Αντίδοτα στα νεότερα αντιπηκτικά. Τι νεότερο υπάρχει σήµερα?

Transcription

1 ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Αντίδοτα στα νεότερα αντιπηκτικά. Τι νεότερο υπάρχει σήµερα? Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχηµείας - Κλινικής Χηµείας

2 Σύγκρουση Συµφερόντων Καµία

3 Oral Anticoagulant Target Sites Factor IX Factor VII Factor X FVIIa Anti-FXa Apixaban Rivaroxaban Edoxaban Betrixaban FIXa Factor Xa Antithrombin VKA Warfarin Factor II (Prothrombin) Factor IIa (Thrombin) Anti-FIIa Dabigatran Fibrinogen Fibrin

4 Forest plot for bleeding for TSOACs versus Warfarin in AF Major bleeding Intracranial bleeding GI bleeding Miller CS, et al. Am J Cardiol 2012;110:

5 Forest plot for Major bleeding for TSOACs vs Warfarin Chai-Adisaksopha C, et al Blood. 2014;124(15):

6 Forest plot for Intracranial bleeding for TSOACs vs Warfarin Chai-Adisaksopha C, et al Blood. 2014;124(15):

7 Forest plot for Major GI Bleeding for TSOACs vs Warfarin Chai-Adisaksopha C, et al Blood. 2014;124(15):

8 Forest plot for Fatal bleeding for TSOACs vs Warfarin Chai-Adisaksopha C, et al Blood. 2014;124(15):

9 Pharmacokinetic properties of TSOACs and warfarin Liotta EM, et al. Curr Opin Crit Care. 2015

10 Non-Specific Reversal Agents Composition of selected clotting factor products Beriplex Cofact Profilnine Bebulin NovoSeven FEIBA Shah N, et al. AMSRJ 2014; 1(1):16 28

11 INR correction with both vitamin K and PCC administration Schematic diagram showing the effect of vitamin K and PCC on INR correction! Vitamin K has slow effect on INR (time to re-synthesize coagulation factors)! PCC infusion is needed for quick correction! The pharmacodynamic effects may overlap when given at the same time

12 EHRA guidelines Reversal of TSOACs in life-threatening bleeding

13 Specific Reversal Strategies for TSOACs Ongoing research

14 Specific Reversal Agents in Development for TSOACs Company Compound Reversal for: Portola Pharmaceuticals ANNEXA TM, Andexanet alfa, (PRT064445) Boehringer Ingelheim Perosphere, Inc. Idarucizumab (BI ) Aripazine (PER977) Factor Xa inhibitor Universal No Factor IIa inhibitor No Specific for dabigatran LMWH/ fondaparinux Yes (antithrombinmediated Factor Xa inhibition) No Universal Universal Universal Status Phase II ongoing phase III started (apixaban/ rivaroxaban) planned (edoxaban) Phase I completed; phase III started Phase I completed phase II ongoing

15 ANNEXA TM Andexanet alfa A universal Factor Xa inhibitor Reversal Agent Normal FXa Serine in protease catalytic triad Binding pocket! Andexanet alfa is inactivated Factor Xa Lower molecular weight owing to truncated chain No GLA domain Mutated serine Active binding site to Factor Xa substrates γ-carboxyglutamic acid (GLA) domain Andexanet alfa! The molecule has no catalytic activity and does not bind to the protaminase complex Mutated serine in protease catalytic triad Binding pocket! Intact binding site allows binding to: Direct Factor Xa inhibitors, e.g. Rivaroxaban, Apixaban ATIII activated by LMWH or fondaparinux Truncated chain No GLA domain

16 Schematic structure and mechanism of action of Andexanet alfa Shah N, et al. AMSRJ 2014; 1(1):16 28

17 Study of rats infused with boluses of Enoxaparin and Andexanet alfa Shah N, et al. AMSRJ 2014; 1(1):16 28

18 Reversal of TSOACs by Andexanet alfa Ex vivo Lu G, et al. Nature Medicine 2013; 19:

19 Addition of Andexanet alfa Reverses Rivaroxaban-induced PT prolongation Ex vivo experiment in PPP: Andexanet alfa itself in absence of rivaroxaban has no effect on PT (blue bar) Lu G, et al. Nature Medicine 2013; 19:

20 Addition of Andexanet alfa decreases rivaroxaban-induced blood loss Lu G, et al. Nature Medicine 2013; 19:

21 Andexanet alfa (ANNEXA TM ) - Human studies Phase I single ascending-dose study in healthy volunteers In 32 healthy volunteers andexanet alfa was generally well tolerated with no apparent safety signals Phase II proof-of-concept studies in healthy volunteers Results from 4 separate studies demonstrated that andexanet alfa immediately reversed the anticoagulation activity of apixaban, rivaroxaban edoxaban and enoxaparin No thrombotic events, serious or severe adverse events or antibodies against FX or FXa were reported

