Abstract WP282: DS-1040 an Inhibitor of the Activated Thrombin Activatable Fibrinolysis Inhibitor Improves Behavior in Embolized Rabbits

Introduction: DS-1040 is an inhibitor of the activated thrombin-activatable fibrinolysis inhibitor (TAFIa) being developed for the treatment of acute ischemic stroke (AIS). We evaluated the effect of DS-1040 infusiontreatment on rabbit TAFIa activity; plasma concentrations and we also determined if DS-1040 treatment affected behavioral outcome following embolization using the standard rabbit small clot embolic stroke model (RSCEM). Safety was assessed by measuring the effect of DS-1040 on intracerebral hemorrhage (ICH) and mortality. Methods: The inhibitory effect of DS-1040 on TAFIa was evaluated using hippuryl-Arg, a substrate of carboxypeptidase. The study was conducted randomized and blinded per RIGOR guidelines. Male New Zealand white rabbits (2-2.5kg) were embolized by injecting a suspension of small blood clots into the brain via an indwelling carotid catheter. Saline (control), tPA (3.3 mg/kg, i.v., 10% bolus/90% infusion for 0.5 h), high and low doses of DS-1040 (approx. 940 mg/per rabbit and 470 mg/per rabbit, respectively) were given 1 h following embolization as an i.v. bolus followed by a s.c. infusion for 47 h. Behavioral analysis was conducted 48 h following embolization, resulting in the calculation of an effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. ICH was also assessed in all treatment groups. Results: DS-1040 inhibited rabbit TAFIa with an IC50 value of 11.7 ng/mL. Using the dosing regimen described above, the mean plasma concentration of DS-1040 at 48 h was 1838 ng/mL (high dose) and 591 ng/mL (low dose). Rabbits treated with high and low doses of DS-1040 had P50 values of 1.61 ± 0.23 mg (p Conclusions: DS-1040 significantly improved behavioral function in small clot embolized rabbits, suggesting that DS-1040 should be further pursued as a treatment for stroke victims.