Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial

Abstract

Objective— Factor XI (FXI) contributes to thrombotic disease while playing a limited role in normal hemostasis. We generated a unique, humanized anti-FXI antibody, AB023, which blocks factor XIIa-mediated FXI activation without inhibiting FXI activation by thrombin or the procoagulant function of FXIa. We sought to confirm the antithrombotic activity of AB023 in a baboon thrombosis model and to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult subjects. Approach and Results— In a primate model of acute vascular graft thrombosis, AB023 reduced platelet and fibrin accumulation within the grafts by >75%. To evaluate the safety of AB023, we performed a first-in-human study in healthy adult volunteers without any serious adverse events. Overall, 10 of 21 (48%) subjects experienced 20 treatment-emergent adverse events, with 7 of 16 (44%) subjects following active treatment and 3 of 5 (60%) subjects following placebo. AB023 did not increase bleeding or prothrombin times. Anticoagulation was verified by a saturable ≈2-fold prolongation of the partial thromboplastin time for over 1 month after the highest dose. Conclusions— AB023, which inhibits contact activation-initiated blood coagulation in vitro and experimental thrombus formation in primates, produced a dose-dependent duration of limited anticoagulation without drug-related adverse effects in a phase 1 trial. When put in context with earlier observations suggesting that FXI contributes to venous thromboembolism and cardiovascular disease, although contributing minimally to hemostasis, our data further justify clinical evaluation of AB023 in conditions where contact-initiated FXI activation is suspected to have a pathogenic role. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT03097341.

The contact pathway and sepsis

“…While these data suggest that the CAS contributes to the pathology of sepsis in humans, further study is needed before any major conclusions are drawn to determine if targeting this pathway could offer a meaningful benefit to septic patients. As multiple novel contact pathway inhibitors enter clinical testing, additional clinical investigations may begin to address this question …”

“…Finally, while contact pathway inhibition in general holds promise, it remains to be clarified which specific component(s) of this pathway should be targeted to optimize clinical outcomes. Phase 1 clinical trial data have now been published on 4 different monoclonal antibodies targeting FXI, all with unique mechanisms . Our group has worked extensively with 14E11/3G3, a monoclonal antibody inhibiting FXIIa‐mediated activation of FXI.…”

The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials

“…Data on FXI activity were not provided in the report. 15 AB023 administration resulted in no serious adverse events, including no bleeding events or prolongation in bleeding time compared with controls. Total treatment emergent adverse events were similar between treatment and placebo groups (44 and 60%, respectively).…”

“…AB023 binds to the apple 2 domain of the zymogen FXI, specifically inhibiting the action of FXIIa to generate FXIa as well as interactions between FXIa and HK. 15 The ability of thrombin to reciprocally activate FXI, as well as the enzymatic active site of formed FXIa itself, is left uninhibited. With this different mechanism, AB023 has also proven effective at preventing thrombosis in several animal models.…”

The contact activation system as a potential therapeutic target in patients with COVID‐19

“…Similarly, antibody‐mediated inhibition of FXIa was associated with a trend for less bleeding than that observed with low‐molecular‐weight heparin in a large prospective trial of thromboprophylaxis in patients undergoing elective knee arthroplasty 21 . In a phase 1 trial, AB023 appeared to be safe without any notable drug‐related adverse effects in healthy volunteers 22 . While recent retrospective analyses have suggested anticoagulation with heparin products may improve clinical outcomes in patients with COVID‐19, 4 selective targeting of contact activation may offer a more refined approach, with no impact on hemostasis, and would likely be associated with fewer bleeding complications.…”