Comparative ex vivo analysis of Mim8 in thrombin generation assays triggered by activated factor XI or tissue factor

Mim8 is a next-generation activated factor (F)VIII-mimetic, bispecific antibody, currently in clinical development for the prophylactic treatment of hemophilia A. To evaluate the ex vivo pharmacodynamic effects of Mim8, a thrombin generation assay (TGA) using activated FXI (FXIa) as trigger was employed in the phase 1/2 FRONTIER1 (NCT04204408) study, whereas tissue factor (TF) was used in the phase 3 FRONTIER2 (NCT05053139) study.

To compare the pharmacodynamic results from FRONTIER1 and FRONTIER2 by evaluating Mim8 ex vivo and in vitro thrombin generation (TG) responses in TGAs triggered by either FXIa or TF.

TG was assessed ex vivo in 125 plasma samples from 34 participants with hemophilia A from FRONTIER1 and FRONTIER2 studies, using 2 TGAs triggered with either 1 pM TF or 8 mU/mL FXIa. Additionally, TG was assessed in vitro in FVIII-deficient plasma spiked with Mim8 in both TGAs. Bland-Altman plots were utilized to compare TG responses.

Within the tested Mim8 concentration range, a constant TG response ratio was observed between the 2 triggers. TF-triggered peak thrombin levels were approximately 3 to 4 times lower than those triggered by FXIa. Both triggers exhibited similar endogenous thrombin potential responses, although FXIa showed slightly higher values. These differences were consistent in both ex vivo and in vitro TG assessments.

While both assays are considered relevant for assessing Mim8 pharmacodynamic response, systematic and consistent differences between TGAs triggered by FXIa and TF were observed, indicating different kinetics in the intrinsic and extrinsic pathways.