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

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Presentation on theme: "Welcome Ask The Experts March 24-27, 2007 New Orleans, LA."— Presentation transcript:

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

2 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 New Approaches to Chronic Anticoagulation: Factor XA Inhibition

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

4 PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet Therapy Lewis BS, et al. Am Heart J. 2005;150: Cumulative Hazard Rates Death / MI Days of Follow-up <48 hrs after rand RR:0.53 ( ) Denotes median Time to PCI Denotes median Time to PCI Days of Follow-up PCI ≥ 48 hrs from rand and during initial hosp RR:0.72 ( ) ASA + Clopidogrel ASA PCI after hospital discharge PCI after hospital discharge Days of Follow-up RR:0.70 ( ) ASA + Clopidogrel ASA

5 Thrombus & Complex Lesion Remains One Month After STEMI Van Belle et al. Circulation. 1998;97: % Thrombus on Angioscopy < 8 Days (n=18) 8 < & < 10 Days (n=10) > 15 Days (n=14) 10 < & < 15 Days (n=14) 83% 70% 71% 79% 0% 20% 40% 60% 80% 100% Days after lysis or medical therapy 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. 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. Only 16% of clot seen on angio Only 16% of clot seen on angio 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. 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. Only 16% of clot seen on angio Only 16% of clot seen on angio

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

7 10.1%10.1% 19.6%19.6% 0%0% 5%5% 10%10% 15%15% 20%20% 25%25% No Reinfarction ReinfarctionReinfarction n=19,265n=19,265n=836n=836 p<0.0001p< Gibson CM et al, JACC 2003 % Mortality 2 yrs Recurrent MI Following Lysis For STEMI Recurrent MI is associated with a doubling in mortality at 2 yearsRecurrent MI is associated with a doubling in mortality at 2 years Patients at risk cannot be identified clinicallyPatients at risk cannot be identified clinically Recurrent MI is associated with a doubling in mortality at 2 yearsRecurrent MI is associated with a doubling in mortality at 2 years Patients at risk cannot be identified clinicallyPatients at risk cannot be identified clinically

8 Incidence of LV Mural Thrombus in the Era of Modern Reperfusion Therapy Series from Among first anterior STEMI patients echoed within 72 hours LV clot was seen in 23.5%. (36/153) Series from Among first anterior STEMI patients echoed within 72 hours LV clot was seen in 23.5%. (36/153) Porter A et al. Coron Artery Dis Aug;16(5):275-9 * STEMI pts managed with lytic or medical mgt

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

10 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 Death,MI,CVA ASACoumadinCombo % Major Bleed Tranfusion Minor Bleed van Es et al Lancet 360:109,2002 Rate of Discontinuation 10% 19%20% Efficacy SafetySafety

11 OASIS 2: Impact of Anticoagulation Discontinuation % Pts P=0.33 CVD,MI,CVA CVD, MI, CVA, Rehosp UA Compliance:Good BadGoodBad (% on Oral AC) >70 % 70% 70 % 70% < 70% P=0.02P=0.005P=0.16 Std Rx Oral A/C + ASA OASIS Inv JACC 37:475,2001

12 AgentDisadvantages HeparinParenteral administration Risk of heparin-induced thrombocytopenia (HIT) Narrow therapeutic window (low bioavailability, short half- life) WarfarinRequires frequent monitoring due to: –Narrow therapeutic window –Unpredictable pharmacology –Multiple drug–drug and food–drug interactions –Increased risk of major and minor bleeds LMWHParenteral 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 Limitations with Current Anticoagulation Therapy Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.

