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

Abstract

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.

First‐in‐Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of an Oral Formulation of DS‐1040, an Inhibitor of the Activated Form of Thrombin‐Activatable Fibrinolysis Inhibitor, in Healthy Subjects

“…Multiple daily dosing of DS‐1040 did not lead to a significant accumulation in exposure; steady state was attained by day 7 with minimal accumulation (mean accumulation ratio 1.15‐1.25) compared with predose plasma DS‐1040 concentrations on day 10. The t ½ values observed in this study for the oral formulation of DS‐1040 were in line with previously reported results for DS‐1040 administered via IV . This suggests that the oral formulation of DS‐1040 will be suitable for use in patients.…”

“…Approximately 10% of the administered dose was recovered as intact parent drug in urine. This is lower than the percentage of parent drug recovered in urine after IV administration (44%‐93%) . Multiple daily dosing of DS‐1040 did not lead to a significant accumulation in exposure; steady state was attained by day 7 with minimal accumulation (mean accumulation ratio 1.15‐1.25) compared with predose plasma DS‐1040 concentrations on day 10.…”

“…Blood samples for the determination of total TAFIa activity, D‐dimer levels, and TAFI antigen were collected predose and at multiple time points postdose over 72 hours in part A and over 14 days in part B (Supplemental Table ). Methods for the measurement of biomarkers have been previously described in detail . Briefly, the Pefakit TAFI (Stago, Parsippany, New Jersey) plasma‐based chromogenic assay was used to determine TAFI enzyme activity.…”

“…In the first‐in‐human phase 1 study, intravenous (IV) infusion of DS‐1040 (doses ranging from 0.1‐40 mg) was well tolerated by young and elderly healthy adults and led to a substantial decrease in TAFIa activity with no impact on bleeding time, thus confirming a potential for safe thrombolytic therapy with a low risk for bleeding …”

“…DS‐1040, a new low‐molecular‐weight (<500 g/mol) imidazole derivative, inhibits enzymatic activity of thrombin‐activatable fibrinolysis inhibitor (TAFIa), thereby enhancing endogenous tissue plasminogen activator–triggered fibrinolysis . In preclinical studies, DS‐1040 exhibited potent and selective anti‐TAFIa activity without prolonging bleeding time, restored cerebral blood flow in a rat thromboembolic stroke model, and did not augment cerebral hemorrhage in a recombinant tissue plasminogen activator–sensitive cerebral hemorrhage rat model, suggesting that DS‐1040 could be beneficial for the treatment of patients with acute ischemic stroke.…”