A Weak Prognosis for Vytorin and Zetia

Schering-Plough and Merck will likely see plunging sales after Dr. Harlan Krumholtz advises cardiologists not to prescribe the cholesterol drugs

In what may go down as a seminal lesson in the dangers of over-aggressive drug-industry marketing, share prices of Schering-Plough (SGP) and Merck (MRK) plunged on Mar. 31 after their top-selling cholesterol drugs got hammered at a scientific meeting. Schering shares were down 26% at the close of trading on Mar. 31, to 14.41, and Merck was down 14.7%, to 37.95—representing a combined loss of $22 billion in shareholder value from the previous Friday.

Schering sells a blockbuster cholesterol-lowering drug called Zetia, which it also combines with a generic Merck cholesterol medicine into a drug called Vytorin, which is marketed with Merck. Together, Zetia and Vytorin raked in more than $5 billion in sales last year. But on Mar. 30, Yale University cardiologist Harlan Krumholtz told thousands of doctors at the meeting of the American College of Cardiology, or ACC, in Chicago that the two drugs should not be used as a first- or even second-line treatment. Other doctors agreed.

That probably translates into a dramatic drop in sales for the two drugs, analysts and doctors said. "When you get a panel of cardiologists saying don't use this drug, and if you do you are using it at own risk, it's a powerful message," says Dr. John LaRosa, president of the State University of New York Downstate Medical Center in Brooklyn, N.Y., and a cholesterol expert.

Old News Is Bad News

Schering-Plough sales representatives were stunned. "It's Over!" writes one on a message board at CafePharma, an online café for drug salespeople. "Now, we are supposed to get doctors to write [a prescription for] those products? On top of that, every patient has seen the story as well. Get used to hearing "No Way!"

The ironic twist to this story is that the Mar. 30 meeting of the ACC brought no actual news. The data presented at the gathering (and published simultaneously in the New England Journal of Medicine) had already made front-page headlines back in January. And the data are inconclusive. The science doesn't say that Zetia, either by itself or combined with another medicine, is a bad drug. Instead, it simply casts doubt on whether it works. Proof either way won't come until a much larger trial is completed in 2012. "These are very difficult questions and may take years to answer definitively," says Dr. LaRosa. Adds Raymond James pharmaceutical analyst Michael Krensavage, "We don't know if the drug saves lives."

Dr. Robert J. Spiegel, Schering's chief medical officer and senior vice-president at the Schering-Plough Research Institute, says the company believes the study is being viewed far too negatively. At the ACC meeting, he says, "There was one vocal individual who served as judge and jury and delivered a verdict not shared by most doctors. Our position is and has been that this single trial should not change the current practice of medicine," which sees LDL lowering as important.

But the fallout illustrates how the marketing of these two drugs got way out in front of the scientific proof—and how that has backfired for the companies. In the U.S., sales of Zetia and Vytorin represent 16% of all cholesterol-lowering drug sales, according to an accompanying paper in the NEJM. In contrast, they grabbed only a 3% share in Canada, where there is no direct-to-consumer advertising. That may be a more appropriate level of use, at least until the data are more definitive.

A National Cholesterol Obsession

LaRosa is among many doctors who have always believed Zetia should only be used in cases where the more common cholesterol-lowering drugs, known as statins, aren't doing enough—and that there's no reason to take Vytorin at all. But the marketing pushed sales far beyond their known medical utility. And now that's causing a big hit to the companies' bottom lines.

That's why the rise and fall of these drugs is a cautionary tale about money that can be made aggressively promoting unproven medicines—until something bad happens. It's also part of a larger story about how the national obsession with lowering cholesterol levels (BusinessWeek, 1/17/08) created the underlying environment in which Zetia and Vytorin could thrive.

The general message from drug company ads, doctors, and the press is that lowering "bad" cholesterol (or LDL) is key to reducing risks of heart disease, heart attacks, and death. The most potent weapons to reduce LDL are statins, which have become the best-selling medicines in history, with sales topping $27.8 billion in 2006. More than 18 million Americans take them. The drugs work by reducing the production of cholesterol in the liver.

