A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor

Background: Active and safe reversibility of anticoagulation is an unmet need in clinical care. Factor IXa, required for rapid thrombin generation on platelet surfaces, is a novel target for modulating coagulation. REG1 comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, exerts its anticoagulant effect by selectively binding FIXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-FIXa activity. Objective: To test the multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of REG1. Methods: We randomized 39 healthy volunteers to receive either three consecutive weight-adjusted, drug-antidote treatment cycles, or double placebo. Each treatment cycle included an intravenous bolus of 0.75 mg kg(-1) RB006, followed 60 min later by a descending dose of RB007, ranging from a 2 : 1 to 0.125 : 1 antidote/drug ratio (1.5 mg kg(-1) to 0.094 mg kg(-1) RB007). Serial clinical assessments and coagulation measurements were performed through 14 days postrandomization. Results: Repeat doses of RB006 achieved highly reproducible activated partial thromboplastin time (APTT) levels with low intrasubject variability (coefficient of variation 5.5%, intraclass correlation coefficient 5.8 at 15 min postdose), while repeat doses of RB007 reversed the APTT levels dose-dependently and reproducibly. There was no major bleeding and there were no other serious adverse events. Conclusions: This is the first human study demonstrating multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of an RNA aptamer-oligonucleotide antidote pair. The results lay the foundation for studying the translation of this novel anticoagulation platform to a wide variety of clinical applications.