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.

DS‐1040, a novel low‐molecular‐weight inhibitor of activated thrombin‐activatable fibrinolysis inhibitor, is under development for the treatment of thromboembolic diseases including venous thromboembolism and acute ischemic stroke. Here we describe the results of 3 studies that evaluated the safety and tolerability of DS‐1040 along with the effect on DS‐1040 pharmacokinetic (PK) parameters, when dosed alone or when coadministered with aspirin (NCT02071004), clopidogrel (NCT02560688), or enoxaparin in healthy subjects. Concomitant administration of single‐dose DS‐1040 with multiple‐dose aspirin, multiple‐dose clopidogrel, or single‐dose enoxaparin, consistent with clinically relevant dose regimens, was safe and well tolerated with no serious treatment‐emergent adverse events (TEAEs), TEAEs leading to discontinuation, bleeding‐related TEAEs, and no significant changes in coagulation parameters. DS‐1040 did not prolong bleeding time when administered concomitantly with aspirin or clopidogrel. In the aspirin study, DS‐1040 PK was evaluated following the concomitant administration with multiple‐dose aspirin, where the plasma DS‐1040 exposure (peak plasma concentration [Cmax] and area under the concentration‐time curve [AUCinf]) was to be similar to the data previously published in the first‐in‐human study of DS‐1040 in healthy subjects. The PK parameters of DS‐1040 coadministered with clopidogrel were similar to those of DS‐1040 alone, with small increases in geometric means for Cmax (7%) and AUClast (9%). When coadministered with enoxaparin, the PK parameters of DS‐1040 were not affected (1.1% and 1.5% decreases in geometric means for Cmax and AUClast, respectively). Therefore, concomitant administration of DS‐1040 and clopidogrel or enoxaparin did not demonstrate PK drug‐drug interactions.