Disclosure Information… The following relationships exist related to this presentation: Michael R. Lassen Consulting Feessanofi-aventis Modest Level Dirk Zielske Employeesanofi-aventisSignificant Level Ola Dahl Consulting Fees sanofi-aventisModest Level Patrick Mismetti Consulting Fees sanofi-aventisModest Level A. Graham TurpieConsulting Feessanofi-aventis Modest level SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip Replacement Surgery – DRIVE: a Dose Ranging Study

Michael Rud Lassen Hørsholm 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 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 Sulphated tetrasaccharide Pentasaccharide Sulphated tetrasaccharide Pentasaccharide SR123781A Synthetic Hexadecasaccharide

T domain = Tetrasaccharide sequence factor Xa AT Arg Lys A domain = Pentasaccharide sequence neutral spacer Inhibition of activated Factor X

T domain = Tetrasaccharide sequence AT Arg Lys A domain = Pentasaccharide sequence thrombin neutral spacer 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 days Double 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 SR123781AEnox 0.25 mg0.5 mg1 mg2 mg4 mg40 mg All randomized Safety population Primary efficacy population

DRIVE demographics BMI: body mass index; CrCL: creatinine clearance SR123781AEnox 0.25 mg0.5 mg1 mg2 mg4 mg40 mg Median age, years Age range, years25–8618–8633–8325–9023–8628–83 Age ≥75 years, % Female, % BMI ≥30 kg/m 2, % Baseline CrCL, % <30 mL/min ≥30 – <50 mL/min

Surgical characteristics and treatment exposure SR123781AEnox 0.25 mg N= mg N=163 1 mg N=170 2 mg N=168 4 mg N= mg N=166 Mean duration of surgery ± SD, min 92 ± 4487 ± 3489 ± 3691 ± 3995 ± 4489 ± 36 Use of cement, % Anesthesia type, % General only Regional only Post-op treatment exposure, median (range), days 9 (1–11) 9 (4–11) 8 (1–11) 9 (2–11)

Primary efficacy endpoint SR123781AEnox 0.25 mg N= mg N=124 1 mg N=126 2 mg N=128 4 mg N= mg N=126 Any VTE n % 95% CI – – – – – –15.1 Significant dose response: p-value =

Primary efficacy endpoint SR123781A 0.25 mg0.5 mg 61% RRR [33–84] p= % RRR [50–92] p= mg2 mg4 mg enoxaparin 40 mg Any VTE (%)

Secondary efficacy endpoints SR123781AEnox 0.25 mg0.5mg1mg2mg4 mg40 mg Proximal DVT n/N % 95% CI 9/ –12.3 9/ –11.6 2/ –4.8 1/ –3.7 0/ –2.8 2/ –5.2 Distal DVT n/N % 95% CI 16/ – / – / –19.0 8/ –11.7 5/ –9.9 10/ –14.0 Significant dose response in proximal DVT( p = ) No Symptomatic VTE were observed in any of the groups

Bleeding assessment SR123781AEnox 0.25 mg N= mg N=163 1 mg N=170 2 mg N=168 4 mg N= 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– § (5.8) ‡ (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– (6.0) 2.9– (18.7) 13.2– (3.0) 1.0–6.9 Any, n (%) 95% CI 7 (4.1) 1.7–8.3 9 (5.5) 2.6– (2.9) 1.0– (6.5) 3.3– (24.6) 18.3– (3.6) 1.3–7.7 Significant dose response in major bleeding: p-value = any bleeding: p-value < *Fatal; **Surgical site leading to intervention; ‡ Non-surgical with bleeding index ≥2; § 5** and 5 ‡

SR123781A (mg) Enoxaparin (mg) Any VTE (%) DRIVE summary of results

SR123781A (mg) Enoxaparin (mg) Major bleeding (%) DRIVE summary of results

SR123781A (mg) Enoxaparin (mg) Any VTE (%) Major bleeding (%) DRIVE summary of results

Safety evaluation SR123781AEnox 0.25 mg N= mg N=163 1 mg N=170 2 mg N=168 4 mg N= mg N=166 Any averse event, n (%) 58 (33.9)68 (41.7)54 (31.8)55 (32.7)103 (60.2)60 (36.1) Drug-related13 (7.6)12 (7.4)9 (5.3)17 (10.1)51 (29.8)7 (4.2) Serious4 (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 1 (0.6)12 (7.0)3 (1.8) Severe Intensity4 (2.3)2 (1.2)3 (1.8)1 (0.6)16 (9.4)2 (1.2) Leading to death1*(0.6)0001**(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