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Discovering How a Cholesterol Drug Works

Company researchers uncover the mystery after the fact

THURSDAY, Feb. 19, 2004 (HealthDayNews) -- In a twist on the typical story of drug development, Schering-Plough scientists report they have finally figured out the secret to the success of their cholesterol-lowering drug.

The standard scientific saga starts with a discovery that leads to development of a drug. But in this case, development, testing and marketing of the drug, ezetimibe, came almost a decade before the company's researchers figured out how it does its job.

Ezetimibe is marketed as Zetia by Schering-Plough Pharmaceuticals and Merck & Co. More than 3.5 million prescriptions have been filled for the drug since it was approved by the U.S. Food and Drug Administration in November 2002.

Ezetimibe works in a different way than statins, the best-known cholesterol-lowering medications. While statins prevent the production of cholesterol, ezetimibe inhibits its absorption by the intestines.

Now, a report in the Feb. 20 issue of Science says the key to ezetimibe's success is a protein, named NPC1L1, which plays a leading role in that cholesterol absorption.

"This is an important step in understanding that molecular process," says Michael Graziano, senior director of cardiovascular/metabolic research at Schering-Plough. "With further research, we hope we can identify other pathways of cholesterol absorption."

It is also a fascinating illustration of the power of new knowledge about genes, says Dr. Christie Ballantyne, director of the Center for Cardiovascular Disease Prevention at the Baylor College of Medicine. He has worked on ezetimibe for years.

"This was a genomic approach that was not even dreamed about 10 years ago," Ballantyne notes.

That was when Schering-Plough researchers first began looking for drugs that might lower cholesterol levels by stepping up its destruction in the intestines.

At first, it was a guessing process, says Harry Davis, a distinguished research fellow at Schering-Plough.

"We looked for inhibitors of cholesterol absorption, and we found a promising compound," he says. "Then we studied related compounds in cholesterol-fed hamsters."

Laboratory work eventually produced a compound that did the job well enough to lead to ezetimibe, Davis says, but a big theoretical hole remained.

"We were lacking a biochemical target," he says. "We have been searching for this biochemical target since then."

The search eventually centered on intestinal cells called enterocytes, because they were believed to be the ones that actually absorbed cholesterol, Graziano says. He and his colleagues began looking for candidate genes for a cholesterol-related protein.

They found that while the list of genes in the heart and lung was long, the list for genes in the intestine was short. "So, we constructed our own library of genes," Graziano says.

Eventually they came up with NPC1L1, a protein that had been described by other researchers but had no known function. Mice bred to lack the gene for NPC1L1 absorbed 70 percent less cholesterol from their diet than did normal mice.

Now the researchers are working on other proteins in the cholesterol-absorption pathway that might be targets for other drugs.

Meanwhile, Schering-Plough and Merck have filed for FDA approval of a single pill that would combine ezetimibe with a statin and lower cholesterol at both ends.

"It is interesting to watch the evolution of science in combination with therapeutics," Ballantyne says.

More information

A review of cholesterol-lowering drugs is given by the American Heart Association, while the National Library of Medicine has more on high cholesterol.

SOURCES: Christie Ballantyne, M.D., director, Center for Cardiovascular Disease Prevention, Baylor College of Medicine, Houston; Michael Graziano, Ph.D., senior director, cardiovascular/metabolic research, and Harry Davis, Ph.D., distinguished research fellow, both of Schering-Plough Research Institute, Kenilworth, N.J.; Feb. 20, 2004, Science
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