Welcome Ask The Experts March 24 -27 2007

Welcome Ask The Experts March 24 -27, 2007 New Orleans, LA

New Approaches to Chronic Anticoagulation: Factor XA Inhibition C. Michael Gibson, MS, MD Associate Professor of Medicine Harvard Medical School Chief of Clinical Research Cardiology Division Beth Israel Deaconess Medical Center Boston, MA

Meeting The Unmet Needs in Chronic Anticoagulation C. Michael Gibson, M. D. , M. S.

PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet Therapy Cumulative Hazard Rates Death / MI <48 hrs after rand 0. 20 Denotes median Time to PCI ASA 0. 15 PCI after hospital discharge PCI ≥ 48 hrs from rand during initial hosp 0. 20 ASA 0. 15 0. 10 0. 05 ASA 0. 05 0. 10 ASA + Clopidogrel 0. 05 ASA + Clopidogrel RR: 0. 53 (0. 27 -1. 06) 0. 0 0 100 200 300 Days of Follow-up RR: 0. 72 (0. 51 -1. 01) 0. 0 0 100 200 300 Days of Follow-up RR: 0. 70 (0. 48 -1. 02) 0. 0 0 100 200 300 Days of Follow-up Lewis BS, et al. Am Heart J. 2005; 150: 1177 -1184.

Thrombus & Complex Lesion Remains One Month After STEMI % Thrombus on Angioscopy 100% 83% 80% 79% 70% 71% 60% 40% 20% • Only 16% of clot seen on angio 0% < 8 Days 8<& 10 < & (n=18) < 10 Days < 15 Days (n=10) (n=14) • Angioscopic findings suggestive of plaque instability are extremely frequent (75% to 80% of the study population) as is the presence of clot even in the absence of clinical symptoms. > 15 Days (n=14) Days after lysis or medical therapy Van Belle et al. Circulation. 1998; 97: 26 -33.

Angioscopy Follow up 6 Months After SES or BMS Implantation Grade 1 Thin neointima Stent Coverage Grade 2. 5 2 1. 5 P<. 05 P=. 63 P=. 80 Edge Body Overlapping Segment * * * 1 *P<. 001 compared with the corresponding segment in the BMS. 0. 5 0 Visible Thrombus P=. 70 P<. 001 P<. 0005 Grade 2 Full neointima n=21 n=33 n=12 SES n=28 n=33 n=5 BMS Frequency of Persistence of Thrombus (%) Grade 0 No neointima 100 >80% 80 P=. 031 60 40 20 0 SES BMS (N=46, 66 lesions: 33 SES, 33 BMS) Takano M, et al. Eur Heart J. 2006; 27: 2189 -2195.

Recurrent MI Following Lysis For STEMI 25% 19. 6% % Mo r ta l i ty 2 y r s 20% p<0. 0001 15% 10. 1% 5% n=19, 265 n=836 0% No Reinfarction • Recurrent MI is associated with a doubling in mortality at 2 years • Patients at risk cannot be identified clinically Reinfarction Gibson CM et al, JACC 2003

Incidence of LV Mural Thrombus in the Era of Modern Reperfusion Therapy • Series from 1997 -2002 • Among first anterior STEMI patients echoed within 72 hours LV clot was seen in 23. 5%. (36/153) * STEMI pts managed with lytic or medical mgt Porter A et al. Coron Artery Dis. 2005 Aug; 16(5): 275 -9

Meta Analysis of Anticoagulation Rates of Recurrent MI Rothberg et al. Ann. Int. Med. 2005; 143: 241 -250

ASPECT II: Coumadin is Efficacious in ACS, But Discontinuation is Common 999 Pts within 8 wks of UA or Acute MI Rx : ASA 80 mg; Coumadin (INR 3 4); or Combination: ( INR 2 2. 5)+ ASA 80 mg Efficacy Safety % Death, MI, CVA 30 Major Bleed Tranfusion Minor Bleed 20 15 8 10 5 1 1 2 1 0 ASA Rate of Discontinuation 10% Coumadin 19% Combo 20% van Es et al Lancet 360: 109, 2002

