Biotech Values

[DewDiligence]

What's Next For Vytorin?

[Expert opinion is all over the map.]

http://www.forbes.com/2008/01/14/enhance-merck-schering-biz-healthcare-cx_mh_0115bizenhance.html

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Matthew Herper
01.15.08, 6:00 AM ET

When Merck and Schering-Plough revealed Monday that the active ingredient in their top-selling cholesterol meds Zetia and Vytorin had flunked a clinical trial measuring its effect on artery plaque, they opened themselves up to a barrage of attacks.

"This drug doesn't work. Period. It just doesn't work," said Steven Nissen, head of cardiology at the Cleveland Clinic. U.S. Rep. Bart Stupak, a Michigan Democrat helping to lead a congressional investigation of the study, said, "It is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data." Investors voted with their feet, pushing Schering-Plough shares down 8% and Merck shares off 1%.

Zetia and Vytorin, which is a combination pill of Zetia and the generic drug Zocor, are prescribed 100,000 times a day and together generate annual sales of $5 billion. Merck and Schering split the profits from the medicines equally, and the drugs have been growth engines, with sales up 25% in the most recent quarter over the same period last year.

Robert Spiegel, Schering's chief medical officer, points out that Nissen himself has said that lowering bad cholesterol, or LDL, is the "cornerstone" of cholesterol therapy. The study, dubbed ENHANCE, did show a reduction in LDL levels for patients on Vytorin. "Any way you can lower LDL cholesterol," Spiegel says, "lower is better."

The failed ENHANCE study, finished in April 2006 but not analyzed until now, has been under the spotlight since Forbes reported on delays in analyzing the data that had led many cardiologists to speculate that there would be a negative result. The companies implied they would change the main measurement used in the study, and then changed back after they were hit by even more criticism and the congressional investigation. Now the negative result seems sure to spark more controversy and to crimp the fast sales growth that has helped the revivals of both Merck and Schering-Plough.

"It certainly throws a monkey wrench into this whole field," says Prediman K. Shah, director of cardiology at Cedars-Sinai Medical Center in Los Angeles. Doctors had thought that lowering bad cholesterol, or LDL, was always good. But in this study, LDL was cut 40% more for the people on Vytorin than those on the older drug Zocor, yet there was no benefit in terms of preventing the buildup of artery plaque.

Still, Shah thinks Zetia and Vytorin, which is a combo pill of Zetia and generic Zocor, have a place in the cardiology arsenal. He
believes future studies measuring whether Vytorin prevents heart attacks, strokes, and deaths better than Zocor alone are likely to come out positive. So does Roger Blumenthal, head of preventive cardiology at Johns Hopkins. "I'm much more optimistic than Steven Nissen," Blumenthal says.

But both doctors agreed that the ENHANCE study could change the way doctors think when they write prescriptions for a cholesterol drug, and such changes don't bode well for Vytorin.

Zetia is used in patients who can't take a statin--the class of cholesterol drugs that includes Zocor, originally sold by Merck, Lipitor
from Pfizer, or Crestor from AstraZeneca. It's also used in people who can't tolerate higher doses of a statin and need more cholesterol lowering. For those patients, there just aren't other options.

But Vytorin, which combines Zetia and the now generic Zocor, is a different matter. Pharmacy plans are pushing generic Zocor as its costs plummets well below $1 a pill, compared to $3 a day for Vytorin. Switching a patient from Zocor to Lipitor or Crestor is more likely to cause elevated liver tests or complaints of muscle weakness.

Now, many doctors may decide to give the other drugs a try, or raise the dose of Zocor. The net result could be that sales of Vytorin, instead of growing as Merck and Schering predict, could stall. "If you're a physician and you use this drug in your practice, I think it might be worth reconsidering," says Allen Taylor, head of cardiology at Walter Reed Army Medical Center.

The ENHANCE study was conducted in 720 patients with heterozygous familial hypercholesterolemia, a genetic disease that can boost untreated cholesterol levels above 300. That high level of cholesterol makes them more likely to have heart attacks, and it should make it easier to cut down on the buildup of artery plaque. But though the patients on Vytorin had a 58% drop in LDL, or bad cholesterol, after two years compared to 41% for Zocor, the change in artery plaque was no different--if anything, it was a little worse for Vytorin.

Another study, called ASAP, conducted by some of the same experts who ran ENHANCE, compared the top dose of 80 milligrams of Pfizer's Lipitor with the second-highest dose of Zocor. It studied a similar group of patients, people who have a genetic disorder that predisposes them to have high cholesterol. Bad cholesterol, or LDL, was cut 50% on Lipitor, compared to 41% on Zocor. But while artery thickness increased by 0.036 millimeters on Zocor, it actually decreased by 0.031 mm on Lipitor.

In other words, Lipitor succeeded where Vytorin failed. In the ASAP trial that compared Lipitor and Zocor, patients had arteries that were about 0.9 mm thick. By comparison, the patients in the ENHANCE study comparing Vytorin and Zocor had arteries that were only 0.7 mm thick. Robert Spiegel, Schering' chief medical officer, says these newer patients may have already had a lot of gunk yanked out of their arteries by years of statin treatment.

But even as Merck and Schering fight to keep their market share from slipping, their reputations are also under attack. ENHANCE lacked many of the safeguards that many clinical trials have, and it seems to have been plagued by problems.

Studies often have pre-specified committees that deal with any problems that come up. ENHANCE didn't, and as a result when things went wrong, the companies had to put together a confidential panel on the fly.

"I would call this a Bill Buckner type of study," says Robert Califf, vice chairman for clinical research at Duke University who is leading a big study of Zetia and takes the drug himself. "The ball went through their legs."

But Califf defends Zetia. He takes the drug himself, along with Lipitor, because he can't tolerate a higher Lipitor dose. And he says imaging studies like ENHANCE have not been proven to be any more meaningful that reductions in LDL or C-reactive protein (CRP), a marker of inflammation. Zetia does lower those. He is helping to head up a 10,000-patient study comparing Vytorin and Zetia for preventing heart attacks, strokes and deaths, with results expected in 2011. "People will be arguing about what this means," he says, "until that study is done."
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