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)].