Phase 1 dose‐escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXaI16L)

Unlabelled Box •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. Summary 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.