Improved efficacy/safety profile of factor XIa inhibitor BMS‐724296 versus factor Xa inhibitor apixaban and thrombin inhibitor dabigatran in cynomolgus monkeys

Figures

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  FIGURE 1. Chemical structure of the FXIa inhibitor BMS‐724296. FXIa, activated factor XI

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  FIGURE 2. Schematic representation of the NHP study protocol. ECAT, electrolytic‐mediated arterial thrombosis; KBT, kidney bleeding time; i.v., intravenous; NHP, nonhuman primate

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  FIGURE 3. Antithrombotic effects in the NHP model of electrolytically mediated carotid arterial thrombosis. Effects of vehicle, BMS‐724296, apixaban, and dabigatran on carotid blood flow after thrombus induction in the injured carotid artery. Carotid blood flow was expressed as a percentage of control carotid blood flow. Vehicle (n = 8); BMS‐724296 at 0.025 + 0.05 (LD; n = 5), 0.05 + 0.1 (MD1; n = 6), 0.102 + 0.2 (MD2; n = 6), and 0.4 + 0.8 (HD; n = 6) mg/kg+mg/kg/h i.v.; apixaban at 0.024 + 0.036 (LD; n = 4), 0.12 + 0.18 (MD; n = 4), and 0.6 + 0.9 (HD; n = 4) mg/kg+mg/kg/h i.v.; and dabigatran at 0.024 + 0.036 (LD; n = 3), 0.12 + 0.18 (MD; n = 3), and 0.6 + 0.9 (HD; n = 3) mg/kg+mg/kg/h i.v. Data are mean ± SEM. HD, high dose; i.v., intravenous; LD, low dose; MD, medium dose; NHP, nonhuman primate; SEM, standard error of the mean

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  FIGURE 4. Top panel: Effects of vehicle, BMS‐724296, apixaban, and dabigatran on integrated blood flow expressed as a percentage of control carotid blood flow (ie, preinjury blood flow) in NHPs. Bottom panel: Effects of vehicle, BMS‐724296, apixaban, and dabigatran on thrombus weight reduction (percent inhibition) in ECAT NHPs. Vehicle (n = 8); BMS‐724296 at 0.025 + 0.05 (LD; n = 5), 0.05 + 0.1 (MD1; n = 6), 0.102 + 0.2 (MD2; n = 6), and 0.4 + 0.8 (HD; n = 6) mg/kg+mg/kg/h i.v.; apixaban at 0.024 + 0.036 (LD; n = 4), 0.12 + 0.18 (MD; n = 4), and 0.6 + 0.9 (HD; n = 4) mg/kg+mg/kg/h i.v.; and dabigatran at 0.024 + 0.036 (LD; n = 3), 0.12 + 0.18 (MD; n = 3), and 0.6 + 0.9 (HD; n = 3) mg/kg+mg/kg/h i.v. Data are mean ± SEM. *P < .05 compared to vehicle. + P < .05 compared to preceding column. ECAT, electrolytic‐mediated arterial thrombosis; HD, high dose; i.v., intravenous; LD, low dose; MD, medium dose; NHP, nonhuman primate; SEM, standard error of the mean

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  FIGURE 5. Effects of vehicle, BMS‐724296, apixaban, and dabigatran on kidney bleeding time model in NHPs. Vehicle (n = 8); BMS‐724296 at 0.025 + 0.05 (LD; n = 5), 0.05 + 0.1 (MD1; n = 6), 0.102 + 0.2 (MD2; n = 6), and 0.4 + 0.8 (HD; n = 6) mg/kg+mg/kg/h i.v.; apixaban at 0.024 + 0.036 (LD; n = 4), 0.12 + 0.18 (MD; n = 4), and 0.6 + 0.9 (HD; n = 4) mg/kg+mg/kg/h i.v.; and dabigatran at 0.024 + 0.036 (LD; n = 3), 0.12 + 0.18 (MD; n = 3), and 0.6 + 0.9 (HD; n = 3) mg/kg+mg/kg/h i.v. Data are mean ± SEM. *P < .05 compared to vehicle. + P < .05 compared to preceding column. HD, high dose; i.v., intravenous; LD, low dose; MD, medium dose; NHP, nonhuman primate; SEM, standard error of the mean

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  FIGURE 6. Effects of vehicle, BMS‐724296, apixaban, and dabigatran on clotting times (top panel: aPTT; middle panel: PT; bottom panel: TT) in NHPs. Vehicle (n = 8); BMS‐724296 at 0.025 + 0.05 (LD; n = 5), 0.05 + 0.1 (MD1; n = 6), 0.102 + 0.2 (MD2; n = 6), and 0.4 + 0.8 (HD; n = 6) mg/kg+mg/kg/h i.v.; apixaban at 0.024 + 0.036 (LD; n = 4), 0.12 + 0.18 (MD; n = 4), and 0.6 + 0.9 (HD; n = 4) mg/kg+mg/kg/h i.v.; and dabigatran at 0.024 + 0.036 (LD; n = 3), 0.12 + 0.18 (MD; n = 3), and 0.6 + 0.9 (HD; n = 3) mg/kg+mg/kg/h i.v. Data are mean ± SEM. *P < .05 compared to vehicle. aPTT, activated partial thromboplastin time; HD, high dose; i.v., intravenous; LD, low dose; MD, medium dose; NHP, nonhuman primate; PT, prothrombin time; TT, thrombin time; SEM, standard error of the mean

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  FIGURE 7. Dose‐dependent effect of BMS‐724296 (top panel), apixaban (middle panel), and dabigatran (bottom panel) on thrombus reduction and BT in NHPs. Thrombus reduction was expressed as a percentage reduction of drug‐treated thrombus weight relative to thrombus weight in the control artery. BT effect was expressed as a ratio of drug‐treated value versus the mean vehicle‐treated value. Data are mean ± SEM. Group sizes were reported in the Figure 2 legend. BT, bleeding time; i.v., intravenous; NHP, nonhuman primate; SEM, standard error of the mean