Data Supplement

1
Data Supplement

• RIO-Europe
• RIO-Lipids
• RIO-Diabetes
• RIO-North America
• European labeling

2
RIO-Europe Study design
N 1507 BMI 30 kg/m2 or gt27 kg/m2 with
comorbidity-600 kcal/day advised to ?PA
PlaceboEnrolled 305 Completed 178
Rimonabant 20 mgEnrolled 599 Completed 363
Primary endpoint Weight change from
baselineSecondary endpoints Weight loss 5
and 10, waist circumference, FG, fasting
insulin, total-C, HDL-C, LDL-C, TG, MetS, HOMA-IR
Follow-up 1 year
Hypertension and/or dyslipidemiaLast
observation carried forward
Van Gaal LF et al. Lancet. 20053651389-97.
3
RIO-Europe Treatment effect on weight and waist
circumference
0
0
LOCF
LOCF
-2
-2
? Body weight(kg)
-4
-4
? WC(cm)
-6
-6


-8
-8
-10
-10
0
12
24
36
52
0
12
24
36
52
Weeks (intent-to-treat population)
Placebo
Rimonabant 20 mg
P 0.002 vs placeboLOCF last observation
carried forward
Van Gaal LF et al. Lancet. 20053651389-97.
4
RIO-Europe Treatment effect on lipids
30
15
10
25

5
20
? HDL-C()
? TG()
15
0
5
10

5
10
15
0
0
12
24
LOCF
36
52
52
36
LOCF
0
12
24
Weeks (intent-to-treat population)
Placebo
Rimonabant 20 mg
No significant effect on LDL-C or total-C
P 0.002 vs placebo
Van Gaal LF et al. Lancet. 20053651389-97.
5
RIO-Europe Adverse events
5 incidence in any group
Placebo ()(n 305) Rimonabant 20 mg ()(n 599)
Nasopharyngitis 15.7 15.5
Influenza 10.5 9.0
Gastroenteritis 7.9 8.5
Upper respiratory tract infection (URTI) 7.5 5.5
Bronchitis 5.2 5.7
Sinusitis 5.6 4.3
Headache 13.4 9.8
Dizziness 4.9 8.7
Nausea 4.3 12.9
Diarrhea 3.0 7.2
Arthralgia 6.9 7.8
Back pain 8.5 9.2
Fatigue 5.6 4.2
Van Gaal LF et al. Lancet. 20053651389-97.
6
RIO-Lipids Study design
N 1033 BMI 27-40 kg/m2 with untreated
dyslipidemia-600 kcal/day advised to
?physical activity
PlaceboEnrolled 342 Completed 214
Rimonabant 20 mgEnrolled 346 Completed 221
Primary endpoint Weight change from
baselineSecondary endpoints HDL-C, TG,
insulin, OGTT, MetS, leptin, adiponectin
Follow-up 1 year
TG 150-700 and/or Total-C/HDL-C gt4.5 (women) or
gt5 (men) LOCF OGTT oral glucose tolerance test
Després J-P et al. N Engl J Med. 20053532121-34.
7
RIO-Lipids Treatment effect on weight and WC
Intent-to-treat population
0
0
-2
-2
-4
-4
? Body weight (kg)
? WC (cm)
-6
-6
-8
-8


-10
-10
52
0
24
36
52
0
12
24
36
12
Weeks
Placebo
Rimonabant 20 mg
P lt 0.001 vs placebo
Després J-P et al. N Engl J Med. 20053532121-34.
8
RIO-Lipids Treatment effect on lipids
Intent-to-treat population
30
10
25
5

