Abstract Number: PB0469
Meeting: ISTH 2021 Congress
Background: Marzeptacog alfa (activated) (MarzAA) is a novel increased potency rFVIIa being developed for subcutaneous (SQ) treatment of bleeding in FVII deficiency (FVIID) and other bleeding disorders.
Aims: To conduct clinical trial simulations to support dose selection for SQ MarzAA in a Phase 1/2 trial in FVIID.
Methods: A population pharmacokinetic (popPK) model based on clinical data from subjects with hemophilia was adapted for dose selection in FVIID. Clinical trial simulations following different doses were conducted in 1000 virtual FVIID subjects by baseline adjusting FVIIa levels to 0 and assuming lower FVIIa recovery (specifically 43.5% of that observed in Hemophilia A). Assuming that MarzAA is at least 5-fold more potent than wild type FVIIa, secondary PK parameters and the expected time-to-target of 2 ng/mL and percentage of the population above target at different time-points were derived.
Results: A single dose of 20, 30 or 60 μg/kg resulted in median Cmax (and 80% prediction intervals (PI)) of 4.8 (2.4-9.7), 7.3 (3.7-14.5) or 14.5 (7.3-29.0) ng/mL, respectively. The median and 80% PI of time-to-target following a single dose of 20, 30 or 60 μg/kg were 1.5 (0.8-3.2), 1.2 (0.6-2.3) and 0.8 (0.4-1.5) hours, respectively (Table 1).
A single dose of 20 μg/kg resulted in 80%, 90% and 68% of the population being above target at 3, 6, and 24 hours post dosing, respectively. Doses of 30 or 60 μg/kg expanded the proportion of population above target to 89% and 98% at 24 hours post dosing, respectively (Table 2).
Conclusions: The clinical trial simulations indicated that hemostasis may be achieved with the proposed doses and that good exposure levels may be sustained for 24 hours even in the 20 ug/kg dose group. The Phase 1/2 trial (NCT04548791) is currently enrolling participants.
To cite this abstract in AMA style:Faraj A, Desai S, Neuman L, E Blouse G, Knudsen T, Simonsson US. Dose Selection for Subcutaneous Marzeptacog Alfa (Activated) in Subjects with Factor Vll Deficiency Using Population Pharmacometric Clinical Trial Simulations [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/dose-selection-for-subcutaneous-marzeptacog-alfa-activated-in-subjects-with-factor-vll-deficiency-using-population-pharmacometric-clinical-trial-simulations/. Accessed September 24, 2021.
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