PB0156 - Higher Thrombin Generation Is Predicted When Switching Directly From Emicizumab to MIM8 in Patients With Hemophilia A

Background: Mim8 is an activated factor VIII mimetic in phase 3 development for hemophilia A treatment. Directly switching hemophilia treatment (e.g., from emicizumab to Mim8) results in two products contributing to hemostatic activity during the switch period, which has not been examined before.

Aims: Investigate the combined hemostatic activity in terms of thrombin generation and predict the pharmacokinetic/pharmacodynamic (PK/PD) profile when switching directly from emicizumab to Mim8 in patients with hemophilia A.

Methods: Thrombin generation assays (TGAs) were performed in vitro using hemophilia A platelet-poor plasma triggered with 8 U/L human activated factor XI. This was then spiked with combinations of Mim8 (0–15 µg/mL) and an emicizumab sequence-identical analog (emicizumab-SIA, 0–131 µg/mL).
TGA peak thrombin levels were modeled using a PD model of two drugs competing for the same targets. The PD model was directly linked to PK models for Mim8/emicizumab combinations to derive dose-exposure responses. PK/PD simulations were performed for a 70 kg patient during steady-state dosing of emicizumab 1.5 mg/kg once-weekly (QW) or 6 mg/kg every four weeks (Q4W), switching directly to a fixed dose of Mim8 9 mg QW or 46 mg QM.

Results: Mim8 and emicizumab compete in TGAs, and the PD model adequately described total peak thrombin for any combination of Mim8/emicizumab plasma concentrations (Figure 1). The PK/PD model simulated a decline in emicizumab concentration and an increase in Mim8 concentration post-switch, with corresponding combined peak thrombin levels. Independent of dosing regimens, higher hemostatic activity (~10% on average) was rapidly attained without exceeding the normal range following the emicizumab to Mim8 switch (Figure 2).

Conclusion(s): In vitro TGA combined with PK/PD modeling suggests directly switching from emicizumab to Mim8 rapidly establishes higher hemostatic activity levels without exceeding the normal range, independent of the dosing regimen.