New data fails to quiet cholesterol drug debate

By Julie Steenhuysen

CHICAGO (Reuters) - New data about the controversial cholesterol fighter Vytorin failed to quell concerns that the drug might not be as good as thought at keeping heart disease at bay, leading an expert panel to recommend on Sunday that patients stick with statins.

Full results of the study known as Enhance, released earlier on Sunday, mirrored results in January released by the drug's makers Merck & Co and Schering-Plough Corp <SGP.N that found the combination drug failed to show it worked any better than a cheaper generic statin at reversing heart disease.

That sent shock waves among heart doctors, who had readily prescribed the drug because it does such a great job at lowering low-density lipoprotein, or LDL, the so-called bad cholesterol doctors see as the chief villain in the war against heart disease.

The results do little to ease investor concerns about the profit potential for the drug that is critical to the future of both Schering-Plough and Merck. The two drugmakers have come under fire from the medical community and lawmakers for a long delay in releasing the results of the clinical trial.

The full study was published online in the New England Journal of Medicine and presented at a meeting in Chicago of the American College of Cardiology in a panel debate.

Vytorin combines the statin Zocor, known generically as simvastatin, with another cholesterol medicine, Zetia or ezetimibe, and is marketed by a joint venture of Merck and Schering-Plough.

Although the combination drug did a far better job at lowering cholesterol than Zocor alone, neither drug helped reduce the thickness of artery walls in patients with a condition known as heterozygous familial hypercholesterolemia, which causes very high levels of LDL.

Given the lack of evidence of a benefit, the ACC panel recommended that doctors first put patients on a high dose statin, and then try other drugs before reaching for Vytorin or Zetia. "The strongest recommendation you could make on this panel is to turn back to statins," said panelist Dr. Harlan Krumholz of Yale University, summing up the panel's recommendation.

"We were very disappointed in the ACC panel. We had expected a balanced discussion and we really didn't think the panel today served patients well," Dr. Robert Spiegel, chief medical officer of Schering-Plough told Reuters.

Dr. John Kastelein, the Dutch researcher who led the Enhance study, said in an interview he fully expected the results to be positive, and was shocked when he learned the final outcome of the study in January.

"I fell off my chair. Honestly. I would have never expected it," Kastelein said. He said there were many possibilities about why the drug did not show a benefit, but said the Enhance study was only designed to answer the question of whether one drug that lowers cholesterol worked better than another.

"I think everybody in his right mind thought it is LDL that counts. A study like this makes you shiver a bit," Kastelein said.

Dr. Greg Brown of the University of Washington in Seattle said the study challenged long-held assumptions about the value of lowering LDL cholesterol.

"We've always assumed no matter how you get the LDL down, it's good," Brown said in an interview.

While the Enhance study raises a number of questions, he said it does not answer them. "For now, the study's findings are a red flag, but not a 'black box'," Brown and colleagues wrote an editorial in the New England Journal of Medicine, referring to the strongest warning label possible that U.S. health regulators can put on a prescription drug.

Merck and Schering-Plough, in a statement, said the most likely explanation for the failure to see a benefit is that the patients in the study had already been aggressively treated with statins and there are likely limits to how much more they could improve.

ADVERTISING BOOST

Vytorin and Zetia have annual sales of about $5 billion, helped in large measure by a clever TV advertising campaign that humorously compares people to the food they eat. It makes the case that some kinds of inherited cholesterol can not be treated by statins alone.

A separate study in the New England Journal of Medicine that compared prescribing practices for cholesterol-lowering drugs in the United States and Canada between 2002 and 2006, found a stark contrast between the use of Zetia in Canada, where there is no direct-to-consumer advertising, and in the United States, where there is.

They found the proportion of prescriptions for Zetia rose from 0.2 percent in 2003 to 3.4 percent in 2006 in Canada, while in the United States they rose from 0.1 percent in 2002 to 15.2 percent in 2006.

"If we had adopted it like they did in Canada, we would have saved $1.5 billion to $2 billion in healthcare costs in 2006," said Krumholz, who worked on the study.

"We spent a lot of money on this thing and I think honestly we don't have any idea whether or not, net-net, patients benefited," he said in an interview.

HIGH STAKES FOR SCHERING-PLOUGH

For Schering-Plough, where Vytorin has been the star of an otherwise lackluster pipeline of new drugs, the stakes could not be higher. On the eve of the panel meeting, Schering-Plough questioned the credibility of Krumholz, who is one of Vytorin's more outspoken critics.

The company noted that Krumholz had been paid to give expert testimony in a trial against Merck involving its recalled pain drug Vioxx, and said it posed a conflict.

Dr. Marc Shelton, who chaired the ACC's scientific meeting and hand-picked Krumholz for the panel, said Krumholz had fully disclosed his involvement in the Merck trial. "He's a huge quality expert," Shelton told Reuters. "We didn't think his position on Vioxx was important to the Enhance trial."

Shares of Schering-Plough and Merck have fallen about 30 percent each since mid-January when the Vytorin data was first released. In February, U.S. prescriptions of Schering-Plough's cholesterol drugs fell 13 percent from a month earlier, but the company contended it was too early to discern any trends.

(Additional reporting by Debra Sherman; Editing by Tom Hals)