A first‐in‐human study of DS‐1040, an inhibitor of the activated form of thrombin‐activatable fibrinolysis inhibitor, in healthy subjects

• Published in: Journal of thrombosis and haemostasis Vol. 15; no. 5; pp. 961 - 971
• Main Authors: Zhou, J., Kochan, J., Yin, O., Warren, V., Zamora, C., Atiee, G., Pav, J., Orihashi, Y., Vashi, V., Dishy, V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.05.2017
• Subjects: Adolescent; Adult; Age Factors; Aged; Bleeding; Blood Coagulation Tests; Carboxypeptidase B2 - antagonists & inhibitors; Carboxypeptidase B2 - metabolism; Coagulation; Dose-Response Relationship, Drug; Female; Fibrinolysis; Fibrinolysis - drug effects; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - pharmacokinetics; Geriatrics; Healthy Volunteers; Hemorrhage - chemically induced; Humans; Infusions, Intravenous; Intravenous administration; Ischemia; Kidneys; Lysis; Male; Middle Aged; Molecular weight; Pharmacodynamics; Pharmacokinetics; Platelet aggregation; Protease Inhibitors - administration & dosage; Protease Inhibitors - adverse effects; Protease Inhibitors - pharmacokinetics; Risk Factors; Stroke; Thrombin; thrombin‐activatable fibrinolysis inhibitor; Thromboembolism; Thrombolysis; thrombosis; Young Adult; fibrinolysis; pharmacokinetics; thrombin-activatable fibrinolysis inhibitor; thrombosis; pharmacodynamics
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13658

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.