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.

A polemic in response to Gurewich et al. (J Thromb Haemost 2017; 15: 961-71) is given.Gurewich et al. discussed about the results of first-in human study of DS-1040 demonstrated substantial fibrinolysis-related pharmacol. effects, without any impact on bleeding time in healthy subjects.Author said that TAFI (thrombin activatable fibrinolysis inhibitor) is activated to TAFIa either by the thrombin-thrombomodulin complex or by plasmin.During the initiation phase of fibrinolysis, the activation rate of plasminogen by tPA is low, especially by single-chain tPA (s.c.-tPA) in the absence of plasmin or fibrin.Once fibrinolysis passes the initial stage, more C-terminal lysine residues on fibrin become available, which promotes binding between plasminogen and tPA, and formation of a ternary complex between fibrin, plasminogen and tPA.Author concludes that C-terminal lysine residues on partially degraded fibrin serve critical and multifaceted roles in regulating endogenous fibrinolysis. TAFIa removes those lysine residues from fibrin as it is degraded, preventing plasminogen binding and the pos. feedback mechanisms that stimulate lysis of a clot.TAFIa does not directly inhibit fibrinolysis, but rather interferes with several crucial steps involved in the upregulation of fibrinolysis.