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A first‐in‐human study of DS‐1040, an inhibitor of the activated form of thrombin‐activatable fibrinolysis inhibitor, in healthy subjects
Essentials DS‐1040 inhibits the activated form of thrombin‐activatable fibrinolysis inhibitor (TAFIa). Infusion of DS‐1040 was safe and well tolerated in healthy young and elderly subjects. DS‐1040 substantially decreased TAFIa activity but had no impact on bleeding time. DS‐1040 may provide an opti...
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Published in: | Journal of thrombosis and haemostasis 2017-05, Vol.15 (5), p.961-971 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Essentials
DS‐1040 inhibits the activated form of thrombin‐activatable fibrinolysis inhibitor (TAFIa).
Infusion of DS‐1040 was safe and well tolerated in healthy young and elderly subjects.
DS‐1040 substantially decreased TAFIa activity but had no impact on bleeding time.
DS‐1040 may provide an option of safer thrombolytic therapy.
Summary
Background
Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue‐type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS‐1040 is a novel low molecular weight compound that inhibits the activated form of thrombin‐activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases.
Objectives
This first‐in‐human, randomized, placebo‐controlled, three‐part, phase 1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS‐1040 in healthy subjects.
Subjects/Methods
Young (18–45 years) or elderly (65–75 years) subjects (N = 103) were randomized to receive single ascending doses of DS‐1040 ranging from 0.1 mg to 40 mg, or placebo, administered either as a 0.5‐h intravenous infusion or as a 24‐h continuous infusion.
Results
All doses of DS‐1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS‐1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS‐1040 and prolonged elimination times, probably because of decreased renal clearance. DS‐1040 caused a substantial dose‐dependent and time‐dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D‐dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS‐1040 treatment. No effects of DS‐1040 on coagulation parameters or platelet aggregation were observed.
Conclusions
The novel fibrinolysis‐enhancing agent DS‐1040 has favorable pharmacokinetic/pharmacodynamic properties and a favorable safety profile, warranting further clinical development. |
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ISSN: | 1538-7933 1538-7836 1538-7836 |
DOI: | 10.1111/jth.13658 |