First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Factor XI Monoclonal Antibody SHR-2004 in Healthy Subjects

Introduction: Thromboembolic disease is a major global health problem. Inhibition of coagulation factor XI (FXI) is a novel strategy for the prevention and treatment of thrombotic diseases without affecting exogenous coagulation pathways. SHR-2004 is ahumanized monoclonal antibody that selectively binds to FXI and FXIa, hindering the activation of FXI by FXIIa and thereby blocking the cascade amplification process of endogenous coagulation pathways and exerting anticoagulant effects. This first-in-human, phase I study aimed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of SHR-2004 in healthy Chinese subjects.

Methods: This single-center, randomized, double-blind, dose-escalation, placebo-controlled study (NCT05369767; Figure 1) evaluated SHR-2004 adminstered intravenously (i.v., part A) or subcutaneously (s.c., part B). In part A, 24 healthy subjects (8 for each dose level) received single i.v. dose of SHR-2004 (0.1, 0.3 or 1.0 mg/kg) or placebo in a randomization ratio of 3:1. In part B, 40 subjects (10 for each dose level) received single s.c. dose of SHR-2004 (0.5, 1.0, 3.0 or 4.5 mg/kg) or placebo (4:1). The safety, tolerability, PK, PD and immunogenicity of SHR-2004 were assessed.

Results: SHR-2004 was well tolerated at all tested doses, and all adverse events were mild. A total of 88 treatment-related adverse events (TRAEs) were reported in 35 of 50 subjects assigned to SHR-2004 (70.0% of subjects), and 20 TRAEs were reported in 8 of 14 subjects receiving placebo (57.1%). Two subjects in the SHR-2004 cohorts and one in the placebo cohort showed mild ecchymosis. There was no evidence of other clinically relevant bleeding events.

The plasma exposure of SHR-2004 (maximum concentration, C _max and area under the plasma concentration-time curve, AUC) increased in a dose-dependent manner for both i.v. and s.c. dose cohorts (Figure 2). The median time-to-peak concentration (T _max) was 1.76 -2.79 hours after the start of i.v. infusion, and 4.0-6.5 days after s.c. injection, respectively. The mean elimination half-life (t _1/2) ranged from 12.4 to 13.2 days following i.v. infusion, and 11.7 to 12 days after s.c. injection.

It was observed that FXI activity decreased and activated partial thromboplastin time (APTT) was prolonged after i.v. and s.c. administration in a dose- and time-dependent manner. In the 1.0 mg/kg i.v. cohort, FXI activity was almost completely inhibited immediately after completion of the infusion, with average APTT prolonged to nearly three times that of baseline, and these effects persisted until day 9. Following s.c. administration, more than 80% inhibition was achieved within 12h after injection in the 3 mg/kg and 4.5 mg/kg cohort, and the maximum inhibition was maintained to day 22 and day 29, respectively. Similarly, the APTT was prolonged more than 1.7-fold in a gentle and sustained manner from 12h post-dose to day 29 in the 3 mg/kg and 4.5 mg/kg dose levels.

Conclusion: Single intravenous infusion (0.1-1.0 mg/kg) and subcutaneous injection (0.5-4.5 mg/kg) of SHR-2004 are safe and well tolerated. SHR-2004 showed predictable PK with a relatively slowly elimination, which supports administration once a month in the future clinical and market. The encouraging PD data demonstrated a fast and sustained anticoagulant effect. These data indicate that SHR-2004 is a promising candidate for further development as a potential anticoagulant drug, which is expected to minimize the risk of bleeding while maintaining effective anticoagulation.