Antithrombotic Effect of Antisense Factor XI Oligonucleotide Treatment in Primates

Abstract

Objective During coagulation, factor IX (FIX) is activated by two distinct mechanisms mediated by the active proteases of either factors VII (FVIIa) or XI (FXIa). Both coagulation factors may contribute to thrombosis; factor XI, however, plays only a limited role in the arrest of bleeding. Therefore, therapeutic targeting of FXI may produce an antithrombotic effect with relatively low hemostatic risk. Approach and Results We have reported that reducing FXI levels with FXI antisense oligonucleotides (ASOs) produces antithrombotic activity in mice, and that administration of FXI ASOs to primates decreases circulating FXI levels and activity in a dose- and time-dependent manner. Here we evaluated the relationship between FXI plasma levels and thrombogenicity in an established baboon model of thrombosis and hemostasis. In previous studies with this model, antibody-induced inhibition of FXI produced potent antithrombotic effects. In the present report, ASO-mediated reduction of FXI plasma levels by ≥50% resulted in a demonstrable and sustained antithrombotic effect without an increased risk of bleeding. Conclusion These results indicate that reducing FXI levels using ASOs is a promising alternative to direct FXI inhibition, and that targeting FXI may be potentially safer than conventional antithrombotic therapies that can markedly impair primary hemostasis.

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

“…Strategies to inhibit FXI are illustrated in Table 2 and include (1) ASOs that reduce hepatic synthesis of the clotting protein 27,33,44 ; (2) monoclonal antibodies that block FXI activation, FXIa activity, or both 25,45,46 ; (3) aptamers that block FXI activation or activity 47,48 ; and (4) small molecules that block the active site of FXIa [49][50][51] or induce allosteric modulation.…”

“…Up to a month of ASO treatment is required to lower FXI levels into the therapeutic range, which limits their use for initial treatment of thrombosis or for immediate thromboprophylaxis. 27,33,44 In contrast, small-molecule inhibitors and antibodies typically achieve therapeutic levels within minutes or hours of administration. The prolonged half-life of FXI-directed antibodies or ASOs could be problematic if there is bleeding with trauma or surgery.…”

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

“…[22][23][24][25][26] For example, inhibitory factor XI antibodies, which prevent the activation of factor XI by factor XII, protected mice from ferric chloride-induced arterial and venous thrombosis. 27,28 Furthermore, factor XI and factor XI antisense oligonucleotides have been studied in higher species using a vascular graft occlusion model in primates, 29,30 which paved the way for human studies using factor XI antisense oligonucleotides. Human data from patients undergoing total knee replacement surgery are expected this year.…”

Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques

“…For example, inhibition of factor XI protects rodents and primates from experimentally induced thrombosis in both arteries and veins. [8][9][10][11][12] Another argument for factor XI as antithrombotic target is the epidemiological evidence that patients with factor XI deficiency have a lower incidence of deep vein thrombosis and ischemic stroke. 13,14 See accompanying editorial on page 1607…”