Abstract 12822: Subcutaneous Administration of the Direct FIXa Inhibitor RB006 Provides Persistent Inhibition of Thrombin Generation
Introduction: Factor IXa (FIXa) activity is a proximal determinant of thrombin generation; accordingly, FIXa is an attractive target for treatment of thrombotic diseases. RB006 (SC or IV) is a direct FIXa inhibitor. Administration of RB006 leads to dose dependent prolongation of the aPTT. The onset of action of SC RB006 is 12 hrs based upon changes in aPTT, with a peak effect at 72 hrs and a sustained anticoagulant effect beyond 7 days. We sought to more specifically define the onset and duration of RB006 activity following SC administration by directly measuring changes in thrombin generation over time.
Methods: In the SC101 study, 28 healthy volunteers received a single dose of 0.5, 1, or 3 mg/kg SC RB006 or placebo. At each dose level, thrombin generation measurements by Calibrated Automated Thrombography (CAT) were collected at multiple time points through 96 hrs post-dose. Changes in CAT parameters of Lag Time (LT), Peak Time (PTm), Peak Thrombin Generation (PTG), Endogenous Thrombin Potential (ETP), and Velocity Index (VI) were compared over time.
Results: CAT parameters representing the rate (VI) and amount of thrombin produced (PTG, ETP) were significantly and dose dependently reduced by RB006 (See Figure). At 3 mg/kg, maximum changes in VI, PTG and ETP were observed at 24 hrs (−87%, −80%, −65%, respectively) and persisted with minimal changes through 96 hrs after a single SC injection. At lower dose levels, significant thrombin inhibition was observed at 24 hrs and increased modestly over time.
Conclusions: RB006 profoundly inhibits thrombin generation. Maximal dose dependent changes in CAT parameters representing the rate and amount of thrombin generation are observed 24 hrs post-dose and persist through 96 hrs. Direct measurement of thrombin generation demonstrated both a potent and persistent inhibition of thrombin generation by SC RB006. Thus, SC dosing of RB006 at a frequency of once weekly or greater may provide a predictable and durable anticoagulant effect.
- © 2010 by American Heart Association, Inc.