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SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip Replacement Surgery – DRIVE: a Dose Ranging Study

SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total

Hip Replacement Surgery – DRIVE: a Dose Ranging Study

Michael Rud LassenHørsholm Hospital, University of Copenhagen, Denmark

On behalf of Ola Dahl, Patrick Mismetti, Dirk Zielske, A.Graham Turpie, and the DRIVE Investigators

SR123781A

▲ Synthetic hexadecasaccharide

▲ Mixed profile of antithrombin-dependent anti-Factor Xa

and anti-factor IIa activities

▲ Completely absorbed after subcutaneous injection

▲ Half-life 11–16 h

▲ Dose-proportional and linear PK over doses studied,

0.8–18 mg

Antithrombin domainSpacerThrombin domain

OO

O

O O

O

O OO

O

OO

O

O

SO3-

SO3-

SO3-

SO3-

SO3-

-OOC

-OOC

SO3-

OMeO MeO

MeO

MeOOMe O OMe

OMe

MeOOO

O O

O

SO3-

SO3-

SO3-

OO

O

O O

O

SO3-

SO3-

SO3-

O

O O

O

SO3-

SO3-

SO3-

O

-O3SO

O

MeOMeO

OO

MeOMeO

OMe

O

OMeO

O

MeO MeO

OMe

MeO

OMe

-O3S 3

19 Na+

The 2 functional domains are separated by a central, non sulphated, heptasaccharide

This "spacer" has been introduced to create charge "clusters" to minimize non-specific interactions

Sulphatedtetrasaccharide

PentasaccharideSulphated

tetrasaccharidePentasaccharide

SR123781ASynthetic Hexadecasaccharide

T domain =Tetrasaccharide

sequence

factor Xa

AT

ArgArgLys

A domain =Pentasaccharide

sequence

neutralspacer

Inhibition of activated Factor X

T domain =Tetrasaccharide

sequence

AT

ArgArgLys

A domain =Pentasaccharide

sequence

thrombin

neutralspacer

Inhibition of activated Factor II (Thrombin)

Study Aim

▲ The objective of this study was to assess the dose-response of SR123781A for the prevention of venous thromboembolism in patients undergoing total hip replacement.

▲ To investigate a 16-fold dose range of SR123781A (0.25 mg – 4.0 mg once daily)

▲ To use 40 mg of enoxaparin once daily as calibrator

DRIVE: graphical study design

Day 30 ±3

Patients 18 years

Undergoing elective

total hip replacement

surgery

End of treatment visit

Mandatory bilateral venography

Randomization (Day-1)

Surgery (Day1)

SR123781A 0.25 mg

enoxaparin 40 mg

Follow-up period

SR123781A 0.5 mg

SR123781A 1.0 mg

SR123781A 2.0 mg

SR123781A 4.0 mg

5 – 10 daysDouble blind, double dummy

All regimens injected subcutaneously once daily

SR123781A administration to be started 8 ±1 hours post-operatively, enoxaparin 12 ±1 hours

pre-operatively, or post-operatively in case of loco-regional anesthesia

Day 5 – 11

Main endpoints

▲ Efficacy: – Composite of any deep-vein thrombosis (DVT), non-fatal

pulmonary embolism (PE), venous thromboembolism (VTE)-related death up to Day11

▲ Safety: Major bleeding– Surgical site bleeding leading to intervention– Non-surgical site bleeding: retroperitoneal or intracranial

or into a critical organ, or leading to intervention, or overt bleeding with a bleeding index 2

– Fatal bleeding

All outcomes were confirmed by an independent and blinded Adjudication Committee (Hamilton, Canada)

DRIVE populations

SR123781A Enox

0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg

All randomized 172 164 172 170 176 169

Safety population 171 163 170 168 171 166

Primary efficacy population

118 124 126 128 114 126

DRIVE demographics

BMI: body mass index; CrCL: creatinine clearance

SR123781A Enox

0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg

Median age, years 59 60 60 60 58 59

Age range, years 25–86 18–86 33–83 25–90 23–86 28–83

Age ≥75 years, % 9.9 11.7 8.2 8.9 7.0 9.0

Female, % 58.5 58.9 58.8 58.3 57.9 61.4

BMI ≥30 kg/m2, % 33.5 22.1 34.1 26.8 29.2 28.9

Baseline CrCL, %

<30 mL/min 1.2 0.6 1.2 0 0 1.2

≥30 – <50 mL/min 5.3 4.3 5.9 7.7 7.6 4.2

Surgical characteristics and treatment exposure

SR123781A Enox0.25 mgN=171

0.5 mgN=163

1 mgN=170

2 mgN=168

4 mgN=171

40 mgN=166

Mean duration of surgery ± SD, min 92 ± 44 87 ± 34 89 ± 36 91 ± 39 95 ± 44 89 ± 36

Use of cement, % 39.8 39.3 42.4 36.5 36.8 37.3

Anesthesia type, %

General only 19.9 17.2 15.9 13.8 15.8 15.7

Regional only 77.8 81.6 82.4 83.8 81.3 82.5Post-op treatment exposure, median (range), days

