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A consistent in vivo factor VIII-equivalence is unlikely to exist for non-factor therapies
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Edité par CCSD -
International audience. Introduction : Non-factor therapies are changing the treatment paradigm in hemophilia A, which was previously dominated by replacement-therapy using factor VIII (FVIII)-concentrates. Their FVIII-equivalence has remained unclear since in vitro assays generate variable responses. Here, we explored in vivo testing of two non-factor molecules, emicizumab and a sequence-identical analogue of marstacimab (SIA-marstacimab) in order to evaluate whether or not an absolute FVIII-equivalence exists for these agents.Matériels et Méthodes : We used four different bleeding models, tail vein transection (TVT)-model, tail artery transection (TAT)- model, tail clip-model and saphenous vein puncture (SVP)-model. Both molecules were compared to different dosages of recombinant FVIII for their capacity to correct bleeding in FVIII- deficient mice. Emicizumab and SIA-marstacimab were used at therapeutic doses of 55 microgram/ml and 16 microgram/ml, respectively.Résultats : The severity of these bleeding models was different, with different doses of FVIII needed to reduce blood loss to levels of wild-type (wt)-mice. For instance, a dose of 2.5 IU/kg FVIII was needed for full correction in the TVT-model, whereas 25 IU/kg was needed in the SVP-model. Intermediate doses were required in the TAT-model (5 IU/kg) and tail clip-model (7.5 IU/kg). Importantly, FVIII treatment produced stable clots, without spontaneous rebleeds being observed. Both emicizumab and SIA-marstacimab displayed a variable, model-dependent FVIII-equivalence. For example, emicizumab compared to 5 IU/kg FVIII in the tail clip- model, while corresponding to 10 IU/kg in the SVP-model. For SIA- marstacimab, blood loss was similar to wt-mice in the TVT-, TAT- and tail-clip-models, while corresponding to 10 IU/kg in the SVP- model. Strikingly, both emicizumab- and SIA-marstacimab- treatment was associated with spontaneous rebleeds in the TVT-, TAT- and tail-clip-models, distinguishing them from FVIII- treatment.Conclusion : Our data suggest that a single FVIII-equivalence is unlikely to exist for emicizumab, SIA-marstacimab and similar molecules, and that we should probably consider a range of FVIII- activity to which non-factor molecules may compare. It also pointed out that each molecule seems to behave differently depending on local conditions and the type of injury, making it difficult to predict their efficiency when comparing them to FVIII.
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