OC 50.5 - FVIII In Vitro Bioequivalence of Mim8 Haemostatic Effect by Thrombin Generation Assays

Background: Mim8 (denecimig) is a novel bispecific antibody mimicking activated factor VIII (FVIIIa), developed for subcutaneous prophylaxis treatment of haemophilia A with/without inhibitors. Whereas FVIII substitution therapy results in peak and trough FVIII levels, Mim8 provides steady-state exposure, allowing maintenance of high plasma activity level. Translation of Mim8 exposure to FVIII in vitro bioequivalence may add to the understanding of prophylactic coverage. Although both FVIII substitution therapy and Mim8 support thrombin generation (TG), their mechanisms of action (MoAs) are different, complicating the comparison. We used TG assays (TGAs) in plasma to predict FVIII in vitro bioequivalence of Mim8 and a sequence-identical analogue of emicizumab (emi-SIA).

Aims: To estimate FVIII in vitro bioequivalence of Mim8 and emi-SIA with TGA under multiple assay conditions.

Methods: TG in platelet-poor plasma from a congenital severe haemophilia A pool, supplemented with FVIII, 5 µg/mL Mim8 (clinically relevant concentration), or 50 µg/mL emi-SIA. TG was initiated with different triggers (tissue factor [TF], activated coagulation factor XI, or combinations thereof) to capture differences in MoA.

Results: FVIII in vitro bioequivalence was dependent on trigger type, concentration, and TGA parameter. The mean FVIII in vitro bioequivalence of Mim8 was 36.8% and 16.4% for emi-SIA, based on peak thrombin using a commonly-used trigger (1 pM TF) (Figure 1). Generally, the highest FVIII in vitro bioequivalence was observed at trigger conditions where activated factor IX (FIXa) generation is limited (Table 1). This effect was particularly evident for Mim8.

Conclusion(s): FVIII in vitro bioequivalence for Mim8 was 6.1–36.8% versus 4.7–16.4% for emiSIA, depending on assay conditions. Given the large span in estimated FVIII in vitro bioequivalence for both molecules, its translation to clinical efficacy is currently unknown. Mim8 had a higher thrombin peak in conditions with limited FIXa compared with emi-SIA, suggesting MoA differences.