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Background

A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa Lu G, Deguzman FR, Hollenbach SJ, et al. Department of Biology, Portola Pharmaceuticals Inc., South San Francisco, California, USA Nature Medicine, April 2013, Volume 19 No 4 pp446 - 451.

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  1. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor XaLu G, Deguzman FR, Hollenbach SJ, et al.Department of Biology, Portola Pharmaceuticals Inc., South San Francisco, California, USANature Medicine, April 2013, Volume 19 No 4 pp446 - 451

  2. Background • Noval oral anticoagulants (factorXa & IIainhibitors) widelyused • Higher incidencefor (GI-)bleeding • UntilnownoantidotefornOAC • Management ofbleedingdifficult; Vitamin K, tranexaminacid, FFP, rfVIIa, PCC not effective • -> presentationof a recombinantagentantagonizingfactorXa • -> proofofconceptwith in vitro & in vivo investigations 2

  3. Truncated form ofenzymaticallyinactivefXa Lacks GLA domain, catalyticallyinactive due tomutation in serineresidue Maturefunctional form, expressed in chinesehamsterovary Recombinant Antidote (r-antidote) • Aspectstoprove: • SpecificbindingtofXa? • Reversalofanticoagulation? • pro- orantithromboticproperties? • Reducelossofbleeding? 3

  4. Reversalofanticoagulation in human plasma: r-Antidote: in vitro-essays • clottingassay & thrombingenerationassay: • high affinity for fXa-inhibitors • Inhibitory activity dose-dependently and completely reversed by r-Antidote • no pro- or anticoagulant activity 4

  5. In vivo rat model - reversalofanticoagulation • Rapid normalisationof INR after r-antidote infusion • ReversalofanticoagulationcorrelatestoreductionofunboundfXa-inhibitor-fraction 5

  6. Mouse modelofbloodloss (tailtransection) • ASS+Rivar.+r-antidote reducedbloodlossby 85% • After r-antidote rivaroxabanactivityreducedby >80% 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 6

  7. Rabbit model of blood loss (liver laceration model) • Lacerationof 2 liverlobesandbloodlosscollectionover 15min after injectionofvehicleorrivaroxabanandr-antidote • PT & aPTTincreased 2.3x resp. 1.9x after rivaroxaban, bloodloss3.2x higher • r-Antidote reducedbloodlossby >85%, decreased anti-fXaactivityby 98% • Correlationofbloodlosswithreduction in anti-fXa-activity an freefXa-inhibiton 7

  8. Reversalof ATIII-dependentfXainhibitorsbyr-antidote • r-antidote mimickingbinding-site offXafor ATIII • Enoxaparin (LMWH) & Fondaparinux (pentasaccharide) indirectfXainhibitor (increaseaffinityof ATIII forfXa) Enoxaparin Fondaparinux • anti-fXaactivitiyofenoxaparin & fondaparinux dose-dependentlyreversedwithr-antidote 8

  9. Reversalof ATIII-dependentfXainhibitorsbyr-antidote • Animalmodel (rat tailtransection) Enoxaparin Treat-I: vehicle Treat-II: Enoxaparin & vehicle Treat-III Enoxaparin & r-antidote 2mg/h Treat-IV: Enoxaparin & r-antidote 4mg/h • Normalisationofhemostasis after r-antidote administration • Completereversalof ATIII-dependentfXainhibition Treat-I: vehicle Treat-II: Fondaparinux & vehicle Treat-III Fondaparinux & r-antidote Treat-IV: fondaparinux & Protamine 9

  10. r-antidote does not interferewith normal fXafunction r-antidote withnoanticoagulantorprocoagulantactivity Rapid onsetofaction& completereversaloffXa-inhibitors activity NormaliseshemostasisfromanticoagulantdrugstargetingfXa Universal antidotefordirect & indirectfXainhibition Limitations Possiblethatused in vitro systemare not sensitive enough Preclinicaldatabased on animalmodel, difficultiestoextrapolatetohumans unidentifiedinteractionswithotherproteins immunogenicity Discussion 10

  11. r-antidote capabletoreversenOAC-inducedbleedings Rapid onsetofaction will havemajorimpact in futuredailypractice (bleedingmanagement, surgicalprocedures) IncreasesafetyofusingfXa-inhibitingdrugs. Phase II-studyrunning Further studies (antidoteIIa-inhibitor, unviversalfIIa & fXa-antidote) on theway Conclusion 11

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