Drug Has No Benefit in Trial, Makers Say

By ALEX BERENSON
Published: January 14, 2008
A clinical trial of Zetia, a cholesterol-lowering drug prescribed to
about 1 million people a week, failed to show that the drug has any
medical benefits, Merck and Schering-Plough said on Monday.

The results will add to the growing concern over Zetia and Vytorin, a
drug that combines Zetia with another cholesterol medicine in a single
pill. About 60 percent of patients who take Zetia do so in the form of
Vytorin, which combines Zetia with the cholesterol drug Zocor.

While Zetia lowers cholesterol by 15 percent to 20 percent in most
patients, no trial has ever shown that it can reduce heart attacks and
strokes -- or even that it reduces the growth of the fatty plaques in
arteries that can cause heart problems.

This trial was designed to show that Zetia could reduce the growth of
those plaques. Instead, the plaques actually grew almost twice as fast
in patients taking Zetia along with Zocor than in those taking Zocor
alone.

Patients in the trial who took the combination of Zetia and Zocor were
receiving it in the form of Vytorin pills. The trial, called Enhance,
lasted two years and covered about 720 patients with extremely high
cholesterol, mostly in the Netherlands.

Dr. Steven Nissen, the chairman of cardiology at the Cleveland Clinic,
said the results were "shocking." Patients should not be prescribed
Zetia unless all other cholesterol drugs have failed, he said.

"This is as bad a result for the drug as anybody could have feared,"
Dr. Nissen said. Millions of patients may be taking a drug that has no
benefits for them, raising their risk of heart attacks and exposing
them to potential side effects, he said.

Still, patients who are taking Vytorin or Zetia should talk to their
doctors if they are concerned and not discontinue taking the medicines
on their own, Dr. Nissen said.

Dr. Howard Hodis, a cardiologist at the University of Southern
California, also said he was concerned by the trial's results. Growth
in fatty plaques -- called atherosclerosis -- is highly correlated with
heart attacks and strokes, Dr. Hodis said.

"Clearly, progression of atherosclerosis is the only way you get
events," Dr. Hodis said. "If you don't treat progression, then you get
events."

The results of the trial "necessitate further investigation -- that
just can't be ignored," Dr. Hodis said.

Both companies' stocks fell on Monday, with Merck's share price down a
bit more than 1 percent. Shares of Schering-Plough, whose profits are
much more dependent on the drugs, were down nearly 8 percent.

The results will also add to the controversy surrounding a long delay
in releasing the results of the trial. Merck and Schering-Plough
completed the trial in April 2006 and had initially planned to release
the findings no later than March 2007. But the companies then missed
several self-imposed deadlines, citing the complexity of the data
analysis from the study and saying they did not know when or if the
data would be ready for publication.

Last month, after several news articles highlighted the delay, they
finally agreed to release the results soon.

For Merck and Schering-Plough, which jointly market Zetia and Vytorin
and share profits from the drugs, the trial's results are a serious
setback. Zetia and Vytorin are important contributors to both
companies' profits, especially to Schering, which is smaller and less
profitable than Merck.

Analysts estimate that about 70 percent of Schering's earnings depend
on the drugs. The controversy over the trial is also a problem for
Merck, which is trying to repair its reputation after withdrawing the
painkiller Vioxx from the market in September 2004.

In the United States, Zetia and Vytorin combined account for about 20
percent of the overall cholesterol-lowering market. More than 100
million prescriptions have been filled in the United States for Zetia
and Vytorin since the Food and Drug Administration approved them in
November 2002 and August 2004 respectively. Both drugs cost about $3 a
day.

Because Zetia reduces cholesterol differently from statins like
Lipitor and Zocor, doctors often prescribed it as an additional
therapy for patients whose cholesterol remains high even after they
are already taking statins. But even before Zetia was introduced in
2002, some cardiologists argued that statins had positive
cardiovascular effects that go beyond their ability to reduce
cholesterol, and that Zetia lacks those effects.

The Enhance trial covered patients with a gene that causes them to
produce very high levels of low-density lipoprotein cholesterol,
commonly called L.D.L., or bad cholesterol. Patients in the trial had
L.D.L. levels of about 320 milligrams per deciliter at the beginning
of the trial, about three times the level cardiologists recommend.

Over the two years of the trial, patients who took Zocor alone reduced
their L.D.L. by 41 percent on average, while patients who took Vytorin
reduced their cholesterol by 58 percent. Yet despite the larger
cholesterol reduction, patients taking Vytorin actually had more
growth in fatty plaques in their carotid arteries than those on Zocor.
The carotid artery runs through the neck and delivers oxygenated blood
to the brain.