Background: Mim8 – a novel, human bispecific antibody that mimics factor (F)VIIIa – was designed for subcutaneous prophylactic treatment of patients with hemophilia A (HA) with and without inhibitors. In both, in vitro and HA mouse models, Mim8 has demonstrated superior hemostatic properties to a sequence identical analogue (SIA) of emicizumab. Combination of bispecific antibodies and activated prothrombin complex concentrates (aPCC) can cause synergistic effects, increasing the risk of thrombotic events. No increased safety risk has been shown for the combination of biAbs and recombinant activated FVII (rFVIIa).

Aims: Here, we measure the effects of Mim8+rFVIIa or aPCC in HA-like blood using different global assay conditions.

Methods: Blood from healthy donors (N=5) was made HA-like through addition of FVIII-neutralizing antibody. Mim8 (0–190 nM plasma concentrations) was added to the blood/plasma combined with rFVIIa (0–270 μg/kg dose equivalent) or 1 IU aPCC. Emicizumab-SIA+aPCC was used as a comparator. Clot formation was measured by thromboelastography (TEG) after recalcification with 0.011 M Ca²⁺. Thrombin generation assay (TGA) was initiated by 0.008 U/mL FXIa or 1 pM tissue factor (TF).

Results: The effects of Mim8+rFVIIa on TEG parameters were additive and lower in magnitude than the effects observed with Mim8+aPCC or emicizumab-SIA+aPCC, which had synergistic effects. (Figure A). In FXIa-triggered TGA, Mim8 increased thrombin generation in a concentration-dependent manner, a response unaffected by rFVIIa addition. Supplementing either Mim8 or emicizumab-SIA with aPCC significantly increased thrombin generation (Figure B). In TF-triggered TGA, Mim8+rFVIIa combination appeared to have effects slightly greater than the sum of their individual contributions (possibly caused by TF-rFVIIa interaction). However, thrombin peak was significantly lower than observed for emicizumab-SIA+aPCC (Figure C).

Figure. Clot formation and thrombin generation in HA-like blood supplemented with Mim8+25 nM rFVIIa, Mim8+1 IU aPCC or 350 nM emicizumab-SIA+1 IU aPCC. A) TEG R-time in HA-like blood supplemented with Mim8+25 nM rFVIIa, Mim8+1 IU aPCC or 350 nM emicizumab-SIA+1 IU aPCC. Thrombin peak of TGA triggered using B) FXIa or C) TF in HA-like blood spiked with Mim8+25 nM rFVIIa, Mim8+1 IU aPCC or 350 nM emicizumab-SIA+1 IU aPCC. Error bars represent standard deviation. HA, hemophilia A; rFVIIa, recombinant activated factor VII; FXIa, activated factor XI; SIA, sequence identical analogue; TEG, thromboelastography; TGA, thrombin generation assay; TF, tissue factor.

Conclusions: Mim8+25 nM rFVIIa combination resulted in near-normal thrombin generation and clot formation at most Mim8 concentrations tested, effects far lower in magnitude than those observed for Mim8+aPCC or emicizumab-SIA+aPCC combination.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-effect-of-rfviia-and-mim8-combination-in-hemophilia-a-like-blood/