9 (1–11) 9 (4–11) 9 (4–11) 9 (4–11) 8 (1–11) 9 (2–11)

Primary efficacy endpoint

SR123781A Enox

0.25 mg

N=118

0.5 mg

N=124

1 mg

N=126

2 mg

N=128

4 mg

N=114

40 mg

N=126

Any VTE

n

%

95% CI

25

21.2

14.2–29.7

22

17.7

11.5–25.6

17

13.5

8.1–20.7

9

7.0

3.3–12.9

5

4.4

1.4–9.9

11

8.7

4.4–15.1

Significant dose response: p-value = 0.0001

Primary efficacy endpoint

SR123781A

0.25 mg 0.5 mg

61% RRR [33–84] p=0.0015

79% RRR [50–92] p=0.0001

0

10

20

30

40

1 mg 2 mg 4 mgenoxaparin

40 mg

Any

VT

E (

%)

Secondary efficacy endpoints

SR123781A Enox0.25 mg 0.5mg 1mg 2mg 4 mg 40 mg

Proximal DVT n/N % 95% CI

9/1356.7

3.1–12.3

9/1436.3

2.9–11.6

2/1471.4

0.2–4.8

1/1490.7

0.0–3.7

0/1300.0

0.0–2.8

2/1361.5

0.2–5.2

Distal DVT n/N % 95% CI

16/11713.7

8.0–21.3

14/12511.2

6.3–18.1

15/12512.0

6.9–19.0

8/1316.1

2.7–11.7

5/1154.3

1.4–9.9

10/1277.9

3.8–14.0

Significant dose response in proximal DVT( p = 0.0001)

No Symptomatic VTE were observed in any of the groups

Bleeding assessment

SR123781A Enox

0.25 mg

N=171

0.5 mg

N=163

1 mg

N=170

2 mg

N=168

4 mg

N=171

40 mg

N=166

Major, n (%)

95% CI

2*‡ (1.2)

0.1–4.2

1** (0.6)

0.0–3.4

1** (0.6)

0.0–3.2

1‡ (0.6)

0.0–3.3

10§ (5.8)

2.8-10.5

1‡ (0.6)

0.0–3.3

Minor, n (%)

95% CI

5 (2.9)

1.0–6.7

8 (4.9)

2.1–9.4

4 (2.4)

0.6–5.9

10 (6.0)

2.9–10.7

32 (18.7)

13.2–25.4

5 (3.0)

1.0–6.9

Any, n (%)

95% CI

7 (4.1)

1.7–8.3

9 (5.5)

2.6–10.2

5 (2.9)

1.0–6.7

11 (6.5)

3.3–11.4

42 (24.6)

18.3–31.7

6 (3.6)

1.3–7.7

Significant dose response in major bleeding: p-value = 0.0037 any bleeding: p-value < 0.0001

*Fatal; **Surgical site leading to intervention; ‡ Non-surgical with bleeding index ≥2; §5** and 5‡

0.25 0.5 1 2 4 40

SR123781A (mg) Enoxaparin (mg)

An

y V

TE

(%

)

0

5

10

15

20

25

30

35

DRIVE summary of results

0.25 0.5 1 2 4 40

SR123781A (mg) Enoxaparin (mg)

Maj

or

ble

edin

g (

%)

0

5

10

15

20

25

30

35

DRIVE summary of results

0.25 0.5 1 2 4 40

SR123781A (mg) Enoxaparin (mg)

An

y V

TE

(%

)

0

5

10

15

20

25

30

35

Maj

or

ble

edin

g (

%)

0

5

10

15

20

25

30

35

DRIVE summary of results

Safety evaluation

SR123781A Enox0.25 mg

N=1710.5 mgN=163

1 mgN=170

2 mgN=168

4 mgN=171

40 mgN=166

Any averse event, n (%)

58 (33.9) 68 (41.7) 54 (31.8) 55 (32.7) 103 (60.2) 60 (36.1)

Drug-related 13 (7.6) 12 (7.4) 9 (5.3) 17 (10.1) 51 (29.8) 7 (4.2)

Serious 4 (2.3) 3 (1.8) 5 (2.9) 1 (0.6) 20 (11.7) 3 (1.8)

Leading to study discontinuation

2 (1.2) 0 2 (1.2) 1 (0.6) 12 (7.0) 3 (1.8)

Severe Intensity 4 (2.3) 2 (1.2) 3 (1.8) 1 (0.6) 16 (9.4) 2 (1.2)

Leading to death 1*(0.6) 0 0 0 1**(0.6) 0

*Fatal bleeding; **encephalopathic brain hypoxia unrelated to bleeding or VTE

DRIVE conclusions

▲ SR123781A displayed

– A highly significant dose-response in the prevention of VTE over a 16-fold dose range

– A significant dose-response for any bleeding and major bleeding

▲ SR123781A doses ranging 1.5 – 2.5 mg demonstrated a reasonable risk-to benefit ratio for the prevention of VTE in patients undergoing major orthopedic surgery