UPDATE ON SPECIFIC ANTIDOTES FOR TARGET-SPECIFIC ORAL ANTICOAGULANTS

Transcription

1 UPDATE ON SPECIFIC ANTIDOTES FOR TARGET-SPECIFIC ORAL ANTICOAGULANTS Junporn Kongwatcharapong (Pharm. D.) Clinical Pharmacist, Siriraj Hospital

2 OUTLINE Introduction Approach to the management of TSOACs associated major bleeding Specific antidote for TSOACs Idarucizumab Andexanet alfa Aripazine Limitations to the currently available data Conclusion 2

3 EVOLUTION OF ORAL ANTICOAGULANT THERAPY 1954 Warfarin 2003 Ximelagatran withrawn ~50 years ~ 60 years 2008 Dabigatran 2009 Rivaroxaban 2012 Apixaban 2015 Edoxaban Clin Appl Thromb Hemost Mar;21(2):

4 PROBLEM WITH WARFARIN Slow onset and slow offset Narrow therapeutic window Unpredictable response therefore requires monitoring:- inconvenience, cost Numerous interactions with other medications Anticoagulant response altered by diet and alcohol Variable dosing:- Inter- and intra-individual 4

5 CHARACTERISTICS OF THE IDEAL ANTICOAGULANT Effective Oral administration Rapid onset and offset of action Wide therapeutic window No food or drug interactions Cheap Effective antidote available Predictable response - fixed/weight-adjusted dose - well defined pharmacokinetics in renal or hepatic impairment - no monitoring required and Less Bleeding!!! 5

6 APPROACH TO THE MANAGEMENT OF TSOAC ASSOCIATED MAJOR BLEEDING Severe General life-threatening measures bleeding Initial Intensive assessment care setting Withdraw anticoagulant Early referral for mechanical Assess Hemodynamic or procedural hemodynamic support intervention status Monitor hemodynamic status Identify source of bleeding Maintain intravenous access Consider: and volume replacement Determine timing of last dose Administer 4-factor oral charcoal PCC (50 for U/kg) dabigatran Assess renal function (with apcc 2 hrs (80 of ingestion) U/kg) Determine baseline coagulation testing Blood Adjunctive product therapies transfusion Document co-medications Hemodialysis (e.g. Antiplatelet, RBC transfusion for dabigatran CYP 3A4 for or anemia removal P-gp substrate) Plasma (if for feasible) coagulopathy (e.g. DIC, dilutional Desmopressin coagulopathy) Consider J Thromb platelets Thrombolysis. Antifibrinolytic for 2015 patients Jan 14. agents on antiplatelet agents 6

7 NON-SPECIFIC AGENTS FOR REVERSAL OF DABIGATRAN ANTICOAGULANT EFFECT IN ANIMALS AND HUMANS Reversal strategy PCC apcc Animal studies (dabigatran-treated animals) Rat/mice tail transection model No reduction in blood loss in mice Reduced bleeding time, but not coagulation tests in rat Ex vivo studies (dabigatrantreated Volunteer/ patient plasma) Others aptt PT TT TG Reduced IC hematoma expansion and 24-hr mortality in mice Reduced blood loss following kidney incision in rabbits rviia Reduced IC hematoma expansion and 24-hr mortality in mice Hemo clot Human studies (dabigatrantreated healthy volunteers) No correction of aptt, ECT, TT J Thromb Thrombolysis Jan 14. 7

8 Reversal strategy PCC Animal studies (FXa inhibitors-treated animals) Ex vivo studies (FXa inhibitorstreated Volunteer/ patient plasma) Human studies (FXa inhibitorstreated healthy volunteers) NON-SPECIFIC AGENTS FOR REVERSAL OF FACTOR Xa Anti-Xa aptt PT Others PT TG INHIBITORS ANTICOAGULANT EFFECT activity IN ANIMALS AND HUMANS Rivaroxaban Apixaban + No reduction of blood loss in rabbits R Reduced bleeding time in rats, but not primates R No reduction hepatosplenic blood loss in rabbits A + Corrected PT (4-PCC>3-PCC) R Corrected some TG indices (3- PCC>4-PCC) R No effect on aptt, anti-xa activity R Reversal of prolonged bleeding duration and bleeding volume after punch biopsy (50 IU/kg) dose E apcc Rivaroxaban + rviia Rivaroxaban Apixaban No reduction of blood loss in rabbits R Reduced bleeding time in rats and primates R Reduced bleeding time in rats E Reduced bleeding time in rats, but not primates R No reduction hepatosplenic blood loss in rabbits A Reduced bleeding time in rats E + J Thromb Thrombolysis Jan 14. 8

