Novel anti-coagulant clears hurdle

March 20, 2002

ATLANTA -- Duke University Medical Center cardiologists report that an experimental anti-coagulant that prevents the formation of blood clots earlier in the coagulation process than other agents has cleared another hurdle in becoming a potential new treatment for patients with coronary artery disease.

The new agent, code-named DX-9065a, inhibits the action of Factor Xa (as in Roman numeral X), a pivotal clotting factor of the dozen known factors involved in the complex cascade of biochemical events that ultimately leads to the formation of a blood clot. Duke cardiologist John Alexander, M.D., presented the results of the recently completed Phase II clinical trial today (March 20) at the 51st annual scientific sessions of the American College of Cardiology.

"As cardiologists, what we need is an anti-coagulant that achieves predictable concentrations, is easy to dose for individual patients, and works at least as well,
and hopefully better than, current anti-coagulants," Alexander
said. "The results of an earlier Phase I trial, and the current
Phase II trial, suggest that this new agent has potential."

Anti-coagulation therapy is widely used to keep clots forming in patients at risk for heart attacks or for those undergoing angioplasty procedures; however, their biggest drawback has been the potential for bleeding complications. Many of these agents have "narrow" windows for therapeutic effect - too little can lead to clot formation, too much can cause bleeding.

The most widely used agent is called unfractionated heparin (UFH). According to Alexander, while it is an effective anti-coagulant, UFH is difficult to use since patient responses to the drug vary widely. During administration, it also requires careful monitoring to ensure therapeutic levels in the blood.

The new trial built upon the results of a Phase I trial known as XaNADU (Xa Neutralization for Atherosclerotic Disease Understanding), which demonstrated the safety of DX-9065a, in patients with stable coronary disease. The current trial, XaNADU-PCI (percutaneous intervention) compared the effectiveness and safety of graduated doses of DX-9065a to UFH in patients who were undergoing angioplasty, a procedure used to open clogged coronary arteries.

A total of 96 patients received DX-9065a, 23 received UFH in this five-center trial.

"In terms of side effects, both agents were very similar," Alexander said. "The DX-9065a acted in a predictable fashion and as we expected. This trial involved a small number of patients, so obviously more studies are necessary, especially to determine the optimal dosing for patients."

A second Phase II trial, known as XaNADU-ACS (acute coronary syndrome), is currently enrolling an anticipated 400 high-risk heart patients in a comparison with UFH. The results of these two Phase II trials will form the basis for the design of future Phase III trials.

When Factor Xa is activated, it converts a precursor chemical circulating in the blood known as prothrombin into the enzyme thrombin. Once activated, thrombin then converts circulating fibrinogen (Factor I) into the protein fibrin, the primary building block of a blood clot.

The advantages of interrupting the clotting cascade at the point of Factor Xa activation is that it sits at the intersection of the two classical pathways for blood clot formation and limits the generation of thrombin, Alexander said.

"Heparin works by inhibiting the action of circulating thrombin, meaning that thrombin is produced, but is then inhibited," Alexander said. "The new agent will stop the process even before the formation of thrombin, which theoretically should make it a more effective anti-coagulant."

Unlike other available anti-coagulants, including UFH and the low-molecular-weight heparin, DX-9065a is not dependent on the action of anti-thrombin III and is able to inhibit Factor Xa within clots that have already formed.

"These properties may make it a superior anti-coagulant," Alexander said.

Duke is the coordinating center for all three of the XaNADU trials. XaNADU-ACS is unique in that it is the first clinical trial in this field conducted simultaneously in both the United States and Japan. For cultural and regulatory reasons, this truly global development strategy has not been widely used.
The XaNADU trials were funded by Daiichi Pharmaceutical Co., Ltd., Japan, which developed DX-9065a. Alexander has no financial interests in Daiichi.

Duke University

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