FDA Rejects Merck's Cordaptive

Given the cholesterol-lowering drug's modest test results and unknown long-term effects, rejection by regulators may not be that surprising

by John Carey

The Food & Drug Administration on Apr. 28 rejected one of Merck's (MRK) biggest hopes for a new blockbuster drug, a cholesterol-lowering medicine call Cordaptive. Analysts who had been predicting that the drug could easily top $1 billion in sales were surprised by the news that the agency sent a "Not Approved" letter to the company. The decision sent Merck shares sinking 10% to 37.33 in afternoon trading Apr. 29 on the New York Stock Exchange.

However, the FDA's ruling should not have been such a surprise. Here's why: The guts of Cordaptive are actually a substance called niacin. Most of us know it as a type of Vitamin B. It is nothing fancy. It's found in many multivitamins, as well as foods like milk, poultry, fish, nuts, and eggs. It helps keep the body running smoothly.

In high doses, though, niacin also lowers "bad" cholesterol and raises "good" cholesterol. That's why drugmakers have turned this simple vitamin into a pill, selling it under such names as Niaspan, which is sold by Abbott Laboratories (ABT). Abbott has even bundled niacin with a standard cholesterol-lowering drug, known as a statin, to create a combination drug named Simcor.

Fighting Side Effects

But high doses of niacin have side effects; lots of them. They include stomach upset, headache, and tingling sensations. The most problematic one, which leads many people to stop taking the drug, is flushing of the skin. The effect can be quite dramatic. The skin turns red. It often itches or tingles. The severity, frequency, and duration of this flushing drive people away before they can get up to the recommended dose of niacin, explains Dr. Michael Koren, medical director of the Jacksonville Center for Clinical Research in Florida.

Merck researchers asked themselves, Could they reduce this flushing side effect? They figured out that niacin causes a hormone, prostaglandin, to flow to the skin. There, prostaglandin tells blood vessels to enlarge by attaching to receptors on the cells. More blood flows in, making the skin red.

Could Merck scientists tone down that effect? In a bit of clever biochemistry, the company researchers created a chemical that homes in on precisely the same receptor target as prostaglandin. As a result, the blood vessels don't get the signal to dilate. The flushing is significantly reduced. They called the chemical laropiprant. Merck figured that combining niacin with laropiprant would unleash the beneficial effects of niacin, while reducing the flushing side effect. But one of the strikes against the combination drug, dubbed Cordaptive, was that the positive results were modest.

In trials reported Mar. 31 at the American College of Cardiology meeting in Chicago, 78% of patients taking niacin alone (Abbott's drug Niaspan) had episodes of moderate to very severe flushing. Patients taking Cordaptive fared better, but not dramatically better; 53.3% had moderate or worse flushing.

Risk-Benefit Calculation

Merck, which is based in Whitehouse Station, N.J., tried to spin the results as very positive. "Significantly fewer patients on Cordaptive discontinued therapy due to flushing compared to patients on Niaspan," said one press release. But again, the difference was modest. Twelve percent of those on niacin alone stopped taking the drug because of the side effect, compared to 7% on Merck's drug.

The FDA hasn't revealed exactly why it rejected the drug. But it's not hard to speculate about the reason. The effect of adding laropiprant to niacin to reduce flushing was modest. In many patients, just taking aspirin does as well.

Balance that modest effect with the many unknowns about laropiprant. It's a new chemical. No one knows what its long-term effects on the body are. It blocks a hormone, prostaglandin, that has many important functions in the body. Merck scientists say they are convinced that the substance only acts in the skin, and only to block this one effect—flushing. But the sad lesson from drug development is that few drugs are quite so precise. Unless laropiprant is given to thousands of people for years, we'll never know whether there are dangers lurking in long-term use. If the chemical was life-saving, then those long trials might be worth it. But since it only modestly dampens a nonthreatening side effect, it's easy see why FDA regulators would think the risks far outweigh the benefits.

Cholesterol Drugs Under Fire

The decision also comes at a time when the very idea of cholesterol-lowering is under increasing scientific attack. Yes, doctors know that the statin class of cholesterol-lowering drugs, like Lipitor, do prevent heart disease and heart attacks. But there's growing evidence that a big chunk of the benefits of statins comes from reducing inflammation (BusinessWeek.com, 4/15/08). Also, trials with drugs that lower cholesterol by mechanisms other than statins, such as Zetia, marketed by Merck and Schering-Plough (SGP), show fewer benefits than expected (BusinessWeek.com, 3/31/08).

Add it all up and the FDA's decision shouldn't be seen as coming out of the blue. Cordaptive offers no big improvement over niacin alone—while introducing a new, unknown risk. And even the benefits of niacin's effect on cholesterol may not be that big.

Merck is understandably upset. "We plan to meet with the FDA and to submit additional information to enable the agency to further evaluate the benefit/risk profile of MK-0524A [or Cordaptive]," said Peter Kim, executive vice-president and president of Merck Research Laboratories, in a statement. But it may be a hard sell with the agency.

Carey is a senior correspondent for BusinessWeek in Washington .