Putting the Novel Back in Oral Anticoagulants: Phase II Results of the Factor XIa Inhibitor Asundexian

Direct oral anticoagulants have dramatically changed anticoagulation treatment and prevention practices for patients and are considered the guideline-preferred therapies for atrial fibrillation and venous thromboembolism (VTE).^1,2  Meta-analyses have demonstrated a lower bleeding risk with these therapies when compared with warfarin for atrial fibrillation; however, bleeding risk remains a significant concern for patients and providers, and elevated bleeding risk in some patients prevents them from receiving the potential benefits of anticoagulation therapy. Inhibition of the intrinsic (or contact) pathway by reducing factor XI activity has garnered significant interest as a way to potentially prevent thrombosis without contributing to bleeding risk.³ 

In the PACIFIC-AF study, Dr. Jonathan Piccini and colleagues examined the utility of an oral small molecule factor XIa (FXIa) inhibitor called asundexian in a phase II multicenter, randomized, double-blind, double-dummy, dosing finding study. Patients with nonvalvular atrial fibrillation who were older than 45 years with an elevated CHA₂DS₂-VASc score and an increased risk for bleeding were recruited and randomized. The study randomized patients in a 1:1:1 fashion and ultimately included 755 participants in the analysis with standard dosing of apixaban (n=250), asundexian 20 mg once daily (n=251), or asundexian 50 mg once daily (n=254). Blood samples were obtained for pharmacodynamic analysis at randomization and at four and 12 weeks. The primary clinical end points were assessed through 12 weeks and were a composite of major and clinically relevant non-major bleeding. Thrombotic outcomes such as stroke, systemic embolization, myocardial infarction, and death were considered exploratory outcomes. The mean age of participants was 73.7 years, and 41 percent were women. Low-dose aspirin was used by 14 percent of patients and 9 percent had clinically relevant bleeding in the prior 12 months. Asundexian at the 20 mg dose resulted in an 81 percent and 90 percent reduction and at the 50 mg dose resulted in a 92 percent and 94 percent reduction in baseline FXI activity at trough and peak concentrations, respectively. No major bleeding occurred in any group. Asundexian at either dose when compared to the apixaban group had a lower incidence of the primary composite end point (risk ratio [RR], 0.33; 90% CI 0.09-0.97) with a RR of 0.50 for the 20 mg dose and 0.16 for the 50 mg dose. The composite of cardiovascular death, myocardial infarction, ischemic stroke, or systemic embolization occurred in three participants who received apixaban, four with asundexian 50 mg, and two with asundexian 20 mg.