Aim: The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in Chinese healthy volunteers. Methods: The study consisted of single ascending doses part (part A: 25 - 600 mg) and multiple ascending doses part (part B: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo. Plasma and urine samples were collected to describe its pharmacokinetics and pharmacodynamics (PD) profile. Results: SHR2285 were well tolerated. SHR2285 was absorbed rapidly with median Tmax of 1.50 to 3.00 h. The geometric median of t1/2 of SHR2285 varied from 8.74-12.1 h across 25 to 600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77-3.61 fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7 with low accumulation ratio (0.956-1.20 and 1.18-1.56 respectively). The increase in PK exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure dependent prolongation of APTT, and decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100 to 400 mg, respectively. Conclusions: SHR2285 exhibit a predictable PK profile and exposure related PD profile. These results suggest that SHR2285 is a promising novel oral FXI inhibitor warranting further evaluation.

Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR2285, the first oral coagulation factor XIa (FXIa) inhibitor developed in China in combination with aspirin, clopidogrel or ticagrelor in healthy subjects. Methods: This study was a single-center, randomized, double-blind, placebo-controlled (only SHR2285) design. A total of 52 healthy subjects, 29 male and 23 female, were enrolled in this study. The subjects were divided into three groups: A, B and C, 16 subjects in group A (aspirin+clopidogrel+placebo or SHR2285 200mg bid (1:3)), 16 subjects in group B (aspirin+clopidogrel+placebo or SHR2285 300mg bid (1:3)) and 20 subjects in group C (aspirin+ticagrelor+placebo or SHR2285 300mg bid (2:3)), respectively. All groups were administered orally for 6 consecutive days. Results: 1. SHR2285 was well tolerated, and all adverse events were mild. There was no evidence of an increased risk of bleeding. 2. After 6 days of twice-daily administration, SHR2285 could reach a steady state. The half-life of SHR2285 was 13.9h, 14.5h and 13.8h respectively. 3. SHR2285 markedly inhibited FXI: C and prolonged APTT. The maximum inhibition rates of FXI: C in the three groups were 84.8%, 89.3% and 92.2% and the maximum prolongation time of APTT was 2.08-, 2.36-, and 2.26-fold, respectively. 4. The combination of aspirin, clopidogrel or ticagrelor had limited effect on the AUC of SHR2285. Conclusion: These data suggest that SHR2285, a potential oral FXIa inhibitor, is expected to become a novel, safe and effective anticoagulant.