Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa

Abstract

Background: Factor XI (FXI) inhibition offers the promise of hemostasis-sparing anticoagulation for the prevention and treatment of thromboembolic events. Abelacimab (MAA868) is a novel fully human monoclonal antibody that targets the catalytic domain and has dual activity against the inactive zymogen Factor XI and the activated FXI.

Objectives: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single dose intravenous and multiple dose subcutaneous administration of abelacimab in healthy volunteers and patients with atrial fibrillation, respectively.

Patients/methods: In study ANT-003, healthy volunteers were administered single intravenous doses of abelacimab (30-150 mg) or placebo. The ANT-003 study also included a cohort of obese but otherwise healthy subjects. In study ANT-004, patients with atrial fibrillation were administered monthly subcutaneous doses of abelacimab (120 mg and 180 mg), or placebo, for 3 months. Key PK and PD parameters, including activated partial thromboplastin time (aPTT) and free FXI levels, as well as anti-drug antibodies (ADA) were assessed.

Results: Following intravenous administration of abelacimab, the terminal elimination half-life ranged from 25 to 30 days. One hour after the start of the intravenous infusion greater than 99% reductions in free FXI levels were observed. Following once monthly subcutaneous administration, marked reductions from baseline in free FXI levels were sustained. Parenteral administration of abelacimab demonstrated a favorable safety profile with no clinically relevant bleeding events.

Conclusions: Intravenous and multiple subcutaneous dose administration of abelacimab were safe and well tolerated. The safety, PK, and PD data from these studies support the clinical development of abelacimab.

Keywords: Factor XI; antibodies, monoclonal; blood; pharmacodynamics; pharmacokinetics.