Abstract
Background
Thromboembolic diseases, such as venous thromboembolic diseases represent a significant public health burden. S62798, a selective and potent inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), is being developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases, including pulmonary embolism. TAFIa inhibits the fibrinolysis by limiting plasmin generation.
Objectives
This double-blind, randomised, placebo-controlled first-in-man study was conducted to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of S62798 in healthy subjects.
Methods
Young male (18–40 years) subjects were randomised 3:1 to single ascending doses of S62798 ranging from 3.2 mg to 320 mg or placebo, administered as an intravenous bolus followed by a 7 hour 2-step infusion (part 1), or to 30 mg or 40 mg or placebo administered as a 1-min bolus (part 2). Follow-up ranged from 6 to 13 days post S62798 administration depending on cohorts. Exclusion criteria included bleeding disorders, recent bleeding, and abnormal blood coagulation parameters. Anticoagulant/antiplatelet treatments were not allowed for 30 days prior to and during the study. Safety was assessed by recording adverse events (AE), physical examination, vital signs, biochemical, haematological and haemostasis parameters (prothrombin time, activated partial thromboplastin time, thrombin clotting time, D-Dimers and fibrinogen). Plasma and urine samples for PK assessment were collected pre-dose and up to day 13 to assess the full PK profile. In part 1, ex vivo TAFIa inhibition (spiking of purified human TAFIa) and in vitro clot lysis time were assessed at pre-dose, during and after infusion. The study was performed in France in accordance with the declaration of Helsinki revised in Fortaleza. EudraCT number: 2016–002108–25.
Results
A total of 56 subjects were randomized to part 1 and 16 to part 2. Subjects were (mean ± SD) 29.5 ±- 5.7 years old with a BMI of 23.9±2.6 kg/m2 in part 1 and 31.4±5.2 years old with a BMI of 23.9±2.5 kg/m2 in part 2.
All doses of S62798 administered as a bolus and infusion or a single bolus were well tolerated, and no serious adverse events or discontinuations resulting from AEs occurred during the study. No effects of S62798 on haemostasis parameters were observed. Cardiac safety assessed by 12-lead 24h Holter ECG showed no relevant abnormalities. Plasma exposure of S62798 increased proportionally with the dose. S62798 inhibits TAFIa activity and decreases clot lysis time (reflecting TAFIa activity inhibition) rapidly and dose-dependently in all treated groups.
Conclusions
S62798, a potent TAFIa inhibitor, has a favourable safety profile with a linear PK. PD results on TAFIa inhibition and clot lysis assay suggest that S62798 has relevant properties to pursue clinical development as an enhancer of endogenous fibrinolysis for the treatment of thromboembolic diseases
Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): IRIS
A first-in-human study of DS-1040, an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor, in healthy subjects: reply