By Lisa Seachrist
BETHESDA, Md. — Nearly a year after rejecting Cor Therapeutics Inc.'s first attempt, an FDA advisory panel voted unanimously to recommend that the agency approve the company's inhibitor of platelet aggregation, Integrilin (eptifibatide).
Although the Cardiovascular and Renal Drugs Advisory Committee agreed Integrilin should be approved, the members limited their recommendation to patients who were undergoing balloon angioplasty because the committee determined that neither of the two Phase III trials presented by the South San Francisco company could stand alone.
"Last year, we said we need confirmation to approve eptifibatide for use in angioplasty," said John DiMarco, professor of medicine at the University of Virginia Hospital, in Charlottesville. "This second trial provides us with that supportive data."
The second trial, however, was designed to test the drug's effectiveness in patients with unstable angina and non-Q wave myocardial infarction, not angioplasty. Panel chairman Milton Packer, chief of the division of circulatory physiology at Columbia University, did not support the committee's decision to limit the indication, noting the second trial was a better-conducted trial.
"The sponsor has presented a much larger trial that we 'like' better that doesn't study [solely angioplasty patients]," Packer said. "The strength of the evidence is in the unstable angina and non-Q wave trial."
Integrilin, an inhibitor of platelet aggregation, is a synthetic peptide derived from the venom of the Southeastern pygmy rattlesnake. The drug specifically blocks the GPIIb-GPIIIa receptor, which binds fibrinogen and mediates platelet aggregation — the first step in clotting. It has a very rapid onset of action and a short duration.
Last year, the same panel unanimously agreed that a single Phase III trial of Integrilin didn't provide sufficient evidence to recommend the drug for approval, even though that trial showed Integrilin had some efficacy.
IMPACT II Trial Data Confusing
At that meeting, the company provided data from the trial, called IMPACT II, showing that Integrilin, given as an adjunct to aspirin and heparin in patients undergoing emergency or elective angioplasty, decreased the incidence of death by 22 percent. However, the company's data also showed a low dose of Integrilin was more effective than a high dose at reducing the chemical measures of platelet aggregation.
That result, in particular, concerned the panel because the biology of Integrilin is fairly well understood and the higher dosage should inhibit platelet aggregation more effectively than the lower dose.
"IMPACT II showed a tendency to benefit," said Lemuel Moye, associate professor of biometry at the University of Texas Health Science Center, in Houston, and an advisory panel member. "The investigators had set up prospectively a level of evidence that suggested the findings would not be the result of chance. But the statistical problems make it less acceptable evidence."
In vitro studies conducted at the end of the IMPACT II study showed that Integrilin works more efficiently when concentrations of calcium are lower than found at physiologic levels. In addition, the doses of Integrilin in the IMPACT II study were not high enough to maintain desired levels of inhibition. As a result, the company decided to use increased dosages for future trials.
Wednesday the company presented data from a second Phase III trial of 10,948 patients with unstable angina or non-Q wave myocardial infarction (MI). Patients from North America, Western Europe, Latin America and Eastern Europe were enrolled in the study; however, more than 8,500 patients were from North America and Western Europe.
The company began with two different doses for this study, which was called PURSUIT, with each dose starting with a 180 micrograms per kilogram bolus of Integrilin followed by infusions of either 1.3 micrograms per kilogram per minute or 2.0 micrograms per kilogram per minute up to 96 hours. Following a Data and Safety Monitoring Committee review, the lower dosing regimen was dropped.
Participating physicians were permitted to use aspirin, heparin and surgical intervention at their discretion.
Integrilin reduced the incidence of deaths or MI from 15.7 percent to 14.2 percent in the 30 days following treatment, which was a statistically significant result. An absolute reduction of 1.5 percentage points in the rate of death or MI was demonstrated at 96 hours, 7 days and 30 days. The benefit of Integrilin was driven by the reduction in MI.
Angioplasty, Stent Patients Benefited Most
The greatest reduction in death or MI occurred in patients in North America and Western Europe, where treatment with Integrilin reduced death and MI from 14.9 percent to 12.7 percent. And those who received either angioplasty or stent placement saw the greatest benefit from Integrilin, where the drug reduced deaths and MI from 16.8 percent in the placebo group to 11.8 percent in the treatment group.
"Overall, there were 15 clinical events prevented for every 1,000 patients treated with eptifibatide," said Robert Harrington, assistant professor of medicine at Duke University Medical Center, in Durham, N.C., and principal investigator for the PURSUIT trial.
Integrilin caused no significant increase in stroke or thrombocytopenia (a potentially life-threatening depletion of platelets). Patients in the Integrilin arm were more likely to suffer a major bleeding event, with 10.6 percent of the treated patients having a bleed, compared with 9.1 percent of the placebo group. However, the bleeding events were considered manageable.
The panel, however, voted that the bleeding events were of such concern that they would recommend using the dosages in the IMPACT II trial, which were lower than those in the PURSUIT trial. The IMPACT II dosages were 135 micrograms per kilogram bolus followed by a 24-hour infusion of either 0.5 micrograms per kilogram per minute or .75 micrograms per kilogram per minute.
"I understand the committee is concerned," Packer said. "But this is a dose the sponsor doesn't believe in any more." *