By Mary Welch
In an attempt to broaden the potential applications for the anticoagulant Hirulog (bivalirudin) - particularly in light of an FDA panel's rejection of its use with angioplasty in patents suffering from unstable angina - The Medicines Company began a Phase III international study of the drug in heart-attack patients.
The study, which will test up to 17,000 patients, has as its endpoint death within 30 days of the attack. In two earlier Phase II studies with more than 450 patients, the endpoints were restoration of coronary blood flow in heart-attack patients, a highly prophetic indicator of mortality in this patient population. Those studies showed that Hirulog was significantly more effective than heparin in restoring coronary blood flow in heart-attack patients.
"The Phase II studies and the Phase III studies are similar, except the endpoints are different," said Clive Meanwell, president and CEO. "In this study the endpoint is death. It's an unequivocal, definite endpoint."
The current Phase III trial, known as HERO-2 (which stands for Hirulog Early Reperfusion/Occlusion), is intended to show that, when compared with heparin, Hirulog, administered within six hours of the attack, significantly reduces 30-day mortality in patients with classic heart-attack symptoms who are eligible for thrombolytic therapy. The open, randomized trial will take place at some 600 sites in 47 countries.
"This Phase III study is part of our strategy to position Hirulog as a cost-competitive anticoagulant with broad application across a spectrum of acute coronary syndromes," Meanwell said. "We have strong data that shows Hirulog to be superior to heparin when compared in safety or effectiveness - or both. We see use in a wide spectrum of diseases and syndromes."
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 abandoned the drug's development and sought a marketing partner when its Phase III studies showed there was no statistical difference between Hirulog and heparin in procedural failures - including death, myocardial infarction, and abrupt vessel closure - even though Hirulog proved much safer than heparin. (See BioWorld Today, Nov. 1, 1994, p. 1.)
Hirulog Deal Worth Up To $30M For Biogen
In 1997, The Medicines Company, also of Cambridge, bought the licensing rights from Biogen in a deal worth up to $30 million. The Medicines Company determined that, despite failing to meet its protocol endpoints, Hirulog was at least as effective as heparin while being safer and was, for some subgroups, significantly more effective. A new drug application was filed in February 1998. (See BioWorld Today, March 26, 1997, p. 1, and Feb. 18, 1998, p. 1.)
In late October, the FDA's Cardiovascular and Renal Drugs Advisory Committee voted 4-3 not to recommend the anticoagulant for approval in the unstable-angina indication. Panel members questioned how to interpret the data, given the widespread use of glycoprotein 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. (See BioWorld Today, Oct. 26, 1998, p. 1.)
"We are having conversations - a dialogue - with the FDA," Meanwell said. "That's all I can say." N