20
0
? TG level()
? HDL-C ()
15
-5
10
-10
5
-15

0
-20
24
36
52
0
12
24
36
52
0
12
Weeks
Placebo
Rimonabant 20 mg
P lt 0.001 vs placeboNo significant effect on
LDL-C and total-C
Després J-P et al. N Engl J Med. 20053532121-34.
9
RIO-Lipids Rimonabant weight-independent effect
on adiponectin
4
3
? Adiponectin level(?g/mL)
57 of adiponectin increase was independent of
weight loss
2
1
0
05
510
10
Weight gain
Weight loss ()
Placebo
Rimonabant 20 mg
Després J-P et al. N Engl J Med. 20053532121-34.
10
RIO-Lipids Adverse events
5 incidence in any group
Placebo ()(n 342) Rimonabant 20 mg ()(n 346)
Nasopharyngitis 21.6 19.4
Headache 15.8 15.3
Nausea 3.2 12.7
Dizziness 6.7 10.4
Influenza 5.3 9.5
URTI 9.9 8.7
Anxiety 3.8 8.7
Back pain 10.2 7.2
Diarrhea 4.1 7.2
Gastroenteritis 6.4 6.6
Insomnia 2.6 6.4
Arthralgia 9.6 5.5
Després J-P et al. N Engl J Med. 20053532121-34.
11
RIO-Diabetes Study design
N 1047 T2DM, BMI 2740 kg/m2, A1C 6.510,
and FG 100271 mg/dL-600 kcal/day advised to
?PA
PlaceboEnrolled 348 Completed 231
Rimonabant 20 mgEnrolled 339 Completed 229
Primary endpoint Weight change from
baselineSecondary endpoints A1C, HDL-C, TG,
FG, fasting insulin, hsCRP, leptin, MetS, waist
circumference, BP
Follow-up 1 year
LOCF
Scheen AJ et al. Lancet. 20063681660-72.
12
RIO-Diabetes Treatment effect on weight and
waist circumference
Intent-to-treat population
Weight
Waist circumference
0
0
-5
-1
? Body weight (lb)
? WC(in)
P lt 0.0001
P lt 0.0001
-10
-2
-15
-3
0
12
24
36
52
0
12
24
36
52
Week
Week
Placebo
Rimonabant 20 mg/day
Scheen AJ et al. Lancet. 20063681660-72.
13
RIO-Diabetes Treatment effect on lipids
HDL-C
Triglycerides
20
10
5
15
0
P lt 0.0001
? from baseline ()
? from baseline ()
P lt 0.0001
10
-5
-10
5
-15
0
-20
0
12
24
36
52
0
12
24
36
52
Week
Week
Placebo
Rimonabant 20 mg
No significant effect on LDL-C and total-C
Scheen AJ et al. Lancet. 20063681660-72.
14
RIO-Diabetes Treatment effect on glucose
metabolism
A1C
HOMA-IR
? from baseline()
? from baseline
P lt 0.0001
P 0.03
Placebo
Rimonabant 20 mg
Scheen AJ et al. Lancet. 20063681660-72.
15
RIO-Diabetes Adverse events
5 incidence in any group
Placebo ()(n 348) Rimonabant 20 mg ()(n 339)
Nausea 6 12
Nasopharyngitis 21 12
Dizziness 5 9
Arthralgia 8 9
Headache 9 8
Diarrhea 7 7
Back pain 7 7
URTI 9 7
Vomiting 2 6
Hypoglycemia 2 5
Fatigue 4 5
Anxiety 3 5
Scheen AJ et al. Lancet. 20063681660-72.
16
RIO-North America Study design
N 3045 BMI 30 kg/m2 or gt27 kg/m2 with
comorbidity
Year 1Rimonabant 20 mgEnrolled 1222Completed
673
Year 1PlaceboEnrolled 607Completed 309
Year 2PlaceboEnrolled 327 Completed 225
Year 2Rimonabant 20 mgEnrolled 333 Completed
257
Year 2PlaceboEnrolled 299Completed 214
Primary endpoints Weight change from baseline
prevention of weight regainSecondary endpoints
Weight loss 5 or 10, waist circumference,
lipids, MetS, BP, FG, fasting insulin, HOMA-IR
LOCF
Pi-Sunyer FX et al. JAMA. 2006295761-75.
17
RIO-North America Weight change by treatment
assignment
Intent-to-treat population
Year 1
Year 2
0
0
-2
-2
-4
-4
? Body weight(kg)
-6
-6
-8
-8
-10
-10
52
0
24
36
12
104
52
76
88
64
Weeks
Placebo
Rimonabant 20 mg
Placebo/Placebo
Rimonabant 20 mg/Placebo
Rimonabant 20 mg/Rimonabant 20 mg
Pi-Sunyer FX et al. JAMA. 2006295761-75.
18
RIO-North America Waist circumference by
treatment assignment
Year 1
Year 2
0
0
-2
-2
-4
-4
? WC (cm)
-6
-6
-8
-8
-10
-10
52
0
24
36
12
104
52
76
88
64
Weeks
Placebo
Rimonabant 20 mg
Placebo/Placebo
Rimonabant 20 mg/Placebo
Rimonabant 20 mg/Rimonabant 20 mg
Pi-Sunyer FX et al. JAMA. 2006295761-75.
19
RIO-North America Treatment effect on lipids at
1 year
10
5
0
8
-5
6
-10
? HDL-C(mg/dL)
? TG (mg/dL)
4
-15
2
-20
0
-25
-2
-30
24
36
52
0
12
24
36
52
0
12
Weeks
Placebo
Rimonabant 20 mg
No significant effect on LDL-C or total-C
Pi-Sunyer FX et al. JAMA. 2006295761-75.
20
RIO-North America Weight-independent and
weight-dependent effects on lipids
Rimonabant 20 mg vs placebo
58 Weight-independent effect
TG
42 Weight-dependent effect
HDL-C
47 Weight-independent effect
53 Weight-dependent effect
ANCOVA
Pi-Sunyer FX et al. JAMA. 2006295761-75.
21
RIO-North America Weight-independent and
weight-dependent effects on insulin and IR
Rimonabant 20 mg vs placebo
49Weight-dependent
50Weight-dependent
?
?
51Weight-independent
(?U/mL)
50Weight-independent
ANCOVA
Pi-Sunyer FX et al. JAMA. 2006295761-75.
22
RIO-North America Adverse events
5 incidence in any group
Placebo () (n 498) Rimonabant 20 mg ()(n 1042)
URTI 15.2 18.5
Nasopharyngitis 14.0 17.0
Nausea 5.8 11.2
Arthralgia 8.2 8.8
Sinusitis 11.7 8.7
Headache 10.2 7.8
Back pain 6.1 5.9
Influenza 7.7 8.8
Diarrhea 5.1 5.3
Viral gastroenteritis 4.8 5.7
Pi-Sunyer FX et al. JAMA. 2006295761-75.
23
RIO-North America Adverse events, contd
5 incidence in any group
Placebo ()(n 498) Rimonabant 20 mg ()(n 1042)
Dizziness 4.0 5.6
Anxiety 2.1 6.1
Bronchitis 5.1 4.3
Depressed mood 3.1 5.2
Fatigue 3.6 5.2
Insomnia 4.4 5.8
Pi-Sunyer FX et al. JAMA. 2006295761-75.
24
Obesity program depression-related events
Overall incidences
Rimonabant
PlaceboN 2472()
5 mgN 2520()
20 mgN 2742()

