14
4
14
2
12
0
10
Placebo
Rimonabant 20 mg
Placebo
Rimonabant 20 mg
Baseline
1 Year
JP. Després, presented as a poster in ENDO
congress 2004, Abst P1-345
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Metabolic syndrome NCEP-ATP IIICriteria
To fulfill the diagnostic criteria for the
metabolic syndrome patients must meet three of
the following criteria

• Abdominal obesity men waist circumference
  gt102 cm,
• women waist circumference gt88 cm
• Hypertension ?130/?85 mmHg
• Hypertriglyceridaemia ?150 mg/dl
• Low HDL-cholesterol men lt40 mg/dl,
• women lt50 mg/dl
• Abnormal fasting glucose ?110 mg/dl

NCEP-ATP-III, JAMA 2001, 285 2486-2497
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Reduction in metabolic syndrome
1 year
ITT
L.Van Gaal, Lancet 2005 365 1389-97, X.
Pi-Sunyer, Circulation 2005111(13)1727, JP.
Després, Int J. Obes. Relat Metab Disod 2004, 28
(Suppl1) pS28 T5O2-005
21

• Rimonabant
• induces improvement
• in atherogenic parameters

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LDL peak particle size RIO-Lipids
ITT-LOCF
? 1.2 Å plt0.001
Baseline
1 Year
Data on file
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Change in proportion of small and large LDL
particles RIO-Lipids
ITT-LOCF
Proportion of large LDL particles
Proportion of small LDL particles
R, Després J-P. Presented at the ACC congress,
March 2004, Abstr. 409-1
24
C-reactive protein RIO-Lipids
ITT-LOCF
Excluding valuesgt10mg/L
R, Després J-P. Presented at the ACC congress,
March 2004, Abstr. 409-1
25

• Rimonabant maintains metabolic benefits
• over 2 years

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Waist circumference maintenance over 2 years in
re-randomized patientsRIO-North America
ITT-LOCF
Weeks
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)
X. Pi-Sunyer, presented at a late breaking
session at the AHA congress 2004
28
Consistent Waist Circumference Changes in RIO
Studies
RIONA
20 mg vs. placebo -4.2cm (plt0.001)
Van Gaal L., . Presented at the ACC congress,
March 2005, presentation 410-13
29
Weight loss in completers on the same treatment
for 2 years RIO-North America
gt5 weight loss
gt10 weight loss
ITT LOCF Placebo 19.3 5 mg
19.0 (ns vs placebo) 20 mg 39.7 (plt0.001
vs placebo)
ITT LOCF Placebo 8.3 5 mg
8.5 (ns vs placebo) 20 mg 16.5 (plt0.001 vs
placebo)
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 ()
X. Pi-Sunyer, presented at a late breaking
session at the AHA congress 2004
31
Consistent Reduction in Metabolic Syndrome at 2
Years
COMPLETERS
Placebo
Rimonabant20 mg
Placebo
Rimonabant20 mg
0
-10
-20
-28
-34
-30
-40
-54
-54
-50
-57
-57
OR 0.599 (plt0.05)
-60
OR 0.483 (plt0.05)
Reduction in Metabolic Syndrome ()
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 plt0.001
Data on file
33
Fasting insulin over 2 years by visit RIO-North
America
ITT-LOCF
Data on file
34

• Rimonabant
• improves quality of life

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

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RIO programme pooled 1-year overall safety
Data on file
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RIO programme pooled 1-year overall safety AEs
leading to discontinuation
Placebo Rimonabant Rimonabant
(N1254) n () 5 mg (N2162) n () 20 mg (N2164) n ()
Psychiatric disorders 40 (3.2) 79 (3.7) 146 (6.7)
Depressed mood disorders 19 (1.5) 48 (2.2) 63 (2.9)
Anxiety 5 (0.4) 8 (0.4) 24 (1.1)
Irritability 2 (0.2) 4 (0.2) 10 (0.5)
Nervous system disorders 14 (1.1) 25 (1.2) 46 (2.1)
Headache 5 (0.4) 7 (0.3) 10 (0.5)
Dizziness 1 (lt0.1) 4 (0.2) 14 (0.6)
Gastrointestinal disorders 5 (0.4) 18 (0.8) 49 (2.3)
Nausea 1 (lt0.1) 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
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RIO programme pooled 1-year cardiovascular safety
Data on file
40
RIOEurope Overall Safety
Rimonabant 20mg
Rimonabant 5mg
Placebo
n599
n305
n603
18.9
10.9
13.1
Subjects discontinued due to adverse event Yr 1
and Yr 2
14.5
8.3
9.2
Year 1
2.6
Year 2
3.9
4.4
Van Gaal L., . Presented at the ACC congress,
March 2005, presentation 410-13
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

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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

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DISCLAIMERRimonabant is not yet licensedThis
information is provided for medical information
purpose