First-In-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of SHR2285, a Small-Molecule Factor XIa Inhibitor in Healthy Subjects

Abstract

Background: Targeting factor XI (FXI) is a promising therapeutic strategy for the treatment and prevention of thrombosis without increasing the risk of bleeding. Here, we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR2285, a novel FXIa inhibitor, in healthy subjects.Methods: In this randomized, double-blinded, placebo-controlled, dose-ascending single-dosing trial (NCT03769831), eligible volunteer subjects receive either SHR2285 or placebo in a 3:1 ratio. Subjects assigned to the SHR2285 group received a single oral dose of SHR2285 at 50 mg, which was subsequently escalated to 100 mg, 200 mg, and 400 mg. Safety, pharmacokinetics, and pharmacodynamics parameters were assessed. All subjects were followed for 6 days.Results: SHR2285 was well tolerated. All adverse events were grade 1, and there was no evidence of bleeding events. The PK results revealed a rapid onset of action of SHR2285 (median time to maximum plasma concentration [Tmax] in different dose groups ranged 3.0–4.0 h) and the mean half-life ranged from 7.6 to 15.8 h. The metabolite SHR164471 had a slightly longer Tmax than the parent SHR2285, reaching a peak at a median of 6.0–7.0 h, and its mean half-life were 10.1–14.7 h in different dose groups. The sums of the area under the concentration–time curve from zero to time infinity of SHR2285 and SHR164471 in the 200 and 400 mg groups were similar, indicating the sum pharmacological activity of SHR2285 and SHR164471 showed a saturation trend between 200 and 400 mg. PD analysis showed that the inhibition of FXI activity was synchronized with prolonged activated partial thromboplastin time after SHR2285 administration, but the serum prothrombin time and international normalized ratio levels were not affected by SHR2285.Conclusion: SHR2285 demonstrated favorable safety, PK, and PD profiles in the dose range of 50 mg–400 mg. This first-in-human study supports the further development of SHR2285 for indications requiring anticoagulation.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03769831, identifier [NCT03769831].

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

“…The pharmacokinetics of SHR2285 and its main active metabolite were well characterized. The t 1/2 of SHR2285 and its active metabolite SHR164471 is 12.3–14.5 h, similar to the SHR2285-101 study ( Chen et al, 2022 ), which supports oral administration twice a day, both inside and outside the hospital. In this study, C max and AUC of SHR2285 were apparent higher than 101 study, and T max was significantly apparent.…”

“…In the SHR2285-101 study, the maximum FXI inhibition was 60.92%, and the APTT pro longed 1.52 times, slightly inferior to the PD of SHR2585 in this study (different dosage forms). In the first-in-human study of SHR2285, no bleeding events were reported, suggesting that SHR2285 may be a potential anticoagulant option for patients who underwent PCI and required DAPT in combination with anticoagulants ( Chen et al, 2022 ). However, the antithrombotic effect and bleeding risk after FXIa inhibitor combined with the existing standard dual antiplatelet therapy, the standard treatment of myocardial infarction and stroke recommended by the international and China, has not been studied.…”

“…At present, systematic preclinical pharmacology, pharmacokinetics and toxicology studies have been completed, and animal tests have confirmed that it selectively inhibits human FXIa, reduces thrombosis weight, prolongates APTT and reduces bleeding risk. Up to now, SHR2285 has completed three clinical trials (including SHR2285-101, SHR2285-102 and SHR2285-104), all of which are phase I trials in healthy subjects ( Perera et al, 2018 ; Chen et al, 2022 ).…”

“…However, these therapies are associated with a high risk of bleeding. In the first-in-human study of SHR2285 ( Chen et al, 2022 ), no bleeding events of SHR2285 were reported, indicating that SHR2285 might be a potential choice of anticoagulants for patients with a trial fibrillation who underwent PCI and required a combination of dual antiplatelet therapy with the anticoagulant drug. Refer to most guidelines for recommendations ( Degrauwe et al, 2017 ; Wang et al, 2017 ), SHR2285 may be combined with aspirin, clopidogrel, or ticagrelor in the phase II clinical study planned to be carried out, and the patients are given multiple times of medication for a long time.…”

Factor XI, a potential target for anticoagulation therapy for venous thromboembolism

“…FXI inhibitors are not only orally available but also maintain anticoagulant effect for up to 1 month (38,39), which significantly improves patient compliance by eliminating the need for routine monitoring and avoiding the effects of discontinuation or irregular readministration after discontinuation. In addition, FXI inhibitors, regardless of different application strategies, have stable pharmacokinetics, good anticoagulation, and a low incidence of adverse events such as headache and fatigue (37)(38)(39)(40). Therefore, FXI inhibitors are safe, but more studies are needed to observe patients with renal insufficiency, combination dosing, and bridging therapy.…”