Cardiovascular Disease

Xemilofiban Summary (continued page 2 of 3)

Key points relative to xemilofiban are as follows:

• Initial Target market is percutaneous coronary intervention (PCI with Stent).
  
  
• Xemilofiban is an oral GP IIB/IIIA antagonist that prevents platelet aggregation, and there is no other similar product on the market because the alternatives are administered intravenously.
  
  
• VDDI has a clear path to commercialization with a high probability of success with a small phase II trial and a Phase III European trial that could result in sales in 2 years.
  
  
• Xemilofiban's patent portfolio is extensive and does not infringe any other existing patents for the 2-4 day treatment around an intervention procedure

Competitive Advantage:

Presently, three therapies are on the market, vying to serve more than 2,000,000 annual percutaneous coronary intervention (PCI) procedures globally; with almost 1,000,000 procedures annually in the US alone. Xemilofiban is designed to be short-term, cost effective and in a patient and physician preferred mode. For these reasons VDDI believes it will now be able to mitigate concerns about oral fibans.

Rationale for the Development Strategy

Platelet aggregation is important in the etiology of several cardiovascular diseases including myocardial infarction, stroke, and peripheral arterial disease. Activation and the subsequent aggregation of platelets is thought to be responsible for the initiation and growth of thrombi leading to both acute arterial occlusions and the reocclusion that follows recanalization of coronary arteries and other vessels by thrombolysis and percutaneous coronary angioplasty.

Xemilofiban is a novel anti-platelet agent that blocks the binding of fibrinogen to specific membrane GPIIb/IIIa integrin receptors and thus prevents platelet aggregation induced by any known platelet agonist.

Platelet aggregation is important in the etiology of several cardiovascular diseases including myocardial infarction, stroke, and peripheral arterial disease. Activation and the subsequent aggregation of platelets is thought to be responsible for the initiation and growth of thrombi leading to both acute arterial occlusions and the reocclusion that follows recanalization of coronary arteries and other vessels by thrombolysis and percutaneous coronary angioplasty.

Xemilofiban is a novel anti-platelet agent that blocks the binding of fibrinogen to specific membrane GPIIb/IIIa integrin receptors and thus prevents platelet aggregation induced by any known platelet agonist.

Although platelet activation is produced by a wide variety of thrombotic stimuli, fibrinogen (fgn) binding to the platelet is required for significant aggregation to occur regardless of the initiating event. Therefore no matter which physiological stimuli are present blockade of GPIIb/IIIa eliminates platelet initiation of thrombus formation.

Xemilofiban was previously withdrawn from the registration process when it was clear that the proposed dosing strategy and duration of treatment (6 months) would not succeed given a lack of clear patient benefit. In the three main trials of oral GP IIb/IIIa inhibitors published to date (EXCITE, OPUS and SYMPHONY), there has been no obvious benefit and there were excess bleeding complications in the groups assigned these drugs. The increase in mortality in some of these trials may relate to a prothrombotic effect. There is a possibility that paradoxical platelet activation may occur with these drugs, as has been shown in some (but not all) studies of ex-vivo platelet function. [1-4]

A critical issue with the use of the Fibans, either oral or intravenous, is the extent, duration and timing of platelet inhibition. According to the GOLD study at the time of PCI, greater than 80% inhibition is required for maximum efficacy. [5] Failure to achieve these high levels of inhibition is associated with lack of protection from acute events, mainly periprocedural MI. In fact, it is likely that the level of platelet inhibition, rather than pharmacological differences between TiroFiban®, ReoPro® or Aggrastat®, is the major factor in the observed differences in efficacy between the agents at the time of PCI. This was clearly seen in TARGET (do Tirofiban And ReoPro Give similar Efficacy Trial?), in which abciximab was superior to tirofiban in the prevention of early ischemic events after coronary stenting. [6] Recent data suggest that the tirofiban dose used in this trial fails to achieve 80% platelet inhibition in the early stages of the infusion.[7,8] Similar conclusions can be drawn from the AU-Assessing Ultegra (GOLD) study, which related the degree of inhibition after an abciximab bolus and 12-hour infusion to ischemic outcome in patients undergoing PCI. Platelet inhibition below 95% at 10 minutes, 80% at 1 hour, or 70% at 8 hours was associated with a marked increase in major adverse cardiac event (MACE) rates; as many as 1 in 4 patients suffered an event with the lowest levels of inhibition. [5]

