Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation

BackgroundWe previously reported that a humanized anti-factorIXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophiliaA. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation. ObjectivesTo elucidate the invivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use. MethodsA non-human primate model of acquired hemophiliaA was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2days. Bleeding symptoms were monitored for 3days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed. ResultsA single bolus of 1 or 3mgkg(-1) ACE910 showed hemostatic activity comparable to that of 10Ukg(-1) (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis. ConclusionsACE910 may offer an alternative on-demand treatment option for patients with hemophiliaA, as well as user-friendly and aggressive routine supplementation.