Lower Not Always Better

But as doctors kept lowering the target for acceptable levels of LDL in the blood, statins weren't always potent enough. Plus, many Americans have come to believe that lower is always better. So in 2002, Schering-Plough introduced Zetia, which lowers cholesterol by another mechanism; it reduces absorption of cholesterol by the intestines. The company then combined Zetia with a statin originally sold by Merck (simvastatin) to create Vytorin, which was approved by the Food & Drug Administration in 2004.

Both Zetia and Vytorin were approved simply because they lower "bad" cholesterol, not because they were shown to actually reduce heart disease or prevent deaths. Both have been aggressively marketed. Since there still are doubts about whether cholesterol lowering really is a magic bullet, the companies began studies to try to show actual clinical benefits from the drugs.

One such study was the one presented at the recent ACC meeting. It gave patients with genetically high cholesterol either statins alone or Zetia plus a statin. Then doctors then examined the patients' arteries to see if the blood vessels were getting thicker, a sign of atherosclerosis.

The study quickly became controversial. The drugmakers delayed announcing the results, prompting scientific outrage and the threat of a congressional investigation. They finally released the data on Jan. 14. Adding Zetia to the statin did indeed reduce bad cholesterol more than the statin alone did. But that didn't improve the patients' arteries. In fact, the arteries thickened more when they took the combination than with the statin alone.

Both companies' stocks took a beating in January when the results came out. At the time, however, doctors urged caution. They pointed out there are many reasons the study is not definitive. The test that looks at the thickness of arteries may not predict the likelihood of future heart attacks, for instance. In addition, patients who have high cholesterol because of genetics may not be representative of the general population. Doctors weren't going to be stampeded into changing their prescribing by headlines in the press.

Waiting for the Big Trial

Since then, the facts haven't changed. What has changed is that the medical community has had more time to digest the results. And the Mar. 31 session on the trial at the ACC meeting was crucial. This was no longer the press raising doubts, but prominent physicians telling their peers not to prescribe the drugs. That's why analysts are rushing to reduce their estimates for the sales of Zetia and Vytorin, and to downgrade the stocks. One Schering-Plough sales rep posted a bitter message hoping the company would offer buyouts to the sales reps so that "we can rebuild our reputations and get another job with a more credible company."

The long-term prognosis, though, isn't clear. The crucial question is whether Zetia (alone or in combination) reduces heart disease and prevents death. The answer should come from a big trial dubbed Improve-It. If the trial results, due in four years, show that the drugs don't work, it would be the final nail in the coffin for Zetia—and a severe blow to the whole idea that aggressively lowering cholesterol is crucial.

Says LaRosa, "If Improve-It does not show clinical benefits, then we will have to say either that ezetimibe [Zetia] in some way promotes atherosclerosis, or that everything that we know about lowering LDL is wrong."

The Early Results Aren't Promising

The early signs from the Improve-It trial are not good. Schering-Plough recently announced it was expanding the number of patients in the study. "There is only one way to interpret that. It's negative," says analyst Krensavage. Adding more patients means that the beneficial effects of the drug may be smaller than the company expected, he says. To spot an effect, therefore, the trial has to have more patients.

Schering's Dr. Spiegel agrees that the Improve-It trial is more important than ever now. But he says that the expansion (from 12,500 patients to 18,000) is needed. "No one has seen the results, but we do know that the number of events [such as heart attacks] occurring is less than expected," he says. So adding patients will get the results more quickly, he says.

Krensavage expects Schering-Plough's stock will climb from the low levels reached on Mar. 31 (around $14), but perhaps not until the company trims costs to reflect the plunge in Zetia and Vytorin sales. "The concern is that earnings will be decimated," he explains. "But if you put a zero for sales of Vytorin and Zetia, the stock still is trading at 1.7 times revenue. It is worth at least three times revenue, which is $28 per share." The company will have to cut back expenses to compensate for the reduced sales, he says.

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