Fast Onset of Action of Subcutaneously Administered Marzeptacog Alfa (Activated) Supports on-Demand Treatment in Hemophilia a Mice

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.2420-2420
• Main Authors: Del Greco, Frank, Neuman, Linda, Levy, Howard, Reckless, Jill, Knudsen, Tom, Blouse, Grant E.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-128971

Background: Patients with Hemophilia A or B with and without inhibitors lack treatment options that are fast and easy to use for treating acute bleeding. Currently, their only options are intravenous administration of replacement or bypass therapies. Marzeptacog alfa (activated) (MarzAA) is a novel increased potency recombinant FVIIa in clinical development. We hypothesized that, in addition to its clinically demonstrated efficacy in SC prophylaxis, MarzAA could potentially be used SC on-demand to control acute hemorrhage after bleeding has started. Objective: To demonstrate the procoagulant effect of dosing MarzAA subcutaneously at timepoints both before and after injury using a tail clip bleeding model in hemophilia A mice. Methods: Each mouse was initially weighed and briefly anesthetized with isoflurane for collection of 5 µL blood to assess baseline hemoglobin levels. Later, anaesthetized (100 mg/kg ketamine + 10 mg/kg xylazine) F8-/- (Haem A, B6;129S4-F8tm1Kaz/J) mice were submitted to a tail clip injury model completely transecting the tail at a diameter of 1.25 mm from the tip using a sharp razor blade. Following injury, blood loss was monitored with the tail submerged in warm saline for 20 minutes and quantified by hemoglobin content. Mice were dosed with MarzAA SC (1.5 mg/kg) or vehicle at 15, 30, 60, or 90 minutes before or one minute after injury (1.5 and 4.5 mg/kg). An ED50 for MarzAA was determined using various doses ranging from 0.15 mg/kg to 3.0 mg/kg. Statistical significance was set at α = 0.05. Results: SC administration of MarzAA resulted in a dose dependent reduction in bleeding when administered to hemophilia A mice 15 minutes before injury. At the highest dose of MarzAA, full efficacy was achieved as bleeding in the treated mice was comparable to the blood loss observed in normal hemostatically competent mice. The ED50 for MarzAA was calculated to be 387 µg/kg after SC administration in this model. More importantly, when dosed as a rescue therapy one minute after injury, SC MarzAA significantly reduced bleeding to 350±46 µL from 635±50 µL (vehicle), p = 0.02. Conclusion: MarzAA demonstrated efficacy when administered SC both before and after injury. Taken together these data suggest that SC MarzAA could potentially be used on-demand to treat patients with acute bleeding. These results provide a basis for further clinical investigation of the acute treatment of a bleed with SC MarzAA in hemophilia patients. Del Greco:Catalyst Bioscie