13 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 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

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

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

16 16.3%16.3% 12.7%12.7% 0%0% 5%5% 10%10% 15%15% 20%20% PlaceboPlacebo Pooled Ximelagatran n=1,245n=1,245n=638 p=0.03p=0.03 % Death/MI/Recurrent Ischemia ESTEEM: Primary Endpoint Death/MI/Severe Recurrent Ischemia The primary endpoint was lower for pooled ximelagatran compared with placebo (12.7% vs 16.3%, HR 0.76, p=0.03)The primary endpoint was lower for pooled ximelagatran compared with placebo (12.7% vs 16.3%, HR 0.76, p=0.03) Ximelagatran Dc’d in 7% of pts due to LFT abnormalitiesXimelagatran Dc’d in 7% of pts due to LFT abnormalities The primary endpoint was lower for pooled ximelagatran compared with placebo (12.7% vs 16.3%, HR 0.76, p=0.03)The primary endpoint was lower for pooled ximelagatran compared with placebo (12.7% vs 16.3%, HR 0.76, p=0.03) Ximelagatran Dc’d in 7% of pts due to LFT abnormalitiesXimelagatran Dc’d in 7% of pts due to LFT abnormalities Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non-STEMI Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non-STEMI

17 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

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

19 Prothrombin Time Correlates Strongly with Plasma Concentrations of Rivaroxaban Kubitza et al. ASH 2003

20 Rivaroxaban: Persistent Antithrombotic Effect Out to 24 Hours Time (hours) % Inhibition of Factor Xa Anti-Xa Activity Rivaroxaban Placebo (n=25) 1.25 mg (n=8) 5 mg (n=6) 10 mg (n=8) 20 mg (n=7) 40 mg (n=8) 80 mg (n=6) Kubitza, et al. Clin Pharmacol Ther 2005;78(4): ►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

21 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 CrCl to date Faecal/biliary (28%) Minimal drug/drug interactions, no major circulating metabolites, no drug accumulation 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 CrCl 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

22 Rivaroxaban: Anti-Thrombotic Efficacy * ** Rivaroxaban (mg/kg) p.o. Thrombus reduction (%) Arterial thrombosis rabbit arteriovenous shunt model Arterial thrombosis rabbit arteriovenous shunt model Rivaroxaban dose- dependently prevented arterial thrombosis Rivaroxaban dose- dependently prevented arterial thrombosis Arterial thrombosis rabbit arteriovenous shunt model Arterial thrombosis rabbit arteriovenous shunt model Rivaroxaban dose- dependently prevented arterial thrombosis Rivaroxaban dose- dependently prevented arterial thrombosis *P<0.05 ; **P<0.01

23 Rivaroxaban Safety: Bleeding Time 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 Tail Transection Bleeding Time in Rats  Bleeding time comparable to enoxaparin  Lower compared to thrombin inhibitors or warfarin  Bleeding time comparable to enoxaparin  Lower compared to thrombin inhibitors or warfarin

24 Rivaroxaban: Bleeding Time with Combination Therapy Compounds X-fold prolongation of bleeding time Clopidogrel 1 mg/kg [po] Aspirin 3 mg/kg [po] 2.1 +/- 0.3 Clopidogrel 1 mg/kg [po] Aspirin 3 mg/kg [po] + Rivaroxaban 0.1 mg/kg [iv] 2.5 +/- 1 Similiar Bleeding Times Tail Transection Bleeding Time in Rats

25 Dose–response Relationship: Safety And Efficacy Enoxaparin 40 mg Total daily dose (mg) of Rivaroxaban Incidence rate % DVT, PE, and all-cause mortalityMajor, post-operative bleeding Eriksson et al., Circulation 2006

26 Safety and Tolerability Liver function test (LFT) RivaroxabanEnox 5 mg10 mg20 mg30 mg40 mg ALT > 3× ULN % 5/ / / */ / / 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 59­7939 did not exceed the level observed with enoxaparin –There was no dose-dependent increase in transaminase levels *One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study drug)

27 SafetySafety EfficacyEfficacy EaseEase RivaroxabanRivaroxaban CM Gibson 2007

28 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

29 Rivaroxaban: Conclusions Reaches Peak (C max) ) 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

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

31 Question&Answer

32 Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive


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