Abstract 2780: A First-in-Class Oligonucleotide Drug-Antidote Pair Efficiently Modulates Factor IXa Activity in Human Subjects - A Nascent Platform for Antidote-Controlled Periprocedural Anticoagulation

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)

The Structure of Synthetic Oligosaccharides in Relation to Factor IXa Inhibition

SummaryWe investigated the effect of various oligosaccharides (OS) on the inhibition of factor IXa by antithrombin (AT) in a purified system. The OS comprised the AT-binding pentasaccharide sequence prolonged by saccharide chains with various lengths and charges. We show that factor IXa inhibition depended on the molecular weight of the OS. Factor IXa was not inhibited by the AT-binding pentasaccharide alone, but was inhibited if it was prolonged by a sulphated dodecasaccharide at the non-reducing end. The overall charge was also important since factor IXa inhibition was negligible if the pentasaccharide was prolonged by a non-sulphated dodecasaccharide. Using compounds containing a non-sulphated spacer, we showed that the central part of the OS was not critical. This study therefore demonstrates that the minimal OS structure necessary for catalysing factor IXa inhibition by AT is close to that required for catalysing thrombin inhibition.