Merck Braces for Study on Medicines Worth $4 Billion a Year

Merck & Co.’s pills Zetia and Vytorin generated more than $21 billion for the company since they were introduced more than a decade ago. Next week, doctors will find out if they actually save lives in addition to lowering cholesterol.

The drugs, two of Merck’s best-sellers, were developed during a period of explosive growth for medicines that reduce cholesterol, fatty plaque that builds up in the arteries and leads to heart attacks and death. Zetia blocks its absorption in the stomach, a unique method. Vytorin combines Zetia with simvastatin, a proven older pill, to further cut cholesterol.

What’s unclear is whether by combining Zetia and generic simvastatin, Vytorin can also lead to fewer heart problems than just taking simvastatin by itself. A study of Vytorin slated for presentation at the American Heart Association meeting Nov. 17 in Chicago will be the first to provide answers.

A result that shows Vytorin has no additional benefit beyond simvastatin -- and hence that Zetia makes little difference -- could cut into sales of the drugs, while a positive outcome would help Merck eke out more revenue from them in their final years of patent protection.

While the drugs have been available for years, a new paradigm for using cardiovascular treatments has raised the bar for success. Instead of just proving they reduce cholesterol, guidelines released last year said only drugs shown to reduce heart attack, stroke and death should be prescribed, said Kim Williams, chief of cardiology at Rush University Medical Center in Chicago.

Everyone Waiting

“At this time, all of the randomized trial evidence that we have says that these drugs haven’t been shown to improve outcomes,” said Williams, president-elect of the American College of Cardiology, in a telephone interview. “This could change completely, or confirm what we have found. Everyone is waiting for these results to know if we should be using these drugs more, less or not at all.”

Merck fell less than 1 percent to $59.31 at the close in New York. The shares have gained 25 percent in the last year.

While it’s logical to think that lowering levels of a damaging compound like bad cholesterol would improve health, medicine is littered with failed therapies that defy common sense. The guidelines from the American Heart Association and the American College of Cardiology represented a sea change, reversing almost two decades of effort focused solely on cutting bad cholesterol to less than 100 milligrams per deciliter of blood.

‘Forgotten Drug?’

The new focus created a challenge for Whitehouse Station, New Jersey-based Merck, since the company didn’t have proof Vytorin and Zetia could benefit patients under the guidelines, said Stephen Kopecky, a cardiologist at the Mayo Clinic in Rochester, Minnesota. Companies must show their drugs work better than statins, a blockbuster class of medicines that includes simvastatin and generic versions of Pfizer Inc.’s Lipitor, once the best-selling drug of all time.

“Nothing has ever been shown to add anything to a statin, because they are such overwhelmingly good drugs,” Kopecky said. “If the study shows no benefit on heart attack, stroke and death, Zetia will be a forgotten drug. If it does lower those events, we’ll see a marked increase in its use.”

The results may be critical for doctors and patients trying to avert heart disease, the nation’s leading killer. For Merck, the study’s impact is more limited because the drugs lose patent protection, and thus their blockbuster status, by 2017. The company has cut jobs and overhauled its research operations as it works to develop new drugs for growth.

Singular, Januvia

Merck drugs like Singular for asthma and Januvia for diabetes have lost patent protection or are facing an onslaught of new competitors. Last weekend, the company said it was giving up on an attempt to treat hepatitis C with an ultra-short drug cocktail after an initial study yielded disappointing results.

Generic simvastatin was also once a major brand for Merck, known as Zocor. It and other statins have proven so effective at reducing heart problems that almost everyone with high cholesterol receives them. That means Merck’s Zetia can’t be tested alone -- it would be unethical for patients not to receive a statin. Vytorin is acceptable to test because it has both ingredients.

Zetia was Merck’s second-biggest drug last year, with sales of $2.7 billion. Vytorin was fifth, coming in with $1.6 billion. Together, that represented almost 10 percent of Merck’s total revenue. In the third quarter of this year, sales of the drugs fell 3 percent from a year earlier.

Little Value Left

“There’s not a lot of value left,” said John Boris, an analyst at SunTrust Banks Inc. in Atlanta, in a telephone interview. “It’s a declining franchise. You can’t grow it any further unless they come out with a favorable benefit, and that’s viewed as highly unlikely.”

Prescriptions had already slumped since 2008, when a study showed Vytorin didn’t slow clogging of the arteries better than simvastatin, which is available for pennies a pill. Prescription volume worsened after guidelines recommended against the drugs since simvastatin worked well enough on its own. Price increases helped make up the revenue difference for Merck, Boris said.

Officials from Merck and the lead investigators of the trial, dubbed Improve-It, declined interview requests to talk about the importance of the research. The company said Nov. 10 it learned the trial results and determined that the findings won’t require it to write down the drugs’ current value.

Doubled Size

Investigators will present one set of data on Nov. 17 that includes everyone from the study -- the most rigorous trial analysis. The following day, another segment of the findings will include only those who stayed in the study and continued taking the medications as directed, a less definitive approach. All the patients had already suffered a mild heart attack or chest pains and had cholesterol levels well above what was considered ideal.

Merck almost doubled the size of the study to 18,000 patients from 10,000 in 2008, a move the company said was needed to spot small though meaningful differences between the treatment approaches. The decision also delayed its completion date, originally slated for 2011.

Even with more patients, the findings aren’t likely to be significant between the two groups, Boris said. The addition of Zetia to simvastatin is only likely to reduce cholesterol levels by an additional 10 to 15 points, from an already low level of 80 milligrams per deciliter or less, he said.

Possible Surprise

While the drug is widely expected by researchers and investors to miss its goal of showing a benefit, there is increasing evidence that it may surprise, said Timothy Anderson, an analyst at Sanford C. Bernstein & Co. in New York. Academic researchers started laying the groundwork for a failed trial in recent months with speeches at medical conferences cautioning people not to overinterpret the results, Anderson wrote Nov. 11 in a note to clients.

“However, it increasingly appears to us that Improve-It might actually be positive,” he said. “There is likely to be plenty of discussion about how to interpret the findings, but the worst-case scenario will have been averted.”

The study may show a benefit for the Merck drugs that is statistically meaningful -- yet not enough to have a substantial benefit for patients, Anderson said. A positive outcome would reduce investors’ concerns that the study’s results will hurt Merck, though it’s unlikely to have a major impact on sales, he said.

“Results will likely be ‘too little too late’ to make a difference,” he said.

(An earlier version of this story corrected the hospital affiliation of Kim Williams in the fifth paragraph.)

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