Article

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. VavalleAffiliated withCardiovascular Thrombosis Center, Duke Clinical Research Institute
  • , C. P. RusconiAffiliated withRegado Biosciences, Inc.
  • , S. ZelenkofskeAffiliated withRegado Biosciences, Inc.
  • , W. A. WarginAffiliated withPk Pm Associates LLC
  • , T. L. OrtelAffiliated withDuke University Medical Center
  • , J. H. AlexanderAffiliated withCardiovascular Thrombosis Center, Duke Clinical Research Institute
  • , T. J. PovsicAffiliated withCardiovascular Thrombosis Center, Duke Clinical Research Institute
  • , R. C. BeckerAffiliated withDivision of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine Email author 

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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