10 Efficacy and Safety of Ciraparantag in Reversing Apixaban and Rivaroxaban as Measured by Whole Blood Clotting Time in Healthy Adults

Abstract

There is an unmet need for agents that can rapidly reverse the effects of the direct oral anticoagulants (DOACs) in emergency settings. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including DOACs, enoxaparin and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Ciraparantag has been shown to reverse anticoagulation in healthy volunteers treated with edoxaban and enoxaparin, as measured by whole blood clotting time (WBCT). Two Phase 2 studies evaluated the efficacy (measured by WBCT) and safety of ciraparantag for reversal of anticoagulation induced by apixaban or rivaroxaban in healthy adults. Two randomized, placebo-controlled, dose-ranging studies were conducted in healthy subjects 50-75 years of age. In each study, subjects received anticoagulant (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. In both studies, subjects at steady-state anticoagulation were randomized 3:1 to a single 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 WBCT at multiple timepoints over 24 hours. Subjects and technicians performing the WBCT testing were blinded to treatment. In Study 1, 49 subjects were randomized to receive study drug (36 ciraparantag, 13 placebo) and completed the study as planned. In Study 2, 64 subjects were randomized to receive study drug (48 ciraparantag, 16 placebo) and all but one subject (who had an unrelated adverse event) completed the study as planned. In both studies, ciraparantag demonstrated a rapid (within 15 minutes after infusion) and dose-dependent reversal of anticoagulation compared with placebo. In both studies, analysis of least squares mean WBCT values showed statistically significant differences between each ciraparantag group and placebo. Among subjects who were anticoagulated, reversal of WBCT to ≤10% of baseline within 1 hour post-dose and sustained through at least 5 hours was observed in 67%, 100%, 100% with escalating doses of apixaban, and 17% of placebo subjects; and in 58%, 75%, 67% and 100% with escalating dose of rivaroxaban and 13% of placebo subjects. Ciraparantag was well tolerated; the most common adverse events were mild, transient sensations of warmth (typically reported as hot flashes or flushing), which were dose related. Ciraparantag, after a single IV dose, resulted in a dose-dependent reversal of the anticoagulant effect induced by steady-state dosing of apixaban or rivaroxaban in healthy subjects, as determined by manual WBCT testing. The effect was sustained through at least 5 hours after dosing, and ciraparantag was well tolerated.