Anti-thrombotic agents

New and Emerging Anticoagulants  Anti – Xa : direct  Rivaroxaban (oral)  Apixaban (oral)  Betrixiban (oral)  Edoxaban (oral)  Otamixaban (parenteral)  Anti – Xa : indirect  Idraparinux biotinylated (parenteral)  Anti – IIa  Dabigatran (oral)  Odiparcil (oral)  Flovagatran (parenteral)  Pegmusirudin (parenteral)

Site of Action for New Anti-thrombotic Agents Fibrin Clot Intrinsic Extrinsic XII VII VIII IX XI Fibrinogen II V T issue F actor X Direct Xa Inhibitors “-xaban” AT Indirect Xa Inhibitors “-parinux” Direct Thrombin Inhibitors “-gatran” warfarin

Factor Xa vs. Factor IIa  Factor Xa  One Xa forms many IIa  Limited role in diversity of action outside of coagulation cascade  Clinical effectiveness  Fondaparinux  Factor IIa  Supports feedback amplification through Factor V, Factor VIII, and Factor IX  Has many cellular effects  inflammation  Clinical effectiveness  Argatroban  Hirudins

Apixaban  Oral tablet  Bioavailability: 50%  Peak Plasma Levels = 3 hrs  Half-life ~ 12 hours  Metabolized in liver via CYP3A4 and CYP independent mechanisms  Eliminated via multiple pathways  No laboratory monitoring required  Manufactured by Bristol-Myers Squibb/Pfizer  Plan to submit for U.S. approval in

Apixaban Phase III Trials KneeKneeHipMedicallyIll # Patients 3058 ADVANCE-13058ADVANCE ADVANCE ADOPT Est. Completion Date Oct 2008 May 2009 Feb 2009 March2009 Study Arms Apixaban 2.5mg BID vs Enox 30mg BID Apixaban 2.5mg BID vsEnox 40mg QDay Apixaban 2.5mg BID vs Enox 40mg QDay Apixaban 2.5mg BID x 30 days vs Enox 40mg QDay x 6-14 days

ADVANCE – 1: Results of Efficacy vs. Enoxaparin 30 mg BID 8.99% N = % N = 1130 RR: 1.02 (95% CI: 0.78 to 1.32) P=0.06 for non-inferiority Absolute Difference: 0.1% (95% CI: to 2.44) P<0.001 for non-inferiority Lassen MR, et al. NEJM 2009;361:594 – 604.

ADVANCE – 2: Primary Efficacy Results 15.1% n = % n = 997 RR: 0.62; 95% CI: 0.51 – 0.74 p<0.0001* *Composite of adjudicated asymptomatic DVT by venography; objectively confirmed symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.

Summary of ADVANCE – 2 Study  Apixaban 2.5mg BID vs. Enoxaparin 40mg QD  Superior for:  Primary endpoint of ANY DVT/PE/All-Cause Death  Secondary endpoint for Major VTE  Lower observed bleeding rates  Major  Clinically relevant non-major  Similar overall safety profile

Rivaroxaban  Brand name Xarelto ®, Bayer  Oral tablet  High oral bioavailability (>80%)  Onset of action 2-4 hours  Half-life 9-12 hours  No observed effects on agonist-induced platelet aggregation  Primarily renal elimination  No laboratory monitoring required  No dosage adjustment for gender, age, extreme body weight  Approved by Europe and Canadian agencies, and under FDA review currently

Indirect Factor Xa Inhibitors Fibrin Clot XII VII VIII IX XI Fibrinogen II V X TF Intrinsic Extrinsic AT Indirect Xa Inhibitors “-parinux”

Idraparinux  Once weekly SC injection  100% SC bioavailability  Half-life ~ hours  Renal elimination  No monitoring required  Manufactured by Sanofi-Aventis Sanofi-Aventis  Plan to file for U.S. approval in 2009

Summary

PropertyRivaroxabanApixabanIdraparinuxDabigatran Target Factor Xa Factor Xa (indirect) Thrombin ROAOralOralSubcutaneousOral ProdrugNoNoYesYes Bioavailability > 80% > 50% 100%6% Time to peak 33___2 Half-life 9 hrs 9 – 14 hrs 80 hrs 14 – 17 hrs Frequency of Administration QdayBID Q Week Qday or BID Drug Interactions Potent CYP3A4 & P-glycoprotein inhibitors ___ P-glycoprotein inhibitors Renal excretion 66%25%Yes80% Safe in pregnancy NoNoUnknownNo AntidoteNoNoNoNo Adapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:

Conclusion  Several oral and parenteral Anti Xa and Anti IIa drugs are under development at this time  Rivaroxaban and Dabigatran are approved in the European Union and Canada for the prophylaxis of DVT and awaiting FDA review/approval  Safety issues are of prime importance in the development of these drugs and will be strongly scrutinized upon review