22 Results from Phase 2 trials of Andexanet alfa and FXa inhibitors Shah N, et al. AMSRJ 2014; 1(1):16 28

23 ANNEXA-A: Apixaban Healthy volunteers aged years Apixaban 5 mg twice daily for 4 days n=24 Apixaban Andexanet alfa 400 mg iv bolus n=9 Biomarker endpoints Primary end point: anti-fxa levels Secondary end points: Plasma free fraction of Apixaban and Thrombin generation levels Apixaban 3:1 ratio Andexanet alfa 400 mg iv bolus + 4 mg/min for 120 min Study participants will be followed for up to 43 days to assess safety

24 ANNEXA-R: Rivaroxaban Healthy volunteers aged years Rivaroxaban 20 mg once daily for 4 days n=27 Rivaroxaban n=41 Andexanet alfa 800 mg iv bolus n=14 Biomarker endpoints Primary end point: anti-fxa levels Secondary end points: Plasma free fraction of Rivaroxaban Thrombin generation levels Rivaroxaban 2:1 ratio n=40 Andexanet alfa 800 mg iv bolus + 8 mg/min for 120 min Study participants will be followed for up to 43 days to assess safety

25 ANNEXA-A: Apixaban PART I Primary Efficacy Endpoint

26 ANNEXA-A: Apixaban PART I Secondary Efficacy Endpoint

27 ANNEXA-A: Apixaban PART I Secondary Efficacy Endpoint Liotta EM, et al. Curr Opin Crit Care. 2015

28 Dabigatran Managing bleeding complications A specific antidote may provide an additional option for patient management during emergency situations

29 Idarucizumab An antidote specific to Dabigatran Restoration of coagulation Potent binding affinity ~350 times higher than the binding of dabigatran to thrombin No procoagulant or anticoagulant effects Short half-life Easy and rapid administration IV administration, immediate onset of action Low risk of adverse reactions No Fc receptor binding No endogenous targets Fully humanized antibody fragment (Fab) Glund S et al. AHA 2013; abstract 17765; Van Ryn J. AHA 2012; Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928

30 Idarucizumab Fully Restores Dabigatran-Induced Alterations on Platelet and Fibrin Deposition on Damaged Vessels: Studies in Vitro with Circulating Human Blood Healthy Volunteers Eduardo Arellano-Rodrigo, et al. ASH 2014

31 Idarucizumab Fully Restores Dabigatran-Induced Alterations on Platelet and Fibrin Deposition Damaged Vessels: Studies in Vitro with Circulating Human Blood Eduardo Arellano-Rodrigo, et al. ASH 2014

32 Idarucizumab Fully Restores Dabigatran-Induced Alterations on Platelet and Fibrin Deposition on Damaged Vessels: Studies in Vitro with Circulating Human Blood Eduardo Arellano-Rodrigo, et al. ASH 2014

33 Healthy volunteer study Ιmmediate, complete, and sustained reversal of Dabigatran anticoagulation Normal upper reference limit refers to (mean+2sd) of 86 predose measurements from a total of 51 subjects Glund S et al. AHA 2013; abstract 17765

34 Healthy volunteer studies: Conclusions Idarucizumab infusion led to immediate, complete, and sustained reversal of dabigatran anticoagulant activity Idarucizumab had no prothrombotic effect as indicated by the Endogenous Thrombin Potential (ETP) Idarucizumab was safe and well tolerated, both alone and in combination with dabigatran Idarucizumab fulfils requirements for a fast-acting and specific antidote to dabigatran with a good safety profile Glund S et al. AHA 2013; abstract 17765

35 First patient trial of a NOAC-specific antidote Study to evaluate reversal of the anticoagulant effects of Dabigatran with idarucizumab in: Bleeding patients overt bleeding judged by the physician to require a reversal agent Surgical patients require an emergency surgery or procedure for a condition other than bleeding \250 Subjects, iv administration of 5g idarucizumab Started in April 2014, currently recruiting in >35 countries worldwide Estimated completion date: July 2017 NCT : Available at Accessed August 2014

36 Aripazine

37 Molecular Structure of Aripazine (PER977) Binds through non-covalent hydrogen bonding and charge-charge interactions!the direct Xa inhibitors (rivaroxaban, apixaban, edoxaban)!thrombin inhibitor Dabigatran!UFH, LMWH, Fondaparinux Ansell JE, et al. NEJM. 371; 22, 2014

38 Effect of Aripazine on Whole-Blood Clotting Time Administration of a single oral 60-mg dose of Edoxaban, followed 3h later by a single iv dose of 25 mg, 100 mg, or 300 mg of Aripazine or placebo in 80 healthy volunteers Ansell JE, et al. NEJM. 371; 22, 2014

39 Blood clots pre- and post- Aripazine Ansell JE, et al. NEJM. 371; 22, 2014

40 ΣΥΜΠΕΡΑΣΜΑ Yπάρχουν σήµερα πολύ ενθαρρυντικά αποτελέσµατα ως προς την αποτελεσµατικότητα και ασφάλεια εξειδικευµένων αντιδότων των TSOACs τα οποία αναµένεται να φανούν ιδιαίτερα χρήσιµα στην καθηµερινή κλινική πράξη σε ασθενείς που λαµβάνουν TSOACs

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