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.

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa

“…Asundexian and milvexian can be administered orally, whereas osocimab, abelacimab, and IONIS FXI‐R x need to be administered subcutaneously or intravenously. The onset of action of asundexian, milvexian, 26 osocimab, 24 and abelacimab 27 is rapid, whereas it takes longer time periods for IONIS FXI‐R x to lower FXI concentrations to therapeutic levels with a correspondingly long duration of the anticoagulant effect 19 . Osocimab (mean elimination half‐life, 30–44 days 24 ) and abelacimab (elimination half‐life, 25–30 days 27 ) have been shown to have a long duration of effect, whereas milvexian has a half‐life that may be suitable for once‐ or twice‐daily dosing, 26 and phase I data suggest asundexian is a suitable candidate for once‐daily oral anticoagulation 28,29 ; this is being further evaluated in phase II.…”

Factor XI as a target for preventing venous thromboembolism

“…It does not bind to not FXI. Abelacimab, like osocimab, binds and inhibits the FXIa protease domain 32 . However, it also binds zymogen FXI and blocks its conversion to FXIa 32 …”

“…Interestingly, despite its initial effect on the APTT, results for the 30‐mg abelacimab dose only met criteria for noninferiority compared with enoxaparin. Abelacimab binds zymogen FXI 32 . Because FXI is continuously released into plasma by the liver, the drug will become saturated with FXI over time even if it is initially in excess of plasma FXI.…”

“…Abelacimab, like osocimab, binds and inhibits the FXIa protease domain. 32 However, it also binds zymogen FXI and blocks its conversion to FXIa. 32 This results in a FXI deficiency-like state, in the sense that the amount of FXI available for activation in plasma is reduced.…”

“…Abelacimab binds zymogen FXI. 32 Because FXI is continuously released into plasma by the liver, the drug will become saturated with FXI over time even if it is initially in excess of plasma FXI. Little free FXI was measurable in plasmas 3 days after administration of each of the abelacimab doses.…”