Vytorin: A Setback for Merck and Schering

The pharma giants thought their jointly marketed drug could be proved a stronger cholesterol fighter. But a second clinical trial also yields poor results

Merck (MRK) and Schering-Plough (SGP) are taking another big hit. The two drug giants once thought they had a blockbuster in their jointly marketed drug, Vytorin. The drug combines two cholesterol-lowering medicines. One is in a class of drugs called statins, a cousin of Lipitor. The other works in a different way, blocking absorption of cholesterol from the gut.

Vytorin became a $2 billion drug in 2007. But then came some bad news. Doctors know that statins alone help prevent heart attacks in people with heart disease. The hope was that adding the second drug to a statin, which together further lowers cholesterol, would add to the benefit.

It didn't turn out that way in a clinical trial that made headlines in January. The trial showed no benefit at all to the drug combination, compared with a statin alone. And now comes another damaging blow. On July 21 the companies released results of a second trial, which was designed to see if aggressive cholesterol-lowering, using Vytorin, was beneficial to people with partial blockage of one of their heart valves.

The answer: No.

Cancer Risk?

The trial did show a small benefit: fewer heart problems (such as the need for bypass surgery) in patients getting the drug. But the improvements were no different from what would be expected from a statin alone.

More worrisome, there was a statistically significant increase in cancer in patients taking Vytorin. "No one would have expected this result," says Dr. Steven Nissen, chairman of the Cardiovascular Medicine Dept. at the Cleveland Clinic Foundation. Of the 1,873 patients in the trial, which lasted for four years, 39 taking Vytorin died of cancer, compared with 23 on a placebo.

The companies did everything possible to downplay the increase in cancer. On the July 21 conference call announcing the results, they brought in Sir Richard Peto, a noted Oxford University epidemiologist, who had helped pin down the link between tobacco and cancer. Peto spoke about his analysis of the data. He argued that the drug could not be responsible for the increased rate of cancer, for these reasons: The increase didn't go much beyond chance. It included a variety of cancers, which wouldn't be expected if there had been one single cause. Carcinogens don't usually cause cancer that quickly. And there's no known mechanism.

But Nissen, for one, isn't convinced. If the study had shown a statistically significant benefit, the companies and their public relations teams would be falling all over themselves to trumpet the drug as a great advance. "When a study shows statistically significant harm, it deserves the same attention," he says.

The Shares Take a Dive

The bottom line: "We just don't have evidence here for a benefit for Vytorin," Nissen says. "Let's stick with the statins, because we know they work."

What does this mean for the drug—and the companies? First, don't make too much of Vytorin's failure to help the patients with partial blockage of their heart valves (a condition called aortic stenosis). Most cardiologists thought the idea that the drug worked for those patients was a long shot, anyway. Second, while the cancer news will make headlines, it won't convince most doctors that the drug is unsafe.

But the news won't help. Sales of Vytorin nosed down dramatically after Mar. 30, when prominent clinicians at a scientific meeting advised their fellow doctors not to use the drug (BusinessWeek.com, 3/31/08).

The new study is expected to take another, smaller bite out of Vytorin sales. And it makes even more crucial another trial, dubbed IMPROVE-IT, now under way. IMPROVE-IT will either put the final nail in the coffin of the drug or rescue it. But its results aren't coming until 2012—and the fact that researchers recently increased the size of the trial was taken as a bad sign.

Wall Street, certainly, was not happy with the latest news. On July 21, Schering's stock plunged nearly 12%, to 18.35. Merck was off 6%, to 35.33.

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