Adenosine 5'-diphosphate (ADP) is an important physiological and pathological platelet agonist. Upon vascular injury, ADP is released into the bloodstream from damaged cells and activated platelets, and in turn acts on other platelets. ADP induces a number of platelet responses, including shape change from disc to sphere, aggregation and secretion of granule contents. These ADP-induced platelet responses contribute to hemostasis, pathological thrombus formation and vascular occlusion. These responses are considered to be mediated by the interaction of ADP with specific binding sites on the platelet membrane designated as P2Y12 (or P2T) receptors. Prasugrel (CS-747) is a new prodrug-type antiplatelet agent that acts as a P2Y12 receptor antagonist via its active metabolite R-138727.

Oral prasugrel was about 10 times more potent than the marketed P2Y12 antagonist clopidogrel in inhibiting ex vivo ADP-induced platelet aggregation in rats. Plasma levels of the active metabolite of prasugrel were also 10 times higher than those of the active metabolite of clopidogrel, suggesting that prasugrel's greater potency may be due to a faster metabolization rate (Ogawa, T. et al. Eur Soc Cardiol [ESC] Cong (Sept 3-7, Stockholm) 2005, Abst P2954).

A trial compared the effects of prasugrel and clopidogrel in 101 aspirin-treated patients with atherosclerotic disease. Following treatment with 325 mg of acetylsalicylic acid, the patients were randomized to receive clopidogrel (300 mg on day 1, 75 mg/day on days 2-28) or prasugrel (40 mg on day 1 and 5 or 7.5 mg/day on days 2-28, or 60 mg on day 1 and 10 or 15 mg/day on days 2-28). Lack of response was defined as failure to achieve at least 20% inhibition. The percentage of patients who were nonresponders was higher with clopidogrel both at four hours after the loading dose (52% vs. 3%) and before administration of the maintenance dose scheduled for day 28 (45% vs. 0%). No study regimen had any significant effects on the inflammation and coagulation markers of the patients (Jernberg. T. et al., Eur Heart J 2006, 27(10): 1166). The JUMBO-TIMI 26 (Joint Utilization of Medication to Block Platelets Optimally - Thrombolysis in Myocardial Infarction 26) was a multicenter, double-blind, randomized, phase II clinical trial that evaluated the effects and safety of prasugrel. A total of 904 patients undergoing elective or urgent percutaneous coronary intervention were given the standard clopidogrel regimen above or one of three prasugrel regimens (loading doses of 40 or 60 mg, followed by 7.5, 10 or 15 mg/day) for 29-34 days, starting after the diagnostic angiogram. Prasugrel-treated patients showed a lower incidence of major adverse cardiac events than clopidogrel-treated patients, although the difference among study regimens did not reach statistical significance. Only 0.7% of patients had major bleeding, whereas 1.1% had minor bleeding and 2.4% experienced minimal bleeding in all study groups combined. No significant differences among study treatments were found in the incidence of an endpoint combining major and minor hemorrhage unrelated to coronary artery bypass graft. Hemorrhage rates were lower than those expected from historical controls (Wiviott, S.D. et al., Circulation 2005, 111(25): 3366).

Prasugrel was discovered through a collaboration between Sankyo and Ube. Sankyo subsequently entered into a codevelopment agreement with Lilly in 2000. The compound is currently in phase III clinical development for the prevention of thrombosis in patients with unstable angina pectoris and for the prevention of cardiovascular events during percutaneous coronary intervention. The companies plan to file with the U.S. FDA for approval of prasugrel later this year.