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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. Disclosure Information … The following relationships exist related to this presentation:.

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

  2. 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

  3. 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

  4. SR123781ASynthetic Hexadecasaccharide Thrombin domain Spacer Antithrombin domain Sulphated tetrasaccharide Pentasaccharide Sulphated tetrasaccharide Pentasaccharide The 2 functional domains are separated by a central, non sulphated, heptasaccharide This "spacer" has beenintroduced to create charge "clusters" to minimize non-specific interactions

  5. Inhibition of activated Factor X neutral spacer T domain = Tetrasaccharidesequence A domain = Pentasaccharidesequence factor Xa Arg Arg Lys AT

  6. Inhibition of activated Factor II (Thrombin) T domain = Tetrasaccharidesequence neutral spacer A domain = Pentasaccharidesequence thrombin Arg Arg Lys AT

  7. 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

  8. DRIVE: graphical study design 5 – 10 days Follow-up period Double blind, double dummy SR123781A 0.25 mg SR123781A 0.5 mg Patients 18 years Undergoing elective total hip replacement surgery SR123781A 1.0 mg SR123781A 2.0 mg SR123781A 4.0 mg enoxaparin 40 mg Day 5 –11 Day 30 ±3 Randomization (Day-1) Surgery (Day1) End of treatment visit Mandatory bilateral venography 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

  9. 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)

  10. DRIVE populations

  11. DRIVE demographics BMI: body mass index; CrCL: creatinine clearance

  12. Surgical characteristics and treatment exposure

  13. Primary efficacy endpoint Significant dose response: p-value = 0.0001

  14. 79% RRR [50–92] p=0.0001 40 61% RRR[33–84] p=0.0015 30 Any VTE (%) 20 10 0 SR123781A enoxaparin 0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg Primary efficacy endpoint

  15. Secondary efficacy endpoints Significant dose response in proximal DVT( p = 0.0001) No Symptomatic VTE were observed in any of the groups

  16. Bleeding assessment Significant doseresponse 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‡

  17. DRIVE summary of results 35 30 25 20 Any VTE (%) 15 10 5 0 0.25 0.5 1 2 4 40 Enoxaparin (mg) SR123781A (mg)

  18. DRIVE summary of results 35 30 25 20 Major bleeding (%) 15 10 5 0 0.25 0.5 1 2 4 40 Enoxaparin (mg) SR123781A (mg)

  19. 35 35 30 30 25 25 20 20 Major bleeding (%) Any VTE (%) 15 15 10 10 5 5 0 0 0.25 0.5 1 2 4 40 Enoxaparin (mg) SR123781A (mg) DRIVE summary of results

  20. Safety evaluation *Fatal bleeding; **encephalopathic brain hypoxia unrelated to bleeding or VTE

  21. 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

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