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

Abstract

DS‐1040, a low‐molecular‐weight imidazole derivative, inhibits the enzymatic activity of thrombin‐activatable fibrinolysis inhibitor (TAFIa), enhancing endogenous tissue plasminogen activator–triggered fibrinolysis. This first‐in‐human, randomized, placebo‐controlled, phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of an oral formulation of DS‐1040. Healthy adults (aged 20‐45 years; N = 56) were randomized 3:1 to receive DS‐1040 orally administered as single ascending doses (50, 100, 200, or 400 mg) or placebo, or DS‐1040 multiple ascending doses (100 mg once daily, 200 mg once daily, or 150 mg twice daily) or placebo for 14 days. Safety, PK, and PD parameters were assessed. All doses of DS‐1040 were well tolerated; no serious/severe adverse events (AEs) or discontinuations due to AEs occurred. DS‐1040 had no effect on coagulation parameters, and no treatment‐related trends in the bleeding time were observed. DS‐1040 exposure (peak concentration and area under the concentration‐time curve) increased in a dose‐proportional manner across the single‐dose range. With multiple doses, steady state was achieved by day 7 with minimal accumulation (mean accumulation ratio 1.15‐1.25), and the PK was time‐independent. After 72 hours, approximately 10% of the DS‐1040 400‐mg single dose was recovered in urine as intact parent drug. The mean terminal half‐life ranged from 17.2 to 24.9 hours, which was similar to previous intravenous administration data. Dose‐dependent inhibition of total TAFIa activity was observed following single and multiple doses of oral DS‐1040. The safety and PK/PD profiles of oral DS‐1040 in healthy subjects support further clinical development.

Selective inhibition of carboxypeptidase U may reduce microvascular thrombosis in rat experimental stroke

“…The interest in a CPU inhibition strategy for application in AIS treatment is rising. 20,33 In the current study, a clear activation of the CPU system after ischemia induction was observed, both in saline-treated and tPA-treated rats, with peak CPU activities at the end of the treatment, followed by a progressive return to baseline levels. CPU peak activities were higher in tPA-treated rats compared to saline-treated animals.…”

“…However, the inhibition of CPU (alone or in combination with tPA) was not associated with such a bleeding risk in our study. Furthermore, several other CPU inhibitors were not associated with bleeding complications 17,20,33,46 . Similarly, AZD9684 proved to be safe in patients with pulmonary embolism 47 .…”

“…Furthermore, several other CPU inhibitors were not associated with bleeding complications. 17,20,33,46 Similarly, AZD9684 proved to be safe in patients with pulmonary embolism. 47 Nonetheless, further studies are required to confirm the safety of this pharmacological approach in ischemic stroke patients.…”

Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

“…DS-1040 [(2S)-5-amino-2-[[1-(4-methylcyclohexyl)imidazol-4-yl]methyl]pentanoic acid] was developed by Daiichi Sankyo for the treatment and secondary prevention of AIS and acute PE [52,53]. It showed high selectivity for CPU over CPN (510.000-fold) and was 10-fold more potent than PTCI [165].…”

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics

“…Most recently, a low-molecular weight oral TAFIa inhibitor, DS-1040, was suggested as a potential therapeutic agent to enhance fibrinolysis with low bleeding risk [159]. Interestingly, DS-1040 has been further evaluated in a phase 1 human study in order to assess safety (including bleeding time), tolerability, pharmacokinetics and pharmacodynamics [160].…”