OASIS 2: Impact of Anticoagulation Discontinuation P=0. 02 P=0. 33 P=0. 005 P=0. 16 21. 3 20 18. 5 Std Rx 16. 5 % Pts Oral A/C + ASA 15 10 11. 9 8. 9 6. 1 7. 8 9 5 0 Compliance: Good (% on Oral AC) >70 % Bad < 70% CVD, MI, CVA Good > 70% Bad < 70% CVD, MI, CVA, Rehosp UA OASIS Inv JACC 37: 475, 2001

Limitations with Current Anticoagulation Therapy Agent Disadvantages Heparin • • • Parenteral administration Risk of heparin induced thrombocytopenia (HIT) Narrow therapeutic window (low bioavailability, short half life) Warfarin • Requires frequent monitoring due to: – Narrow therapeutic window – Unpredictable pharmacology – Multiple drug–drug and food–drug interactions – Increased risk of major and minor bleeds LMWH • • Parenteral administration Risk of heparin induced thrombocytopenia (HIT) Indirect Xa Inhibitor (e. g. fondaparinux) • • • Parenteral administration Long half life Limitations related to special patient populations Direct Thrombin Inhibitors • • Parenteral administration Current applications limited to cardiovascular management Albans S et al. Eur J Clin Invest 2005; 35(Suppl 1): 12 -20.

Nadia Comaneci 1976: First Perfect Score of 10 In Olympics Anticoagulation is like a balance beam performance Both efficacy and safety are important, and if you fail to balance efficacy and safety, the patient may get hurt

The Search for an Anticoagulant That Balances Safety and Efficacy Thrombosis Optimal Safety and Efficacy Bleeding Dose (concentration) of Anticoagulant

Meeting the Unmet Need in Long Term Anticoagulation in ACS • Unmet anticoagulant needs: • Safe • Effective • Ease of use • One dose • No monitoring • Unaffected by diet

ESTEEM: Primary Endpoint % D e a th / MI / R e c u r r e n t I s c h e m i a 20% Death/MI/Severe Recurrent Ischemia 16. 3% 15% p=0. 03 12. 7% 10% • Ximelagatran Dc’d in 7% of pts due to LFT abnormalities 5% 0% • The primary endpoint was lower for pooled ximelagatran compared with placebo (12. 7% vs 16. 3%, HR 0. 76, p=0. 03) n=1, 245 Placebo n=638 Pooled Ximelagatran • Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non STEMI

Rivaroxaban: An Oral Direct Xa Inhibitor • Direct, specific, competitive Factor Xa inhibitor • Inhibits free and fibrin-bound Factor Xa activity, and prothrombinase activity • Does not directly inhibit thrombin, but inhibits thrombin generation via inhibition of Factor Xa activity • Does not affect agonist-induced platelet aggregation, and therefore has no direct effect on primary hemostasis • Does not require a cofactor • No interaction with aspirin, enoxaparin, digoxin, naproxen, ranitidine, or antacids Perzborn et al. , J Thromb Haemost 2005; ICT 2004; Depasse et al. , ISTH 2005; Kubitza et al. , J Clin Pharmacol 200; ASH 2005; Fareed et al. , ISTH 2005

Rivaroxaban: a Potent and Selective Oral Direct Factor Xa Inhibitor TF (Tissue Factor) XIa XI Intrinsic Pathway IX IXa VIIa + TF VII Extrinsic Pathway VIIIa X If either the Intrinsic or Extrinsic pathway is activated, Rivaroxaban blocks the final common coagulation pathway to form thrombin by blocking Factor XA Xa Va II IIa (Thrombin) Fibrinogen Fibrin

Prothrombin Time Correlates Strongly with Plasma Concentrations of Rivaroxaban Prothrombin time (s) 40 Prothrombin time Model 30 r = 0. 958 20 10 0 0 100 200 300 400 500 Plasma concentration of Rivaroxaban (µg/l) Kubitza et al. ASH 2003 600

Rivaroxaban: Persistent Antithrombotic Effect Out to 24 Hours % Inhibition of Factor Xa 70 Rivaroxaban 1. 25 mg (n=8) Rivaroxaban 5 mg (n=6) Rivaroxaban 10 mg (n=8) Rivaroxaban 20 mg (n=7) Rivaroxaban 40 mg (n=8) 80 mg (n=6) Rivaroxaban Placebo (n=25) 60 Anti Xa Activity 50 40 30 20 10 0 2 4 6 8 10 12 14 16 18 20 Time (hours) ► All once daily dosage regimens demonstrated Xa inhibition for out to 24 hours ► These results provided foundation for selection of once daily dosing regimen for Phase III programs Kubitza, et al. Clin Pharmacol Ther 2005; 78(4): 412 -21. 22 24

