Marstacimab, an antitissue factor pathway inhibitor, combined with bypassing agents: effects on thrombin generation...

Marstacimab is an antitissue factor pathway inhibitor recently approved for treatment of hemophilia without inhibitors and under investigation for treatment of hemophilia with inhibitors. Management of hemophilia in people with inhibitors frequently requires the use of bypassing agents such as recombinant activated factor (F)VII (rFVIIa), activated prothrombin complex concentrate (aPCC), or plasma-derived FVIIa (pdFVIIa)/FX mixture (pdFVIIa/FX).

We explored the potential for excessive thrombin generation and potential additive effects of concomitant administration of marstacimab and bypassing agents.

An in vitro thrombin generation assay was used to assess marstacimab in combination with pdFVIIa/FX in hemophilia A or B with inhibitor and in nonhemophilic donor plasmas. In vivo studies in hemostatically normal rats examined the pharmacokinetic and pharmacodynamic effects of marstacimab (on days 1 and 8) in combination with rFVIIa, aPCC, and pdFVIIa/FX (on days 8-10).

In vitro, the combination of marstacimab plus pdFVIIa/FX decreased lag time and additively increased peak thrombin. In vivo, the combination of marstacimab plus rFVIIa was associated with higher incidence/severity of pulmonary and injection site thrombi/emboli, and marstacimab plus aPCC was associated with alterations in coagulation parameters. Effects of the combination of marstacimab plus pdFVIIa/FX were limited to alterations in coagulation parameters and similar to those of pdFVIIa/FX alone.

These findings suggest marstacimab in combination with pdFVIIa/FX can increase hemostasis without excessive in vitro thrombin generation, and marstacimab in combination with rFVIIa, aPCC, or pdFVIIa/FX is well tolerated in hemostatically normal rats.