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Drug Not Effective in Preventing Bypass Vein Clogging

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Duke Health News 919-660-1306

DALLAS -- A new drug, edifoligide, designed to prevent the
clogging of veins used in coronary bypass surgery was no more
effective than a placebo, according to the results of a Phase
III clinical trial led by researchers at Duke Clinical Research
Institute (DCRI).

In a coronary artery bypass procedure, surgeons typically
remove portions of the saphenous vein from patients' legs and
use them as conduits to reroute blood around a blockage in
arteries supplying blood to the heart. The most common reason
for subsequent failure of the grafts is the progressive
narrowing of the vein, which is largely the result of a process
known as neointimal hyperplasia.

Since veins are structurally different from arteries, the
increased pressure and stress on the implanted vein causes
proliferation of smooth muscle within the vessel. Edifoligide,
an E2F transcription factor inhibitor, showed an ability in
earlier studies to block this cellular proliferation.

"The results of our Phase III trial showed that the
edifoligide was absolutely neutral in all endpoints when
compared to placebo," said Duke cardiologist John Alexander,
M.D., who presented the results of the trial Nov. 13, 2005, at
the annual scientific sessions of the American Heart
Association. The results of the trial are also being published
early and online by the Journal of the American Medical
Association.

"Failure of at least one vein graft is quite common within a
year of bypass surgery" Alexander said. "While edifoligide had
no effect in preventing neointimal hyperplasia, longer-term
follow-up and additional research is needed to determine
whether the drug has longer-term beneficial effects and to
better understand the mechanisms and consequences of vein graft
failure."

In response to shear forces and increased pressures in the
vein, cells growth increases in the inner lining of the vein.
These cells secrete a variety of proteins known as cytokines
that modulate the immune response. These cytokines cause
inflammation that intensifies the process of atherosclerosis in
the newly formed tissue. The family of E2F transcription
factors has been implicated in "turning on" many of the genes
responsible for this process.

The drug edifoligide is an oligonucleotide "decoy" or short
fragment of DNA, that is structurally similar to the E2F
transcription factor binding site, and thereby blocks E2F
transcription factor binding and subsequent gene activation.
The drug appeared to be promising in animal models and two
small clinical trials involving 41 and 200 patients, said the
researchers.

The latest randomized, double-blind trial, known as
PREVENT-IV, enrolled 3,014 patients at 107 U.S. sites who
underwent coronary artery bypass graft procedures involving at
least two vein grafts. Half of the patients had their leg veins
pressure-treated with the drug for ten minutes prior to
implantation, while the veins of control patients were treated
in the same way, but with a placebo. The average number of
veins grafted was about 2.5 per patient.

The primary endpoint measured by researchers was how many
patients had at least one vein graft more than 75 percent
blocked more than a year after surgery.

The researchers found that 45.2 percent of patients with
treated veins had at least one vein more than 75 percent
blocked, compared to 46.3 percent for the control group. In
terms of total veins, 28.5 percent of treated veins were more
than 75 percent occluded, compared to 29.7 percent in the
control group. The differences were not clinically or
statistically significant, said the researchers.

There was also no difference between the two groups in terms
of clinical events, they said. In the treated group, 7.6
percent of patients experienced death, heart attack or need for
another procedure, compared to 9.1 percent for the control
group.

The results of the trial were similar to that of PREVENT
III, which tested the drug in patients who underwent peripheral
artery bypass surgery.

"Given the results we've seen in the latest two large
clinical trials (PREVENT III and IV), the earlier promising
results with edifoligide were probably due to its small sample
size, less complete follow-up, or chance," Alexander said.

The DCRI is currently leading a Phase I/II pilot trial
(PREVENT V), which is assessing the effectiveness of
edifoligide in preventing neointimal hyperplasia in vascular
access grafts in patients undergoing dialysis for kidney
failure.

While the results of PREVENT IV were largely negative,
Alexander said that researchers gained insights. For example,
the process developed to infuse the drug into the vein tissue
could be used in other surgical settings where a drug needs to
be delivered to a single site instead of systemically.

The trial was funded by Corgentech, Inc. South San
Francisco, developer of the drug and Bristol Myers Squibb,
N.Y., who partnered with Corgentech in the development of the
drug. Alexander has no financial interests in Corgentech.

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