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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.

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