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Novel Anti-Coagulant Clears Clinical Testing Hurdle

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Duke Health News 919-660-1306

NEW ORLEANS -- An experimental anti-coagulant that prevents
the formation of blood clots earlier in the coagulation process
than other agents has shown efficacy in phase II clinical tests
-- success that emphasizes its promise as a new treatment for
patients with coronary artery disease, according to Duke
University Medical Center cardiologists.

The agent, code-named DX-9065a, inhibits the action of
Factor Xa (as in Roman numeral X), a pivotal clotting factor in
the complex cascade of biochemical events that ultimately leads
to the formation of a blood clot. The first Phase II trial
demonstrated the safety and effectiveness of DX-9065a in stable
heart patients undergoing angioplasty, while the second and
larger Phase II trial enrolled high-risk heart patients.

Not only do the researchers believe the results of the trial
itself are promising, but they are encouraged that the trial
included patients from the United States, Canada and Japan.
Japan has traditionally not had a major role in international,
multi-center clinical trials.

Duke cardiologist John Alexander, M.D., presented the
results of the trial known as XaNADU-ACS (Xa Neutralization for
Atherosclerotic Disease Understanding -- Acute Coronary
Syndromes) March 9, 2004, at the annual scientific sessions of
the American College of Cardiology.

"Patients who received high-dose DX-9065a tended to have a
reduction in death, heart attack or the need for urgent
revascularization procedure," Alexander said. "Both low and
high doses of DX-9065a also tended to result in fewer bleeding
episodes than the standard therapy of unfractionated heparin.
We believe that the DX-9065a results to date set the stage for
larger Phase III trials for patients with acute coronary
syndromes or undergoing angioplasty."

Anti-coagulation therapy is widely used to prevent clot
formation 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 UFH is an effective
anti-coagulant, it 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.

For the current study, researchers enrolled 402 patients and
randomized them to received either UFH, or two differing doses
of DX-9065a. Of that group, 47 patients were enrolled in
Japanese hospitals, with the rest enrolled at hospitals
throughout the U.S. and Canada.

The trial found little difference in the effects of DX-9065a
and UFH on the primary efficacy endpoint of combined rate of
death, heart attack, urgent revascularization or recurrent
ischemia as measured by continuous electrocardiogram monitoring
(ST-monitor depression). However, patients receiving high-dose
DX did show benefits in the individual secondary measures --
including bleeding -- with the exception of ST depression.

"We do not know why there was no effect of DX-9065a on ST
depression as detected by continuous holter monitoring -- it is
bothersome," Alexander said. "Given the consistent effect on
other endpoints, the most likely explanation for the lack of
effect on recurrent ischemia is chance because of the small
numbers of patients. In subsequent trials with DX-9065a, this
is something that will need to be investigated further."

Additionally, while both low- and high-dose DX-9065a
patients had fewer bleeding episodes than those on UFH, those
receiving the higher dose tended to have more bleeding,
suggesting that there is a "dose-response" relationship between
bleeding and the drug.

Future trials will need to refine the optimal dosing to
maximize efficacy and limit potential bleeding side effects,
Alexander said.

"This was one of the first trials to include patients from
both North America and Japan using the same protocol,"
Alexander said." Japan is the second-largest health-care market
in the world. In Japan the infrastructure for clinical research
is quite limited and they don't usually participate in large
global trials. We think it is very important to include
Japanese patients in these kinds of trials, and hopefully
XaNADU-ACS has played a role accomplishing this."

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

The advantages of interrupting the clotting cascade at the
point of Factor Xa activation is that the regulatory chemical
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 does not depend on the
action of anti-thrombin III and is able to inhibit Factor Xa
directly and within clots that have already formed.

Duke was the coordinating center for all three of the XaNADU
trials. 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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