title: Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXaI16L).
abstract: Essentials FXaI16Lis a recombinant zymogen-like variant of activated coagulation factor X (FXa). A phase 1 dose escalation clinical trial of FXaI16Lwas conducted in healthy adults. FXaI16Lwas safe and tolerated at doses up to 5 μg/kg; no dose-limiting toxicity was observed. Data support further development of FXaI16Lfor patients with acute hemorrhagic conditions.
  
  
  
  Background FXaI16L(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 FXaI16Lby 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 FXaI16Land 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 FXaI16Lwas safe and tolerated at all dose levels tested, with no dose-limiting toxicity or serious adverse events. FXaI16Lplasma 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 FXaI16Lwas 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 FXaI16Lfor hemostatic treatment in individuals with acute hemorrhagic conditions.
authors.affiliation: PharmaTherapeutics Clinical Research, Pfizer Inc., Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Parsons-Rich
authors.affiliation: PharmaTherapeutics Clinical Research, Pfizer Inc., Cambridge, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Hua
authors.affiliation: PharmaTherapeutics Clinical Research, Pfizer Inc., Collegeville, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Pfizer Clinical Research Unit, Pfizer Inc., Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Kantaridis
authors.affiliation: Rare Disease Research, Pfizer Inc., Cambridge, MA, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Pittman
authors.affiliation: Rare Disease Research, Pfizer Inc., Cambridge, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Arkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000097:blood; D000990:Antithrombin III; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects*; D003029:Coagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D015951:Factor Xa / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D011516:Prothrombin; D011517:Prothrombin Time; D011994:Recombinant Proteins; D055815:Young Adult
chemical_list: D000906:Antibodies; D015415:Biomarkers; D003029:Coagulants; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D011994:Recombinant Proteins; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D000990:Antithrombin III; D011516:Prothrombin; D010447:Peptide Hydrolases; D015951:Factor Xa
keywords: PF-05230907; activated partial thromboplastin time; blood coagulation factor; clinical trial; hematologic agents; hemorrhagic disorders