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.

FIGURE 1

(A) Flowchart of study ANT‐003. Cohorts 1–3 enrolled healthy subjects, while cohort 4 enrolled healthy subjects with a BMI ≥ 35 kg/m². (B) In study ANT‐003, healthy subjects in each cohort were randomized to receive a single intravenous dose of 30, 50, and 150 mg abelacimab, or matching placebo. Following a domicile period of 3 days, subjects were monitored as an outpatient out to day 106. Arrows indicate dose administration. (C) Flowchart of study ANT‐004. (D) Patients with low‐risk atrial fibrillation were randomized to receive 3 monthly subcutaneous doses of abelacimab at doses of 120 and 180 mg, or matching placebo and then followed in a washout period out to day 170. Arrows indicate dose administration

FIGURE 2

(A) Arithmetic mean (±SEM) plasma concentration‐time profiles of abelacimab following a 1‐hr intravenous infusion (ANT‐003). (B) Arithmetic mean (±SEM) plasma concentration‐time profiles of abelacimab with once monthly subcutaneous administration (ANT‐004). (*) indicates study visit days with abelacimab subcutaneous administration

FIGURE 3

(A) Arithmetic mean effect‐time profiles of free Factor XI following intravenous abelacimab administration. (B) Arithmetic mean effect‐time profiles of aPTT following intravenous abelacimab administration. (C) Arithmetic mean effect‐time profiles of free Factor XI following monthly subcutaneous administration. (D) Arithmetic mean effect‐time profiles of aPTT following monthly subcutaneous abelacimab administration. Ratios were calculated by dividing by the subject's baseline values