Journal of Thrombosis and Thrombolysis

, Volume 38, Issue 3, pp 275–284

The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study

  • J. P. Vavalle
  • C. P. Rusconi
  • S. Zelenkofske
  • W. A. Wargin
  • T. L. Ortel
  • J. H. Alexander
  • T. J. Povsic
  • R. C. Becker
Article
  • 244 Downloads

Abstract

The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay.

Keywords

Anticoagulation Thrombin generation kinetics Calibrated Automated Thrombogram® Reversibility Antidote Factor IXa inhibition 

References

  1. 1.
    Allen GA, Wolberg AS, Oliver JA, Hoffman M, Roberts HR, Monroe DM (2004) Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. J Thromb Haemost 2:402–413PubMedCrossRefGoogle Scholar
  2. 2.
    Vavalle JP, Rusconi CP, Zelenkofske S, Wargin WA, Alexander JH, Becker RC (2012) A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent. J Thromb Haemost 10(7):1303–1311PubMedCrossRefGoogle Scholar
  3. 3.
    Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smed E, Wagenvoord R, Lecompte T, Beguin S (2002) The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 32:249–253PubMedCrossRefGoogle Scholar
  4. 4.
    Luddington R, Baglin T (2004) Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition. J Thromb Haemost 2:1954–1959PubMedCrossRefGoogle Scholar
  5. 5.
    Povsic TJ, Cohen MG, Chan MY, Zelenkofske SL, Wargin WA, Harrington RA, Alexander JH, Rusconi CP, Becker RC (2011) Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent: translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design. J Thromb Thrombolysis 32:21–31PubMedCrossRefGoogle Scholar
  6. 6.
    Dargaud Y, Beguin S, Lienhart A, Al Dieri R, Trzeciak C, Bordet JC, Hemker HC, Negrier C (2005) Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost 93:475–480PubMedGoogle Scholar
  7. 7.
    Brummel KE, Butenas S, Mann KG (1999) An integrated study of fibrinogen during blood coagulation. J Biol Chem 274:22862–22870PubMedCrossRefGoogle Scholar
  8. 8.
    Tappenden KA, Gallimore MJ, Evans G, Mackie IJ, Jones DW (2007) Thrombin generation: a comparison of assays using platelet-poor and -rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism. Br J Haematol 139:106–112PubMedCrossRefGoogle Scholar
  9. 9.
    van Hylckama Vlieg A, Christiansen SC, Luddington R, Cannegieter SC, Rosendaal FR, Baglin TP (2007) Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 138:769–774PubMedCrossRefGoogle Scholar
  10. 10.
    Tripodi A, Legnani C, Chantarangkul V, Cosmi B, Palareti G, Mannucci PM (2008) High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 6:1327–1333PubMedCrossRefGoogle Scholar
  11. 11.
    Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA (2006) Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA 296:397–402PubMedCrossRefGoogle Scholar
  12. 12.
    Robert S, Ghiotto J, Pirotte B, David JL, Masereel B, Pochet L, Dogne JM (2009) Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs? Pharmacol Res 59:160–166PubMedCrossRefGoogle Scholar
  13. 13.
    Cawthern KM, van’t Veer C, Lock JB, DiLorenzo ME, Branda RF, Mann KG (1998) Blood coagulation in hemophilia A and hemophilia C. Blood 91:4581–4592PubMedGoogle Scholar
  14. 14.
    Dyke CK, Steinhubl SR, Kleiman NS, Cannon RO, Aberle LG, Lin M, Myles SK, Melloni C, Harrington RA, Alexander JH, Becker RC, Rusconi CP (2006) First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 114:2490–2497PubMedCrossRefGoogle Scholar
  15. 15.
    Chan MY, Cohen MG, Dyke CK, Myles SK, Aberle LG, Lin M, Walder J, Steinhubl SR, Gilchrist IC, Kleiman NS, Vorchheimer DA, Chronos N, Melloni C, Alexander JH, Harrington RA, Tonkens RM, Becker RC, Rusconi CP (2008) Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation 117:2865–2874PubMedCrossRefGoogle Scholar
  16. 16.
    Chan MY, Rusconi CP, Alexander JH, Tonkens RM, Harrington RA, Becker RC (2008) A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor ixa inhibitor. J Thromb Haemost 6:789–796PubMedCrossRefGoogle Scholar
  17. 17.
    Brummel KE, Paradis SG, Butenas S, Mann KG (2002) Thrombin functions during tissue factor-induced blood coagulation. Blood 100:148–152PubMedCrossRefGoogle Scholar
  18. 18.
    Lawrie AS, Kitchen S, Purdy G, Mackie IJ, Preston FE, Machin SJ (1998) Assessment of actin FS and actin FSL sensitivity to specific clotting factor deficiencies. Clin Lab Haematol 20:179–186PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • J. P. Vavalle
    • 2
  • C. P. Rusconi
    • 3
  • S. Zelenkofske
    • 4
  • W. A. Wargin
    • 5
  • T. L. Ortel
    • 6
  • J. H. Alexander
    • 2
  • T. J. Povsic
    • 2
  • R. C. Becker
    • 1
  1. 1.Division of Cardiovascular Health and Disease, Heart, Lung and Vascular InstituteUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Cardiovascular Thrombosis CenterDuke Clinical Research InstituteDurhamUSA
  3. 3.Regado Biosciences, Inc.DurhamUSA
  4. 4.Regado Biosciences, Inc.Basking RidgeUSA
  5. 5.Pk Pm Associates LLCChapel HillUSA
  6. 6.Duke University Medical CenterDurhamUSA

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