By Lisa Seachrist
WASHINGTON — An FDA advisory committee decided Friday that data for Cor Therapeutics Inc.'s inhibitor of platelet aggregation, Integrelin, was insufficient to recommend approval.
While concurring that the clinical data presented at the Cardiovascular and Renal Drugs Advisory Committee meeting indicated that Integrelin had activity, the members also unanimously agreed that a single clinical trial did not provide enough evidence.
"We retain an immense amount of confidence in the drug; it's clear why we are here, the committee believes we have an effective product," Cor president and CEO Vaughn Kailian said. "Obviously, we have to talk to the agency in order to know how to proceed."
Integrelin is a synthetic peptide, derived from the venom of southeastern pygmy rattlesnakes, that inhibits the aggregation of platelets. Integrelin specifically blocks the GPIIb-IIIa receptor which mediates platelet aggregation by binding fibrinogen.
Platelet aggregation is the number one cause of potentially fatal clot formation following balloon angioplasty procedures designed to clear blocked coronary arteries. The process of dilating the balloon and compressing the plaque against the artery wall creates microtears in the blood vessels that cause platelets to activate and begin binding fibrinogen. Between 8 percent and 9 percent of all patients who undergo balloon angioplasty suffer from acute myocardial infarction 30 days after their procedures.
Cor, of South San Francisco, tested Integrelin's ability to prevent heart attacks following angioplasty in 3,871 patients undergoing elective and urgent angioplasty procedures. The first group received a large dose (135 micrograms/kilogram) of Integrelin at the time of the procedure followed by an infusion of 0.5 micrograms/kilogram of Integrelin, aspirin and heparin. The second group received the same initial dose of Integrelin followed by an Integrelin infusion of 0.75 micrograms/kilogram. The placebo group received only an infusion of aspirin and heparin.
The company presented results showing that Integrelin decreased the incidence of the death and myocardial infarction by 22 percent and decreased chemical measures of the platelet aggregation by 45 percent in the low dose Integrelin infusion group and 35 percent in the high dose group. Treatment with Integrelin didn't cause any excess in serious bleeding complications.
Michael Kitt, vice president of clinical research for Cor, noted that "patients derived an early benefit that was quickly reversible as demonstrated by the fact that treatment with Integrelin had no effect on subsequent restenosis after angioplasty."
However, the trial originally was designed to show a 30 percent reduction in heart attack and death. The company chose to expand the trial to show statistically significant efficacy.
When asked whether the clinical data showed that Integrelin was efficacious, the committee agreed that Integrelin showed efficacy in a 6-2 vote.
"We have a positive trial that met a prospective endpoint * [but] not by much," said committee member Marvin Konstam, professor of medicine at the New England Medical Center, in Boston.
John DiMarco, professor of medicine at the University of Virginia Hospital, in Charlottesville, Va., disagreed noting that the fact that the higher dose of Integrelin had less efficacy than the lower dose.
However, when the committee was asked to decide if the results from the study provided strong enough data to recommend approval, they unanimously concluded that the results weren't robust enough.
Committee chairman Barry Massie, director of the coronary care unit at the Veterans Administration Hospital, in San Francisco said, "I am not sure we are seeing a consistent effect. I don't think this trial makes it."
Konstam pointed out that while "there is no doubt that decreases in platelet aggregation are associated with a reduction in adverse events, I am waffling because I am not overwhelmed with this study."
The company has another study of Integrelin under way in patients who have unstable angina. And Mike King, an analyst at Vector Securities International Inc., in Deerfield, Ill., noted the company may use data from that study to get the drug approved for this indication. But he said the product is likely to suffer some problems.
"Basically, the company admits that it doesn't have the right dose," King said. "The biology behind this drug is well known so higher doses should show higher activity. I am not surprised by the committee's decision."
The FDA is not required to follow the recommendations of its committees, but usually does. *