Abstract 1555: Antidote-Controlled Modulation of Factor IXa Activity with the First-in-Class REG1 Anticoagulation System: A Randomized Phase 1 Repeat Dose Safety and Antidote Dose-Escalation Study
Background: Active and safe reversibility of anticoagulation is important in surgical care. Factor IXa, critical for rapid thrombin generation on platelet surfaces, is a nascent target for modulating coagulation. The REG1 System comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, exerts its anticoagulant effect by selectively binding factor IXa. RB007, a complementary oligonucleotide, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-factor IXa activity.
Methods: We randomized 39 healthy human subjects in a double-blind study to receive either 3 consecutive drug-antidote treatment cycles, or double placebo. Each treatment cycle consisted of intravenous bolus 0.75mg/kg RB006 followed an hour later by a variable dose of RB007 in a 0.125:1 to 2:1 antidote:drug ratio (0.094mg/kg to 1.5mg/kg RB007). Serial clinical and core laboratory coagulation assessments were performed through 14 days.
Results: A total of 30 subjects received 3 drug-antidote cycles while 8 subjects received 3 double placebo cycles. Repeat doses of RB006 consistently increased the aPTT to >2 times control, a level that eliminated extracorporeal thrombosis in animal bypass models, with low intrasubject variability (coefficient of variation 5.5%, intraclass correlation coefficient 0.58). RB007 reversed the aPTT dose-dependently (Figure 1⇓). No major bleeding or other serious adverse events occurred.
Conclusions: The repeat dose safety and titratable antidote effect support the safe modulation of coagulation using a factor IXa-specific drug-antidote system, laying the foundation for clinical trials studying its role in perioperative anticoagulation.