A model-based framework could inform first-in-pediatric dose selection for marzeptacog alfa, activated (MarzAA) to treat episodic bleeding episodes in children with hemophilia A or hemophilia B with inhibitors in a registrational phase 3 trial.

“A run-in PK [pharmacokinetic] phase was agreed upon with regulators to confirm the dose, prior to initiation of efficacy evaluations, instead of a separate dedicated PK study in pediatrics,” the study’s authors explained in CPT: Pharmacometrics & Systems Pharmacology.

The results of the model-informed work suggest that a first-in-pediatric dose of 60 μg/kg of marzeptacog alfa, activated administered subcutaneously, 1 to 3 doses every 3 hours as needed, could stop an acute bleeding event in pediatric patients.

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The analysis of exposure in pediatric age groups revealed that 60 μg/kg of marzeptacog alfa, activated given once, 2 times 3 hours apart, or 3 times 3 hours apart resulted in an area under the concentration curve over 24 hours and maximum concentrations over 24 hours close to the target adult matching range.

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Therefore, the study suggests that a single 60 μg/kg dose of marzeptacog alfa, activated might be sufficient to stop an acute bleeding event in pediatric patients. However, in case of failure, a second dose can be administered after 3 hours, as previous simulations indicated that it can lead to desirable levels of wild-type recombinant activated coagulation factor VII above target in more than 90% of adult patients.

“The work presented here shows how modeling and simulations coupled with an exposure matching strategy may be used in a rare disease setting to inform first-in-pediatric dose selection for a drug candidate that has not been studied in earlier pediatric trials,” the authors said.

Despite the utility of the model-informed framework for determining first-in-pediatric dose selection, the authors did reiterate that the exposure-matching strategy needs to be confirmed in a pharmacokinetic run-in part of the phase 3 trial before initiating efficacy evaluations.

Marzeptacog alfa, activated is a novel variant of human recombinant activated coagulation factor VII.


Faraj A, van Wijk RC, Neuman L, et al. Model-informed pediatric dose selection of marzeptacog alfa (activated): an exposure matching strategy. CPT Pharmacometrics Syst Pharmacol. Published online April 12, 2023. doi:10.1002/psp4.12967