Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial

Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):799-809. doi: 10.1161/ATVBAHA.118.312328.

Abstract

Objective- Factor XI (FXI) contributes to thrombotic disease while playing a limited role in normal hemostasis. We generated a unique, humanized anti-FXI antibody, AB023, which blocks factor XIIa-mediated FXI activation without inhibiting FXI activation by thrombin or the procoagulant function of FXIa. We sought to confirm the antithrombotic activity of AB023 in a baboon thrombosis model and to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult subjects. Approach and Results- In a primate model of acute vascular graft thrombosis, AB023 reduced platelet and fibrin accumulation within the grafts by >75%. To evaluate the safety of AB023, we performed a first-in-human study in healthy adult volunteers without any serious adverse events. Overall, 10 of 21 (48%) subjects experienced 20 treatment-emergent adverse events, with 7 of 16 (44%) subjects following active treatment and 3 of 5 (60%) subjects following placebo. AB023 did not increase bleeding or prothrombin times. Anticoagulation was verified by a saturable ≈2-fold prolongation of the partial thromboplastin time for over 1 month after the highest dose. Conclusions- AB023, which inhibits contact activation-initiated blood coagulation in vitro and experimental thrombus formation in primates, produced a dose-dependent duration of limited anticoagulation without drug-related adverse effects in a phase 1 trial. When put in context with earlier observations suggesting that FXI contributes to venous thromboembolism and cardiovascular disease, although contributing minimally to hemostasis, our data further justify clinical evaluation of AB023 in conditions where contact-initiated FXI activation is suspected to have a pathogenic role. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03097341.

Keywords: factor XI; factor XII; hemostasis; thrombosis.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Anticoagulants / adverse effects
  • Anticoagulants / immunology
  • Anticoagulants / pharmacology
  • Anticoagulants / therapeutic use*
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Factor XI / antagonists & inhibitors*
  • Factor XI / immunology
  • Factor XIIa / physiology
  • Factor XIa / physiology*
  • Fibrinolytic Agents / adverse effects
  • Fibrinolytic Agents / immunology
  • Fibrinolytic Agents / pharmacology
  • Fibrinolytic Agents / therapeutic use*
  • Graft Occlusion, Vascular / drug therapy
  • Humans
  • Papio
  • Partial Thromboplastin Time

Substances

  • AB023
  • Antibodies, Monoclonal, Humanized
  • Anticoagulants
  • Fibrinolytic Agents
  • Factor XI
  • Factor XIa
  • Factor XIIa

Associated data

  • ClinicalTrials.gov/NCT03097341