Safety, Pharmacokinetics, and Pharmacodynamics of SHR-2004, a Novel Humanized Monoclonal Antibody Targeting Factor XI, in Patients with Atrial Fibrillation: An Open-Label Phase 1b Study

SHR-2004, a humanized monoclonal antibody targeting factor XI (FXI), demonstrates potential for preventing and treating thrombotic events with reduced bleeding risk. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR-2004 in patients with atrial fibrillation (AF). In this open-label dose-escalation phase 1b study, patients with AF aged ≥ 40 and < 80 years with a CHA2DS2-VASc score ≥ 1 (male) or ≥ 2 (female) were enrolled to receive six doses of SHR-2004. The primary endpoints were safety and tolerability. PK and PD parameters, including activated partial thromboplastin time (aPTT) and FXI activity, were also assessed. From 10 April 2024 to 6 May 2024, ten patients were enrolled to receive SHR-2004 (180 mg subcutaneously, every 2 weeks), with a median age of 68.0 years, and male being in the majority (9/10). The median CHA2DS2-VASc score was 2.5 (range 1-6). The trial was terminated after completion of the 180 mg cohort. SHR-2004 was well tolerated. Treatment-emergent adverse events (AEs) occurred in eight (80.0%) patients, and treatment-related AEs were reported in six (60.0%) patients. All AEs were mild or moderate. Notably, no major or clinically relevant nonmajor bleeding events were reported. Plasma exposure of SHR-2004 increased rapidly after administration and reached steady state by day 57 with the geometric mean (CV%) plasma concentration of 24,000 (26.4) ng/mL. This exposure resulted in median FXI activity after the first dose of 1.40% (IQR 1.40-1.40%). The outcomes of PD effects, FXI activity and aPTT prolongation, reached a plateau during the treatment period from day 3 to day 85 indicating that the 180 mg dosage regimen achieved and maintained therapeutic pharmacodynamic steady state. Multiple subcutaneous doses of SHR-2004 were generally well tolerated in patients with AF. These preliminary findings support further clinical development of SHR-2004 in this population. Clinicaltrials.gov identifier: NCT06280768. Trial registration date: 28 February 2024.