Efficacy and Safety of SHR2285 Tablets Following Multiple Oral Administrations in Patients Undergoing Elective Total Knee Arthroplasty: a Multicenter, Randomized, Positive-controlled Phase II Clinical Study

This study is a multi-center, randomized, open-label, double-blind, positive-controlled phase II clinical study evaluating the efficacy and safety of different doses of SHR2285 tablets vs. enoxaparin for the prevention of postoperative venous thromboembolism in patients undergoing elective unilateral total knee arthroplasty.

Start Date08 Mar 2022

Sponsor / Collaborator

Shanghai Hengrui Pharmaceutical Co., Ltd.

CTR20212948

/ RecruitingPhase 2

择期全膝关节置换术患者多次口服SHR2285片疗效和安全性的多中心、随机、阳性对照II期临床研究

[Translation] A multicenter, randomized, positive-controlled phase II clinical study on the efficacy and safety of multiple oral administration of SHR2285 tablets in patients undergoing elective total knee replacement

评价与依诺肝素治疗比较，不同剂量SHR2285片在行择期单侧全膝关节置换术的患者中预防术后静脉血栓栓塞症的疗效与安全性。

[Translation]

To evaluate the efficacy and safety of different doses of SHR2285 tablets compared with enoxaparin therapy in preventing postoperative venous thromboembolism in patients undergoing elective unilateral total knee replacement.

Start Date08 Mar 2022

Sponsor / Collaborator

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

[+1]

NCT04945616

/ CompletedPhase 1

Study on the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SHR2285 Tablets Combined With Aspirin, Clopidogrel or Ticagrelor in Healthy Subjects

The study is a single-center，randomized, doubled-blinded, placebo-controlled, Only for SHR2285 Phase I trial. This study intends to enroll 52 healthy subjects, regardless of gender. The subjects are divided into three groups: A, B, and C, with 16 cases in each of groups A and B, and 20 cases in group C.

Start Date13 Jul 2021

Sponsor / Collaborator

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

100 Clinical Results associated with SHR2285

100 Translational Medicine associated with SHR2285

100 Patents (Medical) associated with SHR2285

Literatures (Medical) associated with SHR2285

01 Jun 2023·Clinical drug investigation

The Safety, Pharmacokinetics, and Pharmacodynamics of SHR2285, an Oral Small Molecule Factor XIa Inhibitor, in Healthy Chinese Volunteers.

Article

Author: Dong, Yanli ; Zhao, Xia ; Cui, Yimin ; Huang, Jie ; Wang, Honghui ; Yang, Guoping ; Yang, Sibo ; Xiang, Qian ; Li, Yijing ; Li, Jinlei ; Zhao, Nan ; Xu, Junyu

BACKGROUND AND OBJECTIVEThere is an unmet need for a safer anticoagulant since bleeding remains a concern with currently approved anticoagulants. Coagulation factor XI (FXI) is an attractive anticoagulant drug target with limited a role in physiological hemostasis. The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in healthy Chinese volunteers.METHODSThe study consisted of single ascending doses part (part 1: 25-600 mg) and multiple ascending doses part (part 2: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo orally. Blood, urine and feces samples were collected to describe its pharmacokinetic and pharmacodynamic profile.RESULTSIn total, 103 healthy volunteers completed the study. SHR2285 was well tolerated. SHR2285 was absorbed rapidly with median time to maximum plasma concentration (T_max) of 1.50 to 3.00 h. The geometric median half-life (t_1/2) of SHR2285 varied from 8.74 to 12.1 h across 25-600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77- to 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 pharmacokinetic 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 activated partial thromboplastin time (APTT) and a 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 100-400 mg, respectively.CONCLUSIONSSHR2285 was generally safe and well tolerated in healthy subjects across a wide range of doses. SHR2285 exhibited a predictable pharmacokinetic profile and an exposure-related pharmacodynamic profile.CLINICALTRIALSgov Identifier NCT04472819; registered on July 15, 2020.

Frontiers in PharmacologyQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: Guan, Xiaoduo ; Zou, Jianjun ; Hu, Pei ; Zhang, Tengfei ; Chen, Rui ; Zhu, Yi ; Zhang, Shuyang ; Dong, Yanli

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].

Frontiers in Pharmacology

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

Article

Author: Yang, Yuanxun ; Sun, Runbin ; Jin, Yun ; Ju, Xitong ; Huang, Lei ; Lin, Hui ; Zhao, Yu ; Ma, Tingting ; Fei, Fei ; Geng, Yan ; Dong, Yanli ; Yang, Zeyu ; Xie, Pinhao ; Li, Juan

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.

100 Deals associated with SHR2285

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Venous Thrombosis	Phase 2	China	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	08 Mar 2022
Venous Thromboembolism	Discovery	China	Shanghai Hengrui Pharmaceutical Co., Ltd.	05 Nov 2021
Embolism	Discovery	China	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	25 Feb 2019
Thromboembolism	Discovery	China	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	25 Feb 2019

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04472819 (Pubmed \| Clin Drug Investig)	Phase 1	-	103	SHR2285	rkmupssnvs(gsoybdgcbu) = kxtmmeqjmv sdqdoqvqfb (ultmmzaypd )	-	16 Jun 2023
NCT03769831 (Pubmed \| Front Pharmacol)	Phase 1	-	28	SHR2285	azevnpqxbm(osehrbooji) = All adverse events were grade 1, and there was no evidence of bleeding events bvqagcezcp (elkapntrnj ) View more	Positive	01 Jan 2022

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