9 SPECIFIC ANTIDOTE AGENTS Agents Target Structure Route MOA Pharmacokinetics Idarucizumab Dabigatran Humanized monoclonal antibody fragment Andexanet alfa Aripazine Direct, indirect FXa inhibitors Universal (oral Fxa and FIIa inhibitors, UFH, LMWH, and fondaparinux Modified recombinant form of FXa Small synthetic molecule IV Binds to dabigatran with a high affinity (~350 times greater affinity than thrombin) No binding to thrombin substrates (no procoagulant activity) IV IV Binds to FXa inhibitors with affinity similar to that of native FXa Binds to TSOACs and heparin and reverses the anticoagulant effects Biphasic t1/2, ranging from 0.4 hrs to a terminal t1/2 of 4.3 hrs Terminal t1/2: ~6 hrs Not available Pharmacotherapy

10 FROM MOUSE MONOCLONAL ANTIBODY TO HUMAN ANTIBODY FRAGMENT (FAB) A. Monoclonal antibodies were raised in mice immunized with dabigatran hapten coupled to carrier proteins B. Fc portion is removed (Fab) C. Constant regions are replaced with human amino acids (chimeric) D. Variable regions of Fab humanized Blood. 2013;121(18):

11 IDARUCIZUMAB Light chain Format K D, pm k a, x10 5 M -1 s -1 kd, x10-6 s -1 adabi-fab Humanized Fab 15c9 Mouse Dabigatran Heavy chain Preclinical Studies: Idarucizumab dose-dependently reduced blood loss following tail transection in dabigatran treated rats. reduced blood loss and improved survival in dabigatran treated pigs with blunt liver injury. corrected dabigatran-induced abnormal dilute PT in monkeys J Thromb Thrombolysis Jan

12 IDARUCIZUMAB In clinical study phase I Idarucizumab showed immediate, complete and sustained reversal of dabigatran anticoagulation Presented at AHA, Dallas, TX, USA, November 2013; Abstract

13 IDARUCIZUMAB Phase I studies are currently underway to further investigate the safety and PK/PD of idarucizumab in healthy Japanese male subjects. A phase Ib trial will study the antidote effects in four different arms: healthy middle-age subjects (ages 45 65), healthy elderly subjects (ages 65 80), Patients with mild renal impairment (CLcrd ml/min) or moderate renal impairment (CLcrd ml/min). These studies are expected to be completed by the end of

14 IDARUCIZUMAB In clinical study phase III the FDA granted idarucizumab Breakthrough Therapy Designation A global phase III trial is underway and enrolling patients who are on dabigatran and experience uncontrolled bleeding or require urgent surgery or procedure In this single-arm clinical case series study, patients will receive 5 g IV idarucizumab to reverse the effects of dabigatran 14

15 ANDETXANET ALFA 3 modifications introduced to human FXa Removal of the Gla-domain Mutation at the active site (S419A) formation of the RKRRKR linker that connects the light chain to the heavy chain by replacing the activation peptide with ArgLysArg (RKR) PRT (r-antidote) No pro- or anti-coagulant activity Retains binding ability for FXa inhibitors Pharmacotherapy

16 Reversal of anticoagulation in human plasma: ANDETXANET ALFA In vitro studies Clotting assay & thrombin generation assay: High affinity for FXa-inhibitors Inhibitory activity dose-dependently and completely reversed by r-antidote No pro- or anticoagulant activity 16

17 ANDETXANET ALFA In vivo rat model - reversal of anticoagulation Rapid normalisation of INR after r-antidote infusion Reversal of anticoagulation correlates to reduction of unbound FXa-inhibitor-fraction Pharmacotherapy

18 MOUSE MODEL OF BLOOD LOSS (TAIL TRANSECTION) ANDETXANET ALFA Treat-I: vehicle + vehicle + vehicle Treat-II: vehicle + rivaroxaban + vehicle Treat-III: ASA + vehicle + vehicle Treat-IV: ASA + rivaroxaban + vehicle Treat-V: ASA + rivaroxaban + r- Antidote ASS+Rivar.+r-antidote reduced blood loss by 85% After r-antidote rivaroxaban activity reduced by >80% Pharmacotherapy

