First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor xa and factor IIa

ABSTRACTBackground SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects.Methods In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events (TEAEs) were recorded to evaluate safety.Results In plasma, from the 0.5 to 20 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5-20 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study.Conclusion SAR107375 exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics.KEYWORDS: AnticoagulantAntithrombinsFactor xa inhibitorspharmacokineticsRandomized controlled trialDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsSAR107375E is a small molecule compound that directly inhibits both Factor Xa and Factor IIa (thrombin).The safety, tolerability, pharmacokinetics, and pharmacodynamics of SAR107375E were studied in healthy subjects.Intravenous administration of SAR107375E was safe and well-tolerated and produced rapid Factor Xa and Factor IIa inhibition.Declaration of interestsThe author(s) declared the following potential conflict of interest concerning the research, authorship, and/or publication of this article: Shuanzhi Wu, Tenghua Wang, Zhixin Zhang, Chen Li, Shuangshuang Xiao, Jin He, Xuan Wang, Zhiqin Hu, Xiaole Wang, Sichao Zheng, Xintong Laing, Yongmei Li, Xianbo Li, Yaoxuan Zhan, Li Ban, and Haiyan Liu are employees or affiliates in the Fifth Affiliated Hospital of Guangzhou Medical University.Fang Yi also worked in the Fifth Affiliated Hospital of Guangzhou Medical University and Peking University People’s Hospital.Guiying Chen and Hongliang Jiang are Wuhan Hongren Biomedical Co., Ltd employees. They declare no conflict of interest.Li Jieyun and Zou Qinwen are employees of Beijing Lianxin Pharmaceutical Co., Ltd. and they also declare that there is no conflict of interest.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresA reviewer on this manuscript has disclosed they are a co-founder of LUNAC Therapeutics developing an anticoagulant targeting FXIIa. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Author contributionShuanzhi Wu, Tenghua Wang, and Yi Fang participated in data analysis, data interpretation, manuscript preparation, review, and revisions. Zhixin Zhang, Xuan Wang, and Haiyan Liu are research doctors. Shuangshuang Xiao and Yaoxuan Zhan are research nurses. Zhiqin Hu and Xiaole Wang participated in the preparation of the study drug. Chen Li, Xintong Liang, and Shuanzhi Wu participated in pre-processing PK blood samples, PK urine samples, and PD blood samples. Jin He, Sichao Zheng, Yongmei Li, Xianbo Li, and Li Ban are responsible for the quality control of the study. Guiying Chen and Hongliang Jiang are responsible for the analysis of biological samples. Qingshan Zheng is responsible for statistics and data analysis. Yi Fang, Haiyan Liu, Jieyun Li, and Qinwen Zhou participated in the study design. Yi Fang and Haiyan Liu are the principal investigators. All authors granted final approval of the manuscript for submission.AcknowledgmentsThe authors thank the subjects who participated in this study. The authors acknowledge Yi Fang, Haiyan Liu, and other clinical study team members for their work in executing this study. The authors also acknowledge the individuals at Beijing Lianxin Pharmaceutical Co., Ltd. who contributed to the research and development of SAR07375E.Data availability statementThe authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.Figure 1. Flowchart of the study. FAS, full analysis set; PDS, pharmacodynamics set; PKS, pharmacokinetics set; SS, safety set.Display full sizeFigure 2. SAR107375E plasma concentrations in all cohorts after a single intravenous dose. Data are arithmetic mean ±standard deviation and are presented on a semi-logarithmic scale.Display full sizeFigure 3. Coagulation parameter-time profiles for all subjects receiving a single dose of SAR107375E or placebo (all subjects received placebo were pooled).Display full sizeA. APTT, activated partial thromboplastin time.B. ECT, ecarin clotting time. C. TT, thrombin time. From the 1.5 mg dose group, the TT value reached the limit of detection at 0.167 hours. D. FIB, fibrinogen. E. PT, prothrombin time. A total of 2 blood samples at 0.167h reached the detection limit in the 10mg and 20mg groups. F. INR, international normalized ratio. G. anti-IIa activity. H. anti-Xa activity. For these outcomes, baseline samples were collected before dosing on Day 1. Data are presented as arithmetic mean ± standard deviation.Figure 4. Scatter plots of concentration-effect relationship. Observed values (blue dots), linear correlation and 95% confidence interval (red solid and dashed lines).Display full sizeAdditional informationFundingThis manuscript was funded by Beijing Lianxin Pharmaceutical Co., Ltd, the Major Project of National Science and Technology “Creation of Major New Drugs” (2020ZX09201026), the Guangzhou Health Science and Technology Project (2021A031005), and the General Guidance Project of Guang-Zhou Municipal Health Commission (20231A010063).