Cardiovascular Disease


Xemilofiban Summary
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Xemilofiban is a GP IIB/IIIA antagonist known as a Fiban; that inhibits platelet aggregation. This particular drug is useful for indications similar to those for Aggrastat®, Integrilin®, and ReoPro®, which are all administered intravenously (IV). Xemilofiban and these alternatives prevent local ischemia, heart attacks and other major adverse cardiac events (MACE) due to platelet activation and aggregation that is a result of percutaneous coronary intervention procedures. Xemilofiban was developed as an oral formulation, giving it certain distinct advantages over the IV alternatives.

Xemilofiban completed Phase III clinical trials with more than 7,000 patients (See materials about the EXCITE trials.). These trials attempted to gain market approval for an oral course of treatment for six months. The FDA did not grant market approval for this protocol because of insufficient evidence of efficacy and concerns about safety over this long of a period of treatment. The agency did suggest a resubmission for a short period of treatment (2-4 days) around intervention procedures such as angioplasties and stent placements. Pharmacia opted to shelve the project, rather than move ahead with this reduced market opportunity.

Background

Although the platelet was once considered to be merely a passive participant in the coagulation cascade, it is now recognized as an active synthesizer of humoral factors that potentiate both clot formation and inflammation.

  • For several decades, antiplatelet therapy centered on the thromboxane pathway and its inhibition by aspirin, and aspirin remains the background template therapy for acute ischemic syndromes, as well as for secondary prevention.

  • However, despite the wealth of data that support the use of aspirin, and indeed the data that suggest it should be more widely prescribed, aspirin remains a suboptimal antiplatelet agent, as evidenced clinically by the fact that even patients who are taking aspirin may nevertheless sustain a thrombotic event. 5-40% incidence of aspirin resistance.

  • Drugs have been developed to improve on the template of aspirin therapy; the glycoprotein IIb/IIIa inhibitors and the thienopyridines have been extensively studied.

  • Large individual variability exists in response to clopidogrel, new data presented at the American College of Cardiology 2003 Scientific Sessions suggests. The researchers, led by Dr Wei Lau (University of Michigan Health System, Ann Arbor), estimate that around 28% of people may not respond adequately to the antiplatelet effects of the drug.

  • The glycoprotein IIb/IIIa receptor is an integrin found in high concentration on the platelet membrane, and is often referred to as the final common pathway of platelet aggregation. The evidence supporting the utility of intravenous GPIIb/IIIa inhibition in percutaneous coronary intervention is overwhelming. However, "platelet escape" has been observed with ReoPro® under constant infusion.

  • In contrast to the favorable data obtained for the intravenous GPIIb/IIIa inhibitors, results with oral GPIIb/IIIa inhibitors have been disappointing. This showed that our understanding of GPIIb/IIIa inhibition was not as deep as believed.

    • Three major factors appear to contribute to undesirable therapeutic effect from oral or IV GP: paradoxical antagonist-induced platelet activation, the level of platelet inhibition "platelet escape", and local and system inflammation.

  • A critical issue with the use of the Fibans, either oral or intravenous, is the extent, duration and timing of platelet inhibition.

    • Moderate levels of platelet inhibition not only lack efficacy but, when prolonged, are associated with a paradoxical increase in ischemic events due to the unmasking of antagonist-induced prothrombic and proinflammatory effects.

  • Cocktails: for the foreseeable future the use of ASA, heparin, (Low Molecular Weight Heparin), thienopyridines and GPIIb/IIIa inhibitors will be the standard of care in PCI with Stent, for the foreseeable future. See Figure 1.

Figure 1 Current and Future therapeutic Scenario's

In yellow are product innovators or market leaders. Axis describes sites of activity or treatment scenario.

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