It is not only the loss of platelet inhibition but also prolonged exposure to low, subthreshold levels of platelet inhibition, as occurred in GUSTO IV and with long-term oral therapy, that has the potential to lead to a paradoxical increase in MACE. 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. [9]

The oral Fibans studied to date were first generation compounds and may not have optimal pharmacodynamic characteristics based on their inherent pharmacokinetic properties and binding dynamics at the receptor level. Other possible explanations for lack of sustained benefit with oral drugs include the concept that providing ongoing and continuous inhibition of platelet-mediated thrombosis in the setting of long-term treatment may not be correct. [10]

There is a lack of confidence that the GPIIb/IIIa class of agent, when given orally for extended time periods will be beneficial. In fact long-term oral GP IIb/IIIa inhibition has uniformly failed to provide protection from ischemic events and was associated with a paradoxical increase in adverse events. Mortality increased in each of the five trials (EXCITE, OPUS-TIMI 16, BRAVO, SYMPHONY, 2nd SYMPHONY). A combined analysis reveals a highly significant 35% relative (or 0.7% absolute) increase in the risk of death in the 45,523 patients studied with a 2-fold increase in the risk of bleeding. [11] However, a little appreciated fact is that mortality and non-fatal MI has been excessive in the intravenous GP IIB/IIIA inhibitor regimens (Gusto IV and Prism-Plus) in selected patient populations e.g., acute coronary syndrome (ACS). A recent summary of these trails and explanation of these paradoxical events concluded that the clinical expression of paradoxical GP IIb/IIIa antagonist adverse effects requires either long-term exposure to low levels of platelet inhibition, as evidenced by the trials of oral blockade, or shorter-term (but >12 hours) exposure in the absence of revascularization, as seen in GUSTO IV. [12] Recent data now provide biological explanations for the unanticipated clinical outcomes. Three major factors appear to contribute to undesirable therapeutic effect: paradoxical antagonist-induced platelet activation, the level of platelet inhibition "platelet escape", and local and system inflammation.
In the pivotal EXCITE trial which evaluated oral xemilofiban over a 6-month treatment period, there were slightly more deaths numerically but not statistically at the lower dose (10 mg tid) of xemilofiban than at the higher dose (20 mg tid).[13] Although the etiology of these deaths has not been conclusively determined, there is a strong body of opinion that believes that sub-optimal doses of GPIIb/IIIa inhibitors promote a prothrombotic effect rather than inhibiting thrombin activation [14-18]This may be a particular problem in patients with unstable angina or in those who require heparin prior to the decision to perform coronary intervention. [12] For this reason, high-risk unstable patients will not be entered initially into the current trial with oral xemilofiban.
FDA correspondence referring to the original xemilofiban development program suggests that short-term treatment may be more appropriate, with the focus on short-term endpoints (48 hours - 1 week) post PCI and that this may ultimately, if proven, be acceptable for registration. This view also found support in documentation from the FDA Advisory discussion on the use of GPIIb/IIIa inhibitors.

The premise of the program is that, given the right dose and dosing regimen, oral and IV products will produce the same benefits.

While there is endorsement of parenteral GPIIb/IIIa therapy as shown by the recommendation of the English treatment advisory body NICE (National Institute for Clinical Excellence) for use of these agents for acute coronary syndromes (Nice Technical Appraisal Document 12; Sept 2001), the use of oral fibans in similar indications has not been successful. One reason for this may be that the doses developed have not been high enough. This possibility was raised by investigators in the TARGET study of tirofiban versus abciximab, as a reason why the intravenous tirofiban was inferior to abciximab. [19] For long-term use, however, one of the reasons that the Fiban dose has not been pushed higher is the concern over bleeding, which might be acceptable and controllable in a hospital setting, but would be a concern for patients once discharged if the treatment were to be continued beyond the hospital stay.

Parenteral GPIIb/IIIa inhibitors have traditionally only been used for a short period of time around PCI and it has been argued that this is the appropriate timeframe required for clinical benefit.

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