ISIS-FXI_Rx, a Potent Antisense Inhibitor of Factor XI, Suppresses FXI Activity and Elevates Aptt without Increased Risk of Bleeding in Cynomolgus Monkeys Following 13 Weeks of Treatment

Abstract ²²⁵⁵

Complications associated with increased bleeding risk are the main limitations with current anticoagulant therapy. Inhibition of factor XI (FXI), a component of the intrinsic coagulation pathway, has received considerable interest because of the potential to produce sufficient anticoagulant activity without bleeding. The objective of these studies were to characterize the efficacy and safety of ISIS-FXrx and to assess the bleeding risk associated with FXI depletion under experimental surgical settings in cynomolgus monkeys. ISIS-FXI_Rx was selected from a series of 2^nd-generation (2'-O-methoxyethyl) antisense oligonucleotides (ASOs) targeted to FXI which were evaluated for both tolerability and efficacy in cynomolgus monkeys (25 mg/kg twice per week for 13 weeks, SC). ISIS-FXI_Rx emerged as the most efficacious among the FXI ASOs evaluated, producing marked reductions of FXI RNA in liver, and FXI protein and activity levelsin plasma with a good tolerability profile. A more extensive dose-response evaluation of ISIS-FXrx (4,8,12 and 40 mg/kg/wk, SC) was conducted over a 13-week treatment period in cynomolgus monkeys to further assess tolerability and activity. ISIS-FXI_Rx produced a dose-dependent reduction in plasma FXI activity (>80% at 4 weeks of treatment at 40 mg/kg) with a concomitant increase in aPTT (33%). No effects on PT, platelets and no evidence of bleeding were observed after 13 weeks of treatment with ISIS-FXrx. ASO treatment was well tolerated at all doses tested and only produced changes typical for this chemical class of ASOs (e.g., basophilic granules in multiple tissues due do drug accumulation). ISIS-FXI_Rx (20 mg/kg, SC for 6 weeks) was also evaluated for bleeding risk in two experimental surgical models in cynomolgus monkeys; a tail amputation model and gum laceration model. Enoxaparin (2 mg/kg), known to increase the risk of bleeding, produced a statistically significant (p<0.05) increase in bleeding time and blood volume loss compared to saline control animals in both the tail amputation and the gum laceration models. Animals treated with ISIS-FXI_Rx displayed no increase in bleeding parameters compared to control animals. These results further support the conclusion that targeting FXI is an effective and safe strategy for development of novel antithrombotic agents with minimal increase in bleeding risk. ISIS-FXI_Rx is currently under evaluation in Phase 1 studies.