• Depressed mood disorders
• and disturbances
• Mood alterations with depressive symptoms
• Depressive disorders

4.5 2.81.7
6.3 3.62.8
8.4 4.73.9
Obesity program (RIO-Europe, RIO-North America,
RIO-Lipids, RIO-Diabetes, REBA, EFC5745 and
ACT3801)Taking into account any patient exposure
Data on file from sanofi-aventis.
25
Completed phase 2 and 3 studies as of March
2007 All suicidality-related events
Rimonabant
PlaceboN 3411N ()
5 mgN 5254N ()
10 mgN 198N ()
20 mgN 7851N ()
40 mgN 206N ()
Definitely suicidal(suicidal behavior/ideation)
Possibly suicidal
21 2
11 1
0 0
48 5
0 0
(0.62) (0.06)
(0.21) (0.02)
(0) (0)
(0.61) (0.06)
(0) (0)
Phase 2 studies ACT4389, DRI3388, ACT4855,
Metatrial study (DFI3077, DFI3024, DFI3067,
DFI3138), PDY3796, DRI5747 and Phase 3 studies
RIO-Europe, RIO-North America, RIO-Lipids,
RIO-Diabetes, REBA, SERENADE, EFC5745, ACT3801
and EFC4474, EFC4796, EFC4964, EFC5794,
EFC4798Originally reported as a completed
suicide but adjudicated as not enough
information, fatalUsing first randomized
treatment
Data on file from sanofi-aventis.
26
Rimonabant clinical safety Summary

• Safety assessment based on extensive exposure up
  to 2 years
• The most frequent adverse events that led to drug
  discontinuation were depression, mood alteration,
  nausea and anxiety
• Psychiatric events
• Increased incidence of depression-related events
  and anxiety with rimonabant vs placebo, overall
  incidence remained relatively low
• Most adverse events were mild to moderate
  intensity
• Similar qualitative characteristics between
  rimonabant 20 mg vs placebo
• No clinical changes in laboratory test,
  electrocardiogram, or vital signs
• Long-term exposure did not identify new or
  increased risks and supports its long term
  administration in overweight/obese patients with
  at least one cardiometabolic risk factor

Data on file from sanofi-aventis.
27
ACOMPLIA European product information

• Therapeutic indication
• As an adjunct to diet and exercise for treatment
  of patients with BMI 30 kg/m2 or gt27 kg/m2 with
  associated risk factors such as T2DM or
  dyslipidemia
• Adult dosing
• 20 mg daily, to be taken in the morning before
  breakfast
• No dosage adjustment in elderly, mild/moderate
  hepatic insufficiency, or mild/moderate renal
  impairment

European Medicines Agency (EMEA).
http//emea.europa.eu.
28
ACOMPLIA European product information, contd

• Contraindicated/Not recommended
• Pregnant or breast-feeding women
• Children below age 18 years
• Uncontrolled serious psychiatric illness such as
  major depression
• Taking antidepressant medication
• Severe renal or hepatic impairment

• Use with caution
• Receiving potent CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Ritonavir
• Telithromycin
• Clarithromycin
• Nefazodone
• Treated for epilepsy
• Moderate hepatic impairment
• Age gt75 years

EMEA. http//emea.europa.eu.