1 Introduction
With growing populations and longer life expectancy, we will see an increase in the prevalence of thrombus formation.1 Thrombotic events can be potentially life threatening and may prolong the length of hospital stay and result in chronic disability2. Thrombosis is the most common underlying pathology of the three major cardiovascular disorders: ischemic heart disease (acute coronary syndrome, ACS), stroke, and venous thromboembolism (VTE).3 ACS, the acute manifestation of ischemic heart disease, resulting from coronary arterial thrombus formation, remains a major cause of morbidity and mortality worldwide.4VTE, primarily including pulmonary embolism and deep venous thrombosis, affects an estimated 750,000 people in the United States each year and causes more than 100,000 deaths annually. 15.4% of people with thromboembolism died within 90 days after the index diagnosis.5,6
Low-molecular heparin and low-dose unfractionated heparin can prevent deep vein thrombosis of the lower extremities.7,8Unlike heparin, hirudin is an antithrombotic substance produced by the salivary glands of the medicinal leech Hirudo medicinalis which can directly act on thrombin and effectively inhibit both free and bound thrombin. In some animal models of deep vein injury, hirudin is a more effective antithrombotic drug than heparin.9,10However, treatment with hirudin increases the risk of systemic bleeding, which is its main adverse effect.11,12
Neorudin (EPR-hirudin, EH) is a targeted hirudin variant 2-Lys47(HV2) fusion protein, which is composed of 68 amino acids, with a theoretical molecular weight of 7284 Da.13-15 EH was developed as a prodrug of HV2 by introducing EPR (Glu-Pro-Arg), which is recognized and cleaved by FXIa, into the N-terminal of HV2.16 EH exerts antithrombotic effects by releasing its active metabolite, HV2, at the thrombus site via FXIa-mediated cleavage of EPR, resulting in direct inhibition of thrombin. However, when intact, EH does not display anticoagulant activity. The construction and mechanism of EH determined that it not only effectively inhibited thrombus formation but also reduced the risk of bleeding by increasing the specificity and efficiency of hirudin.17,18
Pre-clinical studies19 have shown that EH was effective and safe in the treatment of thrombosis in rat models of thrombus formation. Compared with low-molecular-weight heparin and hirudin, the bleeding side effects of EH were lower when the antithrombotic effects were similar. After rhesus monkeys were given EH 1.0, 3.0 and 6.0 mg/kg by intravenous bolus and drip, the half-life(T1/2) of EH were 1.2±0.6, 1.3±0.3 and 1.0±0.1h, and Tmax was 0.05±0.00 h. The clinical indication to be used of EH was the prevention and treatment of arteriovenous thrombosis.
The purpose of this first-in-human study was to assess the elementary safety and pharmaco- kinetics of EH in healthy volunteers, and this study was registered at chinadrugtrials.org.cn (Clinical Trial Registry number: CTR20160444) [PRC CFDA. China drug trials. http:// www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlist?keywords=CTR20160444. (Accessed 15 March 2020)].