19 Animal model (rat tail transection) ANDETXANET ALFA Reversal of ATIII-dependent FXa inhibitors by r-antidote Normalisation of hemostasis after r-antidote administration Complete reversal of ATIII-dependent FXa inhibition Treat-I: vehicle Treat-II: Enoxaparin & vehicle Treat-III: Enoxaparin & r-antidote 2mg/h Treat-IV: Enoxaparin & r-antidote 4mg/h Treat-I: vehicle Treat-II: Fondaparinux & vehicle Treat-III Fondaparinux & r-antidote Treat-IV: Fondaparinux & Protamine 19

20 ANDETXANET ALFA Clinical Development Programs to Date Have Demonstrated Significant Reversal of PD Markers of FXa Inhibitors Multiple Phase 2 Proof-of-Concept Studies Apixaban 5 mg PO q 12 completed Rivaroxaban 20 mg PO qd completed Enoxaparin 40 mg SQ qd completed 1 mg/kg SQ q 12 planned Edoxaban 60 mg PO qd ongoing Betrixaban 80 mg PO qd planned Phase 3 and Confirmatory Registration-enabling Studies Phase 3 studies: older healthy subjects ongoing Confirmatory study with bleeding patients to be initiated end of 2014/early

21 ANNEXA-A (Apixaban) Primary endpoint: anti-fxa levels Result: Percent change anti-fxa from baseline to nadir (=94%); p < All andexanet subjects achieved 90% reversal 22

22 ANDETXANET ALFA Phase 2 Rivaroxaban induced anticoagulation in healthy subjects Oral presentation American Society Hematology, New Orleans, Dec

23 ARIPAZINE PER977 is a synthetic small molecule PER977 directly binds all approved new oral anticoagulants (NOACs) - Dabigatran, rivaroxaban, apixaban and edoxaban Stable for > 1 year at room temperature No CYP inhibition or metabolism in vitro 23

24 PER977 restores Factor Xa activity in a dose - dependent fashion ex vivo in human plasma APTT testing confirms PER977 reverses rivaroxaban in fresh human whole blood ex vivo ARIPAZINE: Preclinical studies PER977 alone shows no dose-dependent effects on platelet aggregation and thromboelastography (TEG) in human blood ex vivo 24

25 p< p< 0.01 p< Dabigatran15 mg p< p< 0.01 Edoxaban 5 mg Full reversal at a dose mass ratio of 2.5:1 Full reversal at a dose mass ratio of 0.83:1 p< 0.05 Rivaroxaban 2 mg p< Apixaban 1.25 mg Full reversal at a dose mass ratio of 6.25:1 Full reversal at a dose mass ratio of 4:1 PER977 reduces blood loss in rats model

26 Metabolism of PER977 occurs in the blood ARIPAZINE Metabolism of PER977 in the blood is slowed in the presence of NOACs 26

27 CURRENT LIMITATIONS 1. Preclinical data based on animal model, difficulties to extrapolate to humans 2. the use of laboratory measurements of coagulation as surrogate markers for hemorrhagic outcomes is not well validated with TSOACs 3. the quantitative analysis of serum TSOACs concentrations and the associated bleed risk are not clearly established 4. The availability of antidotes and their timely administration will likely play a critical role in the success of TSOAC reversal; - Logistic challenges with regard to storage and distribution of the product 5. the economic impact of TSOACs and available reversal agents 27

28 CONCLUSION Although bleeding rates with TSOACs are not expected to be greater than warfarin, the current lack of antidote and reversal options limit the clinical use of TSOACs. However, the development of three promising antidotes has the potential to markedly improve the safety of TSOACs The availability of rapidly effective antidotes will likely allay patient and provider fears related to accidental or unintentional overdose, trauma-related bleeding, or the need for urgent surgery while the patient is taking TSOACs Regardless of the availability of an antidote, however, clinicians should continue to be mindful of the inherent risks associated with anticoagulation 28

29 CONCLUSION The availability of an antidote does not diminish the risk of bleeding; instead it only provides more effective options to treat patients who have timely access to care. Careful patient selection remains critical for the safe use of TSOACs Warfarin will continue to be a safer and possibly more effective alternative in select populations such as the elderly with renal dysfunction, patients with comorbidities associated with frequent fluctuations in renal function, or patients with poor medication adherence 29

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