By Mary Welch

The Medicines Co. was rewarded for its patience as the FDA issued an approvable letter for the use of Angiomax (bivalirudin) as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

"This is a good step forward and we're pleased," said Clive Meanwell, the company's CEO. "It's been a combination of a lot of work by us, the agency and experts. It's quite nice to see progress."

Final approval is dependent upon the satisfaction of conditions specified by the governmental agency.

"Those conditions are quite clear and we're not talking about them," Meanwell said. "They are quite fair and we do expect to meet them in a reasonable time frame. There's a great deal of commitment to work them out and I'm confident we will."

The most common complication of the therapy is major bleeding or complications related to bleeding. In clinical trials, the most frequent side effects were back pain, pain, nausea and headache. Angiomax is not recommended for use in patients hypersensitive to the product or patients who are pregnant or nursing.

The private Cambridge, Mass.-based company also is developing the product for other indications and has a 17,000-patient Phase III trial under way to study the use of Angiomax in patients who are hospitalized for myocardial infarction. This worldwide trial, which is enrolling 200 patients a week, is projected to end early next year.

"We're at least on track with that time frame," Meanwell said.

In addition, a Phase III trial is ongoing for patients undergoing angioplasty who have experienced heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS).

"That is a particularly quite rare disease where people have an immune reaction to heparin," Meanwell said. "Since it is so rare, recruitment is slow. It'll carry on at least through this year. It won't be a large commercial market ,but we feel the need to pursue it."

A Phase III program to evaluate Angiomax in patients with unstable angina is planned for next year. "The Phase II data is promising and we hope to get the trial started in 2001," Meanwell said.

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

Formerly called Hirulog, Angiomax has had a difficult journey on its road to FDA approval.

Biogen conducted Phase III studies that 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. However, the anticoagulant showed no statistical difference between Hirulog and heparin in procedural failures that included death, myocardial infarction, abrupt vessel closure and additional revascularization procedures. However, Hirulog proved much safer than heparin and reduced major bleeding events by 58 percent in one Phase III study and 63 percent in the other.

Subsequently, Biogen abandoned the drug's development and sought a marketing partner. (See BioWorld Today, Nov. 1, 1994, p. 1.)

In March 1997, The Medicines Co. bought the rights to Hirulog in a deal 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 Co. determined that, despite failing to meet its protocol endpoints, Hirulog was at worst as effective as heparin while being safer and was, for some subgroups, significantly better. The company filed a new drug application for the drug in February 1998. (See BioWorld Today, Feb. 18, 1998, p. 1.)

However, months later the FDA advisory panel delivered what some thought was a fatal blow. It refused to endorse the drug's use with angioplasty in patients suffering from unstable angina. (See BioWorld Today, Oct. 26, 1998, p. 1.)

"It's progress," Meanwell said.