STOCKHOLM, Sweden -- An experimental agent that prevents the
formation of blood clots earlier in the coagulation process
than other agents has cleared its first hurdle in becoming a
potential new treatment for patients with coronary artery
disease, according to the results of a recently completed trial
led by Duke University Medical Center cardiologists.

The new drug inhibits the action of Factor Xa (as in Roman
numeral X), the most pivotal of the dozen known clotting
factors involved in the complex cascade of biochemical events
that ultimately leads to the formation of a blood clot. If
larger trials continue to demonstrate the agent's benefit, it
could offer a more effective and safer way to keep potentially
life-threatening blood clots from forming.

While anti-coagulation therapy is widely used to keep clots
from forming in patients at risk for heart attacks or those
undergoing angioplasty procedures, 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 and too much can cause
bleeding.

"This is the first reported clinical trial to provide some
preliminary safety and clinical information on a novel class of
agents for the treatment of coronary artery disease," said Dr.
Christopher Dyke, senior cardiology fellow at the Duke Clinical
Research Institute (DCRI). "Based on the results of this small
Phase I trial, this new anticoagulant appears to effectively
inhibit factor Xa while being well tolerated."

Dyke prepared the results of the DCRI analysis for
presentation Wednesday (Sept. 5) at the annual meeting of the
European Society of Cardiology.

The trial, dubbed XaNADU (Xa Neutralization for
Atherosclerotic Disease Understanding), was a Phase Ib clinical
trial involving 73 patients with clinically stable coronary
artery disease at 10 U.S. academic medical centers. Typically,
Phase I trials test the safety of an agent on healthy
volunteers, and while Phase Ib clinical trials also test an
agent's safety, it does so with a group of patients having the
medical condition under study.

On average, the patients were 63 years old, with 68 percent
having had a prior heart attack and 86 percent having had a
revascularization procedure, either an angioplasty or a
coronary artery bypass surgery. In the double blind, placebo
controlled study, the patients were randomized to either
placebo, or one of four escalating doses of the Factor Xa
inhibitor. The patients were followed in each academic center's
General Clinical Research Center, National Institutes of
Health-funded centers for specialized clinical research.

"We found no statistically significant difference in
bleeding complications among all five groups," Dyke said.
"Also, there were no adverse changes in kidney or liver
function, and the hemoglobin and platelet counts remained
stable across all groups."

When Factor Xa is activated, it responds by converting 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.
Thrombin also exhibits a number of additional properties that
increase the ability of blood to clot, Dyke said.

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

"Because of its location in the cascade, Factor Xa has long
been seen as an attractive target for anti-coagulation
therapy," Dyke said. "Currently available anti-coagulants that
work by blocking other factors in the cascade, for example,
target thrombin after it is generated, either directly or
indirectly, the latter in the case of heparins."

Dr. Robert Harrington, another DCRI cardiologist and senior
researcher for the trial, said the new agent has great
potential in treating heart patients, but says enthusiasm
should be tempered until the results of larger multi-center
trials are completed.

"This is truly the first experience in real patients who
have coronary artery disease with a novel class of drug, so it
is a pretty important step moving along our knowledge of
anti-coagulation therapy," Harrington said. "Even if this
proves to be a modest advance, modest steps forward in treating
a disease that effects millions of people every year is pretty
good. Larger trials will be required to give us the answer as
to whether these are steps forward in reducing blood clotting
while minimizing bleeding."

These answers could be forthcoming in the near future. Two
Phase II trials, both being coordinated by the DCRI, are under
way. The first trial is testing the agent in conjunction with
angioplasty procedures and has already enrolled more than 100
patients. It should conclude this year.

The second trial, which will enroll more than 400 patients
with unstable angina, begins later this month. This will be the
first time a clinical trial involving cardiovascular agents
will be conducted in both the United States and Japan. For
cultural and regulatory reasons, Japan has in the past
preferred to conduct their trials with Japanese participants,
Harrington said.

The trial was funded by Daiichi Pharmaceutical Co., Ltd.,
Japan, which developed the Factor Xa inhibitor, known as
DX-9065a.