Pharmacokinetics and pharmacodynamics of SHR-2004, a novel humanized monoclonal antibody targeting factor XI, in patients with atrial fibrillation

Abstract Background Atrial fibrillation (AF) is associated with increased risks of arterial thromboembolic events, stroke, and mortality. Current treatments are limited by high bleeding risk, poor adherence, and strict renal function requirements. Thus, there is an unmet need for novel anticoagulants with improved safety profiles. SHR-2004, a humanized monoclonal antibody targeting factor XI (FXI), has potential efficacy in preventing arteriovenous thromboembolism. Purpose To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SHR-2004 in patients with AF. Methods This open-label phase 1b study enrolled patients aged ≥40 and 80 years, who were either diagnosed with or had a history of atrial fibrillation or atrial flutter and had a CHA2DS2-VASc risk score ≥1 (male) or ≥2 (female). Patients received 6 doses of SHR-2004 subcutaneously (180 mg, once every 2 weeks), for nearly 3 months. The primary endpoints were safety and tolerability. PK and PD parameters, including activated partial thromboplastin time (aPTT) and FXI activity were assessed. Results Between April 10, 2024 and May 6, 2024, 10 patients were enrolled, with a median age of 68.0 years (IQR, 55.0-70.0), and 9 (90.0%) being male. The median CHA2DS2-VASc risk score was 2.5 (IQR, 2.0-3.0). SHR-2004 was well tolerated at the tested dose. Treatment-emergent adverse events (AEs) occurred in 8 (80.0%) patients, and treatment-related AEs were reported in 6 (60.0%). All AEs were mild or moderate. Only 1 patient experienced a serious AE (atrial fibrillation leading to hospitalization), which was considered by the investigator to be moderate and likely not to be treatment-related. Notably, no major or clinically relevant non-major bleeding events were reported. Two patients (20.0%) experienced minor bleeding events, both of which were positive urinary occult blood. The PK and PD profiles of SHR-2004 are shown in Figures 1 and 2. The SHR-2004 exposure had a rapid increase and achieved the steady state by Day 57, with drug accumulation reaching nearly a 2.0-fold trough ratio. Administration of SHR-2004 led to a rapid and nearly complete inhibition of FXI activity by Day 3. Reductions in FXI activity were associated with a rapid and sustained prolongation of aPTT with approximately a 2.3-fold prolongation reached on Day 3, which was stably maintained up to Day 85. On Day 106, FXI activity inhibition was 91%, and aPTT prolongation was 1.8-fold. By Day 136, FXI activity and aPTT had returned to baseline levels. Conclusion Multiple subcutaneous doses of SHR-2004 were safe and well tolerated in patients with AF, particularly regarding the low risk of bleeding. The safety, PK, and PD data from this trial support further exploration of SHR-2004 in patients with AF.1. Pharmacokinetic profile of SHR-2004 2. Pharmacodynamics profile of SHR-2004