Hemostatic effect of Mim8 and emicizumab SIA in HA mouse models of moderate and severe bleeding. (A) Outline of bleeding studies in HA mice after TVT or tail clip. Before vascular injury, mice received sequential IV administrations of human FIX (1.5 mg/kg), human FX (0.9 mg/kg), and Mim8 or emicizumab SIA at indicated doses. (B) Blood loss (mean ± standard error of the mean [SEM], n = 3-6) after TVT. At a given dose, plasma exposure levels of Mim8 and emicizumab SIA were similar, with mean levels (nM) provided on a separate X-axis. The bleeding ranges in vehicle-treated HA and normal animals, respectively, are marked by light blue bars. Applying a 3-parameter inverse log(dose) response model, 50% effective doses of 0.06 mg/kg [0.04-0.14] (Mim8) and 0.7 mg/kg [0.5-1.5] (emicizumab SIA) were estimated (95% confidence intervals in square brackets). (C) Blood loss (mean ± SEM, n = 12; n = 16 for HA control group) following tail clipping. The mean plasma exposure level (nM) of biAb is shown below each dose. Bars on the right depict the blood loss (mean ± SEM, n = 12) in HA mice after administration of three IV doses of FVIII in the absence of supplemented human FIX and FX. Measured plasma levels of FVIII (mean ± SEM) are indicated. Groups were compared with vehicle by using one-way analysis of variance with Dunnett’s multiple comparison test. In addition, groups receiving emicizumab SIA were compared with Mim8 groups receiving the same dose by using a Student t test (2-way, unpaired). P < .05 was considered statistically significant (*P < .05; **P < .01). n.s., not significant.