Antisense Oligonucleotide Mediated Depletion of Factor XI Prevents Vascular Occlusion in An Experimental Thrombosis Model in Primates

Abstract 2250

It has recently been demonstrated that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents. Furthermore, FXI deficiency is not associated with spontaneous bleeding in humans, and deficiency of a contact factor does not cause abnormal bleeding. We have previously shown that treatment with FXI Antisense Oligonucleotides (ASOs) produces potent, dose-dependent antithrombotic activity in various venous and arterial murine thrombosis models. In the current study we characterize the antithrombotic effects of FXI ASOs in a non-human primate model. Subcutaneous administration of FXI ASOs in cynomologus monkeys resulted in a dose-and time-dependant decrease in FXI mRNA levels in liver (up to 90%), decreased FXI protein and activity levels measured in plasma, and prolonged activated partial thromboplastin times (aPTT). Importantly, FXI depletion in monkeys was not associated with an increased risk of bleeding. Recent studies demonstrated that complete inhibition (>99%) of FXI by a monoclonal antibody reduced thrombin generation and prevented vascular occlusion in a collagen-coated graft inserted into a baboon arteriovenous shunt (Tucker et al., Blood 2009). In the present study, we set out to determine the relationship between FXI levels and antithrombotic activity, and in particular, the minimal level of FXI reduction required to produce an antithrombotic effect in a baboon thrombosis model. Using the FXI monoclonal antibody, we demonstrate that ∼50% inhibition of FXI levels produces antithrombotic activity in baboons. Next we applied baboon-specific FXI ASOs and demonstrated reductions in FXI protein levels and activity, with corresponding increases in aPTT levels. Baboons were then treated with FXI ASOs in a manner that would produce ∼50% reduction of FXI protein levels and measured anti-thrombotic activity. Similar to the antibody approach, ASO-mediated reduction of FXI plasma levels ≥ 50% resulted in a potent antithrombotic effect. Furthermore, reductions in FXI levels do not increase bleeding times in baboons. These results further support the development of FXI ASOs for antithrombotic therapy with the potential for a superior safety profile compared to currently available anticoagulants.