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Therapeutic Angiogenesis Takes Step Forward

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Duke Health News 919-660-1306

DURHAM, N.C. -- In the first demonstration of the
therapeutic benefit of an agent that stimulates blood vessel
growth, a group of cardiologists have improved the functional
abilities of patients with painful blockages in the blood
vessels in their legs.

The phase II randomized double-blind placebo controlled
trial aimed to test whether an "angiogenic growth factor" could
increase the duration of walking by patients with intermittent
claudication -- a condition marked by clogged blood vessels in
the legs -- which leads to severe and often debilitating pain
during walking. This pain is similar to the pain of angina
caused by clogged coronary arteries.

The results of the trial, led by Duke University Medical
Center cardiologist Brian Annex, M.D., and Robert Lederman,
M.D., then with the University of Michigan and now with the
National Heart Lung Blood Institute, were published in the June
15, 2002 issue of the journal Lancet.

While the researchers are not certain that the agent, known
as recombinant fibroblast growth factor-2 (rFGF-2), actually
triggered the creation of new blood vessels, they found that
treated patients could significantly increase their peak
walking times compared to similar patients who did not receive
the agent.

"This is the third large multi-center randomized
placebo-controlled trial looking at the therapeutic use of an
angiogenic agent and the first to show a positive result in its
primary endpoint," said Annex. "This study provides the
strongest and most convincing data to date that an angiogenic
agent can have a positive effect in humans."

For nearly a decade, researchers have been testing different
angiogenic agents for the treatment of heart disease.
Researchers hope that these agents can stimulate new blood
vessel growth into damaged heart muscle, or around arterial
blockages. But so far, the results of recent studies in humans
have not been encouraging, Annex said.

"Angiogenesis is an extremely exciting area with a great
deal of potential. It is also one that has been in need of
positive randomized, placebo-controlled data to accelerate
further research," Annex said. "This study is an important step
in that direction."

Patients with clogged blood vessels in their legs suffer
from a general condition known as peripheral artery disease.
This chronic, progressive condition is similar to heart disease
in that arteries become clogged with the buildup of plaque.
This clogging results in a shortage of oxygen to leg muscles,
which causes pain, or "claudication" -- the same process by
which oxygen-starved heart muscle produces angina.

Walking increases the demand by leg muscles for oxygen, so
patients with his condition typically can only walk short
distances before the pain forces them to stop. The pain
diminishes with rest. Since such pain is the main symptom
limiting the quality of life of these patients, the researchers
wanted to test rFGF-2's ability to allow patients to walk
longer distances.

The researchers enrolled 190 patients at 22 centers across
the U.S. and divided them into three groups: one group received
one dose of rFGF-2, another group received two doses 30 days
apart, and the last group received a placebo. The researchers
then measured peak walking times 90 and 180 days later.

Interestingly, said the researchers, they found that the
patients who received two doses did not do as well as those
receiving one dose.

"Specifically, the placebo group saw a 14 percent increase
in peak walking time, while those who received one dose
improved 34 percent," Annex said. "And those who received two
doses increased their peak walking time 20 percent. Why this
difference appeared is unclear, but we'll probably find with
further studies what types of patients respond better to rFGF-2
-- if someone didn't respond to one dose, they probably
wouldn't respond to the second dose."

Not only did the patients' peak walking times increase, but
they also showed improved scores in the ankle-brachial pressure
index (ABI), which measures blood pressures at the ankle and is
a key test used in diagnosing peripheral artery disease.

"Increases in both peak walking times and the ABI support
the hypothesis that perfusion, or blood flow, was improved in
these patients," Annex said.

While the mechanism of the beneficial effect is not clear,
Annex speculates that the rFGF-2 might have caused new vessels
to grow around blocked arteries, or may have somehow made the
vessels in the area of the blockage work better.

rFGF-2, a recombinant protein made in bacteria, is nearly
identical to the protein produced naturally in humans. Chiron
Corp., Emeryville, Calif, produces rFGF-2 and funded the trial,
which was dubbed TRAFFIC ? Therapeutic Angiogenesis with FGF
for Intermittent Claudication.

Annex has no financial interest in Chiron or the agent.

The Duke Clinical Research Institute was the coordinating
center for the trial.

Other members of the team, most of whom are members of the
Peripheral Atherosclerosis Research Consortium (PARC), included
Farrell Mendelsohn, M.D., a cardiologist in Birmingham, Ala.;
R. David Anderson, M.D., Sarasota Memorial Hospital, Fla.;
Jorge Saucedo, M.D., University of Arkansas for Medical
Sciences, Little Rock; Alan Tenaglia, M.D., Tulane University
Medical Center, New Orleans; James Hermiller, M.D., Nasser,
Smith and Pinckerton, Indianapolis; William Hillegass,
University of Alabama, Birmingham; Krishna Rocha-Singh, M.D.,
Prairie Cardiovascular Consultants, Springfield, Ill.; and
Thomas Moon, M.D. and M.J. Whitehouse, M.D., of Chiron. The
full list of investigators can be found at the PARC website,
http://www.arterial.org.

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