SHR2285, the first selectively oral FXIa inhibitor in China: Safety, tolerability, pharmacokinetics and pharmacodynamics combined with aspirin, clopidogrel or ticagrelor

Abstract

Purpose: 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 (NCT04945616). A total of 52 healthy subjects, 29 male and 23 female, were completed in this study. The subjects were divided into three groups: A, B and C, 16 subjects in group A [aspirin + clopidogrel + placebo or SHR2285 200 mg bid (1:3, 4 received placebo and 12 received SHR2285)] 16 subjects in group B [aspirin + clopidogrel + placebo or SHR2285 300 mg bid (1:3, 3 received placebo and 13 received SHR2285)] and 20 subjects in group C (aspirin + ticagrelor + placebo or SHR2285 300 mg bid (2:3, 8 received placebo and 12 received SHR2285)), respectively. All groups were administered orally for six consecutive days. Safety, tolerability, pharmacokinetics and pharmacodynamics parameters were assessed.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 mean half-life of SHR2285 in group A, group B and group C was 13.9 h, 14.5 h and 13.8 h, respectively. 3) SHR2285 markedly inhibited FXI activity and prolonged activated partial thromboplastin time (APTT). In group A, group B and group C, the mean maximum inhibition rate of FXI activity was 84.8%, 89.3% and 92.2% and the mean maximum prolongation of APTT was 2.08-fold, 2.36-fold and 2.26-fold, respectively.Conclusion: These data suggest that SHR2285, a potential oral FXIa inhibitor, is expected to become a novel, safe and effective anticoagulant when combined with aspirin, clopidogrel or ticagrelor.

Factor XIa Inhibitors as a Novel Anticoagulation Target: Recent Clinical Research Advances

“…In addition,, SHR2285 significantly inhibited FXI activity, with mean maximum inhibition rates of 84.8, 89.3, and 92.2 for FXI activity in the three groups, respectively. SHR2285 prolonged aPTT with good tolerance in normal individuals, and there was no proof that co-administration increased the rate of serious hemorrhaging [ 44 ].…”

Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis

“…SHR2285 was developed as an orally active FXIa inhibitor, , but its structure and preclinical data has not been reported in the literature so far. After a single oral administration of SHR2285 (50–400 mg) in healthy individuals, the peak plasma concentration was observed at 3–4 h and the plasma half-life was approximately 8–16 h (Table ), suggesting twice-daily dosing .…”

“…There were no serious or life-threatening adverse events . Moreover, the pharmacokinetic, pharmacodynamic, and safety profiles of SHR2285 (200–300 mg tablet twice daily) were assessed in healthy humans in combination with 100 mg of aspirin plus a P2Y 12 inhibitor (300 mg clopidogrel loading followed by 75 mg daily or 180 mg ticagrelor loading followed by 90 mg twice daily) . SHR2285 in combination with dual-antiplatelet therapy for 6 days did not alter the time to peak plasma concentration, the half-life, and the FXIa inhibiting activity.…”

“…SHR2285 in combination with dual-antiplatelet therapy for 6 days did not alter the time to peak plasma concentration, the half-life, and the FXIa inhibiting activity. In addition, there was no increase in bleeding risk following this triple therapy . SHR2285 is currently undergoing phase 2 study for the prevention of VTE in patients with total knee arthroplasty (NCT05203705).…”

“…In addition, there was no increase in bleeding risk following this triple therapy. 98 SHR2285 is currently undergoing phase 2 study for the prevention of VTE in patients with total knee arthroplasty (NCT05203705).…”