Together, preventing the occurrence and reoccurrence of myocardial infarction, stroke, PAOD and pulmonary embolism remain a pressing clinical priority. Well over 12.5 million people in the US suffer from one or more of these conditions resulting in around 1 million deaths each year and a health care expenditure of over $US100 billion each year. First line therapy for these conditions includes the use of anticoagulants, a market worth around $US6 billion per year. Unfortunately anticoagulants in current use suffer a number of limitations including a high incidence of serious or dose limiting hemorrhage, and in the case of heparin, heparin-induced-thrombocytopenia and thrombosis syndrome. The development of anti-coagulants with a lower risk of hemorrhage is thus required. The coagulation cascade is activated via the intrinsic and extrinsic pathways. Both pathways produce factor IXa which converts factor X to factor Xa in the presence of factor VIII. The accumulation of factor Xa then converts prothrombin to thrombin, which, in turn causes the generation of clots from fibrin. Factors VIII and Xa have both been targeted in an attempt to develop novel anti-coagulants. Factor VIII has been of particular interest to ThromboGenics Ltd, one of the most advanced biotech companies to focus on cardiovascular disease. Factor VIII has traditionally been avoided as an anti-coagulant target due to the perceived risk of hemorrhage, however ThromboGenics have developed an antibody strategy that is immune to such problems thus providing therapeutic efficacy without the risk of bleeding. Targeting factor Xa has been a more common approach to the development of anti-coagulants and 25 molecules capable of blocking this protein are now in various stages of development. One such molecule, DPC423, has been developed by Bristol-Myers Squibb and is in now in phase I development. The profile of this molecule has recently been published. DPC423 is a synthetic, competitive, and selective inhibitor of factor Xa that has a similar antithrombotic efficacy to enoxaparin and argatroban. However, bleeding time was unaffected by DPC423. The same was true for enoxaparin although argatroban caused a large increase in bleeding time. This study supports the entry of DPC423 into clinical trials.

December, 2002

Adapted from Wong et al, J Pharmacol Exp Ther 2002 Dec;303(3):993-1000

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