CONTENTS
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Clinical Trials of Oral GP IIb/IIIa Therapy
The success of platelet inhibition via parenteral GP IIb/IIIa blockade for the treatment of ACS has fueled interest in the development of oral forms of these agents. Oral GP IIb/IIIa inhibitors could potentially be administered in a subacute or pre-hospital setting, or possibly on a chronic basis for secondary prevention of ACS. Some of the oral GP IIb/IIIa antagonists are listed in Table 1. Like the parenteral agents tirofiban and eptifibatide, the oral agents are competitive inhibitors of the GP IIb/IIIa receptor. They are typically delivered as a pro-drug and metabolized to the active agent. They have longer half-lives than the parenteral agents and only need to be administered two to three times a day, but the longer half-life makes bleeding complications more difficult to manage. Unfortunately, early trials of most of the oral agents have not been promising, and development of both xemilofiban and orbofiban have been abandoned after investing more than $400 million developing and investigating the drugs.
Oral xemilofiban was studied in the 7,200 patient EXCITE trial. This large phase III trial examined cardiac events after revascularization procedures and found no clinical benefit with xemilofiban. Furthermore, nuisance bleeding complications were significantly greater than with placebo. Although there was a 40% reduction in clinical events on day 1, there was a large rebound noted in the number of events on days 2-7. Orbofiban was studied in the more than 10,000 patient OPUS trial, which looked at prolonged treatment (up to 90 days) after ACS. The trial was stopped early due to excess mortality in the treatment group.
Only sibrafiban and SB214857 remain in trials. The results of the Phase III, 9000 patient SYMPHONY trial of sibrafiban versus ASA in the treatment of post-ACS patients are expected in late 1999. The SYMPHONY-II trial , also using sibrafiban and designed to include 8,400 patients is already underway.
Table 1.
| Drug | Trial | Status |
| Xemilofiban | EXCITE | Abandoned-lack of efficacy |
| Orbofiban | OPUS | Abandoned-excess mortality |
| Sibrafiban | SYMPHONY | Comparison with ASA after PCI- to be presented late 1999- SYMPHONY II underway (rx for >1yr and in combination with ASA) |
| Lotrafiban | APPLAUD | Phase II dosing study- BRAVO, a secondary prevention study, soon to begin |
Last modified: October 14, 1999 (PL)
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