Background:
Safe and active reversibility of anticoagulation is highly desirable. Factor IXa, critical for rapid thrombin generation on platelet surfaces, is a novel target for regulating coagulation. The REG1 System comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, selectively binds and inhibits IXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-factor IXa activity.
Methods:
To explore the feasiblity of testing the REG1 system in catheter-based intervention trials, we analyzed data from 2 randomized dose-escalation studies of REG1: phase 1a with 84 healthy subjects and phase 1b with 50 patients with stable coronary artery disease taking aspirin and/or clopidogrel.
Results:
An intravenous (IV) bolus of RB006 produced a similar dose-dependent activated partial thromboplastin time (aPTT) increase in both populations; a weight-adjusted dose of 1mg/kg RB006 consistently achieved 100% factor IXa inhibition (figure 1
), a level effectively eliminating artifical surface thrombosis in animal models. IV bolus RB007 in a 2:1 antidote:drug ratio reversed the aPTT to <10% above the upper limit of normal within a median of 1 min (IQR 1–2), with no rebound increase up to 7 days. Despite dual antiplatelet use in 19 subjects, no major bleeding or other serious adverse events occurred.
Conclusions:
These exploratory data support the safe regulation of coagulation with a factor IXa-specific drug-antidote system. The pharmacodynamic response elicted by a 1mg/kg RB006 dose and 2:1 antidote:drug ratio appears suitable for catheter-based intervention studies.
Figure 1.
Relative APTT and % Factor IXa inhibition versus RB008 Dose (mg/kg)
Aptamer-Based Factor IXa Inhibition Preserves Hemostasis and Prevents Thrombosis in a Piglet Model of ECMO
