DS-1040

DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS.

The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed.

Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity.

Single doses of DS-1040 0.6-4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy.

NCT03198715; JapicCTI-163164.

An activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis by removing C-terminal lysine/arginine residues from partially degraded fibrin. We have identified a novel low-molecular-weight inhibitor of TAFIa, DS-1040, to be potentially useful for treating thrombotic diseases. In this study, we investigated its in vitro pharmacological profile and in vivo effects in animal models of microthrombosis and bleeding. DS-1040 inhibited human TAFIa and carboxypeptidase N (CPN) in vitro with IC₅₀ values of 5.92 and 3.02 × 10⁶ nmol/L, respectively, suggesting that DS-1040 is highly selective for TAFIa over CPN. DS-1040 did not affect platelet aggregation and coagulation time. In a tissue factor-induced rat microthrombosis model, intravenously administered DS-1040 reduced existing fibrin clots in the lung, whereas post-treatment with enoxaparin had limited effect. Both intravenously and orally administered DS-1040 elevated plasma D-dimer levels with similar plasma exposures of DS-1040. DS-1040 significantly augmented plasma D-dimer level on top of silent dose of recombinant tissue-plasminogen activator (t-PA), suggesting DS-1040 enhances fibrinolytic activity of t-PA. In addition, DS-1040 did not prolong the tail bleeding time beyond its efficacy dose. These results indicate that DS-1040 is a potent, selective, intravenously/orally available inhibitor of TAFIa with minimum risk of bleeding. DS-1040 is a potential novel fibrinolysis enhancer useful in treating thrombotic diseases.