Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor...

Essentials FXa^I16L is a recombinant zymogen-like variant of activated coagulation factor X (FXa). A phase 1 dose escalation clinical trial of FXa^I16L was conducted in healthy adults. FXa^I16L was safe and tolerated at doses up to 5 μg/kg; no dose-limiting toxicity was observed. Data support further development of FXa^I16L for patients with acute hemorrhagic conditions.

Background FXa^I16L (PF-05230907) is a zymogen-like variant of activated factor X (FXa). It shows enhanced resistance to inactivation by endogenous inhibitors as compared with wild-type FXa, and restores hemostatic activity in non-clinical models of various bleeding conditions. Objectives To evaluate the safety, pharmacokinetics and pharmacodynamics of FXa^I16L by performing a phase 1, first-in-human, dose-escalation clinical trial in healthy adult volunteers. Methods Participants were assigned to one of six ascending single-dose cohorts (0.1, 0.3, 1, 2, 3 or 5 μg kg^-1 ), each planned to comprise six volunteers treated with FXa^I16L and two treated with placebo. Assessments included safety monitoring, pharmacokinetic and pharmacodynamic (PD) analyses, and immunogenicity testing. Results The trial enrolled 49 male volunteers. Administration of a single intravenous bolus dose of FXa^I16L was safe and tolerated at all dose levels tested, with no dose-limiting toxicity or serious adverse events. FXa^I16L plasma levels appeared to increase dose-proportionally, with a half-life of ~ 4 min. Treatment-related PD changes were observed for activated partial thromboplastin time, thrombin generation assay, thrombin-antithrombin complexes, prothrombin fragment 1 + 2, and D-dimer. One volunteer had a weak and transient non-neutralizing antidrug antibody response, which did not cross-react with native FX or native FXa. Conclusions FXa^I16L was safe and tolerated, and showed a pharmacologic effect in healthy adults when administered at doses up to 5 μg kg^-1 . The safety profile, pharmacokinetics and pharmacodynamics observed in this clinical trial support the further development of FXa^I16L for hemostatic treatment in individuals with acute hemorrhagic conditions.