First Test of a Novel Factor VIII Mimetic for Hemophilia

Recombinant factor VIII is used to prevent bleeding in patients with classical hemophilia, but it must be infused intravenously at least weekly, and it provokes antibodies in up to a third of patients. An alternative approach to factor VIII infusions would be the administration of an antibody that binds to factors IX and X, mimicking the function of factor VIII.

To determine whether such an antibody can safely substitute for factor VIII, investigators conducted a phase I, double-blind, randomized, placebo-controlled, dose-escalation study in which 40 healthy Japanese and 24 white individuals received single doses (0.01 to 1 mg/kg administered subcutaneously) of ACE910, a recombinant humanized bispecific antibody.

The concentration of ACE910 peaked 1 to 2 weeks after administration (median half-life, 4 to 5 weeks). Although the levels of factors IX and X were not affected, the activated partial thromboplastin time (aPTT) was slightly shortened. In plasma samples depleted of factor VIII, a dose-dependent shortening of the aPTT occurred; the aPTT reached normal values at a dose of 1 mg/kg. In addition, the peak values for thrombin generation in the factor VIII–depleted plasma closely mirrored the plasma levels of the drug, reaching almost normal values at the highest drug concentration.

There were no serious clinical adverse effects and no laboratory evidence of ACE910-induced hypercoagulability. One participant developed antidrug antibodies that decreased drug levels and reduced the correction of the aPTT and thrombin generation of factor VIII–depleted plasma.