Abstract 13826: Thrombin Generation Kinetics of the REG2 Anticoagulation System: A First-in-Human Experience
Background: Factor IXa is the rate limiting enzyme in thrombin generation. The REG2 Anticoagulation System contains a factor IX/IXa inhibitor (pegnivacogin) administered subcutaneously (SC) and an active and specific intravenous control agent (anivamersen). Thrombin generation kinetics were analyzed in a first-in-human study of REG2.
Methods: Eight healthy volunteers were dosed once with pegnivacogin (2 mg/kg) and randomized to single-dose reversal with anivamersen (1.0 mg/kg) at 72 h (Arm 1, n=4) or multi-dose reversal at 24, 72 and 120 h (Arm 2, n=4). Peak thrombin generation was determined using the Calibrated Automated Thrombogram® (CAT). In Arm 1, CAT was measured at baseline, 72 h (before anivamersen), 73 h, and 96 h. In Arm 2, CAT was measured at baseline, 24 h (before anivamersen), and 144 h.
Results: Peak thrombin generation at baseline was 94.38 nM (Arm 1) and 131.20 nM (Arm 2)). In Arm 1, just before anivamersen, pegnivacogin concentrations were high [16.2 (5.0) ug/mL] and peak thrombin was suppressed (29.85 nM). One hour after anivamersen (73 h), pegnivacogin concentrations were low [0.27 (0.07) ug/mL] and peak thrombin was restored (59.21 nM), but not fully to baseline levels (Figure 1a). In Arm 1, due to continued absorption of pegnivacogin, peak thrombin at 96 h (34.09 nM) was suppressed similar to that at 72 h. In Arm 2, peak thrombin was suppressed at 24 h (41.45 nM), and with continued pegnivacogin absorption, it remained suppressed at 144 h (56.99 nM) after repeated anivamersen dosing at 24, 72, and 120 h (Figure 1b).
Conclusions: Factor IX/IXa inhibition with pegnivacogin administered SC suppresses thrombin generation. One hour after reversal with anivamersen, peak thrombin generation is restored without a rebound effect. The prolonged suppression of thrombin is consistent with the long half-life of SC pegnivacogin (> 7 d) and continued lymphatic absorption. Future studies are needed to define the optimal dosing strategies for reversal of SC pegnivacogin.
- © 2011 by American Heart Association, Inc.