Introduction: There is an unmet need for safe and effective anticoagulant reversal agents, with rapid onset of effects, for use in cases such as serious or life-threating bleeding, prior to urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including direct oral anticoagulants (DOACs), enoxaparin, and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Two Phase 2 studies evaluated the safety and efficacy of ciraparantag for reversal of anticoagulation induced by apixaban or rivaroxaban in healthy adults.Methods: Two randomized, placebo-controlled, dose-ranging studies were conducted in healthy subjects 50-75 years of age. Subjects received apixaban or rivaroxaban until steady state. Study 1 subjects received apixaban 10 mg orally twice daily for 3.5 days. Study 2 subjects received rivaroxaban 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous (IV) dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120 or 180 mg) or placebo. Efficacy was based on manual whole blood clotting time (WBCT) at multiple timepoints over 24 hours beginning at 15 minutes after dosing. Subjects and technicians performing the WBCT testing were blinded to treatment. WBCT measures were performed in triplicate (simultaneous testing by 3 different evaluators) at 3 separate timepoints to analyze inter-observer variability using an analysis of variance (ANOVA) model with effects for observer and subject.Results: In Study 1 (apixaban), 49 subjects were randomized to receive study drug (36 ciraparantag, 13 placebo) and completed the study as planned. In Study 2 (rivaroxaban), 64 subjects were randomized to receive study drug (48 ciraparantag, 16 placebo) and all but one subject completed the study as planned. Ciraparantag demonstrated a rapid and dose-dependent reversal of apixaban and rivaroxaban anticoagulation as measured by the proportion of subjects whose WBCT decreased to within 10% above baseline at 15 minutes after study drug infusion. A lower dose of ciraparantag was required to achieve reversal of apixaban in a large fraction of subjects compared to the dose required for reversal of rivaroxaban (Figure). Reversal of anticoagulation was sustained in these subjects throughout the 24-hour measurement period. In both studies, there was good agreement among the triplicate manual WBCT measurements; all inter-observer coefficient of variance values were <5%. Ciraparantag was well tolerated; the most frequent adverse events were mild, transient sensations of warmth during or soon after infusion.Conclusions: In healthy subjects at steady-state levels of anticoagulation, ciraparantag single IV doses were well tolerated and produced rapid reversal of anticoagulation in high proportions of subjects within 15 minutes of administration (the first timepoint assessed) at doses ≥60 mg for apixaban and at a dose of 180 mg for rivaroxaban which were maintained throughout the 24-hour measurement period.Figure. Proportion of subjects with WBCT reversed to within 10% above baseline at 15 minutes and 30 minutes after dosingDisclosuresAnsell: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Villano:Amag Pharmaceuticals, Inc.: Consultancy.OffLabel Disclosure:Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.