Rivaroxaban: Human Pharmacokinetics • Dose peaks in 2. 5– 4 hours, half life 5 9 hours (11 13 hours in elderly) • One dose will be selected for clinical use • No monitoring required given consistent dose response • Dual modes of excretion • Renal (66%), but no excess bleeding associated with Cr. Cl to date • Faecal/biliary (28%) • Minimal drug/drug interactions, no major circulating metabolites, no drug accumulation Kubitza et al. , Eur J Clin Pharmacol 2005; Eriksson et al. , J Thromb Haemost 2006; Turpie et al. , J Thromb Haemost 2005; Kubitza et al. , ISTH 2005; Kubitza et al. , ASH 2005; Kubitza et al. , J Clin Pharmacol 2006

Rivaroxaban: Anti Thrombotic Efficacy Thrombus reduction (%) 100 *P<0. 05 ; **P<0. 01 ** 80 * 60 • Rivaroxaban dose dependently prevented arterial thrombosis 40 20 0 • Arterial thrombosis rabbit arteriovenous shunt model 0. 3 1. 0 3. 0 Rivaroxaban (mg/kg) p. o.

Rivaroxaban Safety: Bleeding Time Tail Transection Bleeding Time in Rats Compound X fold prolongation of bleeding time at ED 50 (control =1) Rivaroxaban [po] 1. 8 Enoxaparin [sc] 2. 2 Ximelagatran [po] 3. 7 Dabigatran [po] 4. 9 Warfarin [po] > 6. 3 Ø Bleeding time comparable to enoxaparin Ø Lower compared to thrombin inhibitors or warfarin

Rivaroxaban: Bleeding Time with Combination Therapy Tail Transection Bleeding Time in Rats Compounds Clopidogrel 1 mg/kg [po] Aspirin 3 mg/kg [po] + Rivaroxaban 0. 1 mg/kg [iv] X fold prolongation of bleeding time 2. 1 +/ 0. 3 2. 5 +/ 1 Similiar Bleeding Times

Dose–response Relationship: Safety And Efficacy DVT, PE, and all cause mortality Major, post operative bleeding Incidence rate % 30 20 10 0 0 5 10 15 20 25 30 35 Total daily dose (mg) of Rivaroxaban 40 Enoxaparin 40 mg Eriksson et al. , Circulation 2006

Safety and Tolerability • Rivaroxaban was well tolerated, with similar incidence of AEs as enoxaparin • Rivaroxaban did not affect ECG parameters • Rivaroxaban did not have any substance specific effects on laboratory parameters (except for clotting tests) • LFT increases with BAY 59 7939 did not exceed the level observed with enoxaparin – There was no dose-dependent increase in transaminase levels Liver function test (LFT) ALT > 3× ULN % Rivaroxaban Enox 5 mg 10 mg 20 mg 30 mg 40 mg 5/119 4. 2 6/133 4. 5 4/133 3. 0 7*/129 5. 4 5/127 3. 9 10/140 7. 1 *One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study drug)

Safety Rivaroxaban Efficacy Ease CM Gibson 2007

Rivaroxaban: Conclusions • Is a selective, reversible, active site directed Factor Xa inhibitor that inhibits coagulation triggered by both the collagen (intrinsic) and tissue factor (extrinsic) pathways • Reduces thrombus formation in both venous and arterial thrombosis models • Has a bleeding risk comparable to Enoxaparin, and lower compared to thrombin inhibitors and Warfarin, in preclinical in vivo models CM Gibson 2007

Rivaroxaban: Conclusions • Reaches Peak (Cmax)) in 2. 5– 4 hours; half life of 5– 9 hours at steady state (little longer in older) • Dual modes of excretion: Renal (66%) & Faecal / biliary (28%) • No substantial accumulation after multiple dosing, few drug interactions • Dose dependent prolongation of prothrombin time CM Gibson 2007

Rivaroxaban Clinical Development Program • Ongoing evaluation in acute and chronic settings for prevention and treatment of multiple venous and arterial indications Target Enrollment Phase II III 35, 000 40, 000 CM Gibson 2007

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