Thrombin inhibitor – atopaxar

The underlying cause of atherothrombotic diseases is clotting and platelet aggregation, and many different points on the clotting cascade can be addressed with pharmacological intervention

Atherothrombotic diseases, such as peripheral arterial disease, strokes and acute coronary syndrome, remain undertreated. The underlying cause is clotting and platelet aggregation, and there are many different points on the clotting cascade that can be addressed with pharmacological intervention. The serine protease thrombin is a highly potent platelet activator, and the response of the platelets is mediated by protease activated receptors or PARs.

Atopaxar, a new drug that acts as a thrombin inhibitor by antagonising PAR1, is being developed by Eisai.1 In one randomised, double blind, placebo-controlled, multiple dose Phase I trial, 36 healthy volunteers were given doses of 50, 100 or 200mg of the drug for 14 days, or placebo.2 All doses inhibited platelet aggregation induced by thrombin – by 58–65% in the lowest dosed group, 90–91% in the 100mg dose group, and by 90–95% in those patients given the highest dose.

In a second Phase I trial, subjects were given single doses of 50, 100, 200 or 400mg of the drug.3 It gave a dose dependent inhibition of thrombin-induced platelet aggregation, with maximum effects being achieved after six hours. It had no effect on ADP-induced platelet aggregation.

In two randomised, double blind, placebo-controlled Phase II trials patients with acute coronary syndrome (a total of 241 patients) or high risk coronary artery disease (263 patients) were given atopaxar in doses of 50, 100 or 200mg once a day or placebo in addition to standard therapy, either for 12 weeks if they had acute coronary syndrome, or 24 for those with coronary artery disease.4 The incidence of major, minor and minimal bleeds requiring medical attention was similar across the placebo and atopaxar groups, and there was no difference in the incidence of major cardiovascular adverse events between the groups. The mean inhibition of platelet aggregation was above 90% for those patients given 100 and 200mg doses, and 20–60% inhibition for those given the lower dose. Trials continue.

references

1. M. Kogushi et al. Eur. J. Pharmacol. 2011, 657, 131

2. A. Marion et al. J. Clin. Pharmacol. 2006, 46 (9), Abst. 102

3. M. Takeuchi et al. Eur. Heart J. 2007, 28 (Suppl. 1), Abst. 264

4. S. Goto et al. Eur. Heart J. 2010, 31, 2601

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