A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers.

ABSTRACT

Essentials Tissue factor pathway inhibitor (TFPI) is an antagonist of FXa and the TF-FVIIa complex. PF-06741086 is an IgG1 monoclonal antibody that targets the Kunitz-2 domain of TFPI. Single doses of PF-06741086 were evaluated in a phase 1 study in healthy volunteers. Data from this study support further investigation of PF-06741086 in individuals with hemophilia. SUMMARY: Background Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of the tissue factor-activated factor VII complex and activated FX. PF-06741086 is a mAb that targets TFPI to increase clotting activity. Objectives This study was a randomized, double-blind, sponsor-open, placebo-controlled, single intravenous or subcutaneous dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086. Patients/Methods Volunteers who provided written informed consent were assigned to cohorts with escalating dose levels. Safety endpoints included treatment-emergent adverse events (TEAEs), infusion/injection site reactions, vital signs, electrocardiogram, and coagulation and hematology laboratory parameters. Pharmacokinetic (PK) and pharmacodynamic (PD) endpoints included exposures of PF-06741086 in plasma and measures of PF-06741086 pharmacology, respectively. Results Forty-one male volunteers were recruited overall. Thirty-two were dosed with PF-06741086 from 30 mg subcutaneously to 440 mg intravenously. All doses were safe and well tolerated. TEAEs were mild or moderate in severity, laboratory abnormalities were transient, there were no serious adverse events, there were no infusion/injection site reactions, and no dose escalation stopping criteria were met. Plasma exposures of PF-06741086 increased greater than proportionally with dose under the same dosing route. Coagulation pharmacology was demonstrated via total TFPI, dilute prothrombin time, D-dimer, prothrombin fragment 1 + 2 and thrombin generation assay parameters. Conclusions Single doses of PF-06741086 at multiple dose levels were safe and well tolerated in a healthy adult male population. The safety, PK and PD data from this study support progression to a multiple-dose study in hemophilic patients.