By Lisa Seachrist

Washington Editor

WASHINGTON — The Medicines Company's anticoagulant, Hirulog (bivalirudin), failed to receive the endorsement of an FDA advisory panel for use with angioplasty in patients suffering from unstable angina.

The FDA's Cardiovascular and Renal Drugs Advisory Committee voted 4-3, refusing to recommend the anticoagulant for approval.

Eric Topol, a cardiologist at the Cleveland Clinic Foundation, presented to the panel a meta-analysis comparing the efficacy and safety of heparin to Hirulog, and vehemently disagreed with the committee's decision.

"I think the field of anticoagulation in interventional cardiology has just hit the wall here, with what you've done," Topol told panel members.

Clive Meanwell, president and CEO of the privately held Medicines Company, said it has "some homework to do. We are extraordinarily committed to this drug." So is the medical community, he added, and the company "must respect that."

Hirulog is a direct thrombin inhibitor derived from hirudin, a natural anticoagulating enzyme secreted by leeches. It was originally developed as a rationally designed drug by Biogen Inc. of Cambridge, Mass., to replace heparin as an anticoagulant in percutaneous transluminal coronary angioplasty.

Biogen-directed Phase III studies of the drug were designed to show that Hirulog provided a 33 percent reduction in deaths and myocardial infarction following angioplasty compared to heparin while providing significant reduction in hemorrhages.

But those studies showed no statistical difference between Hirulog and heparin in procedural failures which included death, myocardial infarction, abrupt vessel closure and additional revascularization procedures - although Hirulog proved much safer than heparin reducing major bleeding events by 58 percent in one Phase III study and 63 percent in the other.

It was at this point, in 1994, that Biogen decided to abandon the development of the drug and look for a marketing partner. (See BioWorld Today, Nov. 1, 1994, p. 1.)

In March 1997, The Medicines Company, in keeping with its philosophy of licensing-in drug candidates undergoing late-stage development, bought the rights to Hirulog from Biogen. The deal was worth up to $30 million in up-front licensing fees and milestone payments. (See BioWorld Today, March 26, 1997, p. 1.)

Upon analyzing the data, The Medicines Company determined that, despite failing to meet its protocol endpoints, Hirulog was at worst as effective as heparin while being safer and was, for some sub-groups, significantly better. The company filed a new drug application (NDA) for the drug in February 1998. (See BioWorld Today, Feb. 18, 1998, p. 1.)

"It is possible to achieve reduced thrombosis and reduced hemorrhage," said Meanwell. "Hirulog provides consistent, reversible anticoagulant effect with striking reductions in risk."

The Medicines Company presented to the panel a sub-group analysis showing that patients who had previously suffered a heart attack had much better outcomes following treatment with Hirulog compared to heparin. In the first Phase III trial, these patients had 45 percent fewer procedural failures on Hirulog and 68 percent fewer episodes of bleeding. Patients in the second trial had 58 percent fewer procedural failures with Hirulog and 85 percent fewer episodes of bleeding.

In its presentation to the panel, the company also noted that, when the angiographic lesions were categorized, the more complex lesions were more often found in patients treated with heparin compared to those treated with Hirulog.

The panel, however, had difficulty interpreting the results of the trials because they had been designed in 1992, and the landscape for interventional cardiology has irrevocably changed since then. Members questioned how to interpret the data from this trial, given the widespread use of glycoprotein (gp) IIb/IIIa platelet aggregation inhibitors such as Malvern, Pa.-based Centocor, Inc.'s ReoPro and South San Francisco-based COR Therapeutics Inc.'s Integrilin as a means to reduce doses of heparin while providing adequate anticoagulation.

"What you are showing is probably not relevant for what we are doing now," said Udho Thandani, panel member and professor of medicine at the Oklahoma University Health Sciences Center, in Oklahoma City.

Topol argued that, in light of the increased use of gp IIb/IIIa inhibitors, the risk for bleeding is much greater today than it was when the trial was originally conceived.

"We need this agent today," Topol said. "No matter how you slice the data, the reduction in hemorrhagic events [with Hirulog] is remarkable. And nowhere is bivalirudin inferior to heparin."

While noting the Hirulog trials used much higher doses of heparin than used presently, Topol showed that even when compared to more modern doses of heparin, Hirulog showed a more desirable safety profile. Topol also pointed out that there have been no clinical trials testing the efficacy of heparin, yet it is the standard.

While the panel allowed that heparin has never undergone extensive clinical trials comparing it to placebo, since such a study would be unethical, members felt that the high dose of heparin given in the clinical trials could skew an accurate reading of Hirulog's benefits. In addition, the panel noted, the pivotal trials were designed to show superiority to heparin and were not powered to determine equivalence.

The agency isn't bound by the decisions of its advisory panels; however, officials usually follow the committees' advice. *