In fight vs. cholesterol, closing in on a superpill
GROTON, Conn. -- The way we think about heart disease and cholesterol, and the drugs that can control them, got a powerful jolt last week.
New research showed that drugs that sharply lower levels of LDL, or bad cholesterol, may benefit millions more people than are taking them now.
But largely out of sight, researchers have been nearing a breakthrough on the next frontier in fighting heart disease -- a drug that raises good cholesterol.
Called HDL, for high-density lipoprotein, good cholesterol helps the body eliminate bad cholesterol and can clear out clogged arteries.
"We're very encouraged that if we can raise HDL, we will be able to deter cardiovascular disease," said H. Bryan Brewer Jr., a researcher at the National Institutes of Health.
Pressing on after many of the world's other big drug companies had given up,
Pfizer makes the world's best-selling prescription cholesterol drug, Lipitor. In what could be a marketing and medical coup, the company hopes to combine its two drugs into one superpill that would simultaneously lower bad cholesterol and raise the good.
"There is a lot of excitement, because people are starting to hear that Pfizer has this compound that it considers one of its top drugs for the future," said Margaret Brousseau, an assistant professor at Tufts School of Medicine who has worked on early clinical trials for the drug. "There certainly is a need" for a drug that raises good cholesterol.
Although Pfizer appears to have the lead in this research, competition is beginning to heat up. A Japanese company, Japan Tobacco Inc., is targeting the same protein as Pfizer's drug and has completed initial clinical trials.
Niacin, a vitamin that raises good cholesterol, though slightly, is marketed by Nos Pharmaceuticals Inc. Nos has time-released versions of the vitamin that it says are the only FDA-approved products to enhance HDL.
Pfizer's advantage is that its compound appears to raise good cholesterol by a larger percentage, Brousseau said. "They're furthest along," she said. "There isn't really an agent currently available that raises HDL significantly."
Americans are familiar with the dangers of bad cholesterol, thanks to hundreds of millions of dollars of advertising for such drugs as Lipitor. That drug reduces the amount of low-density lipoprotein, or LDL, in the bloodstream. LDL contributes to the buildup of plaque in arteries, which can cause heart disease. A major study released last week suggested that Lipitor is so effective that millions more Americans than previously thought would benefit by taking the drug.
In the 1980s, medical researchers at Columbia University found a key clue about good cholesterol. They discovered that some Japanese families with a deficiency in a specific protein called CETP had high levels of good cholesterol in their bloodstreams and were less likely to suffer from heart disease. If companies could find a drug to suppress that protein, theoretically they could raise good cholesterol by artificial means.
At Pfizer, the search for a drug to raise good cholesterol began more than a decade ago at the company's sprawling laboratory campus on the east bank of the Thames River in Groton. Pfizer researchers screened hundreds of compounds and found several candidates. But most were either too toxic or not powerful enough. One early version was so weak that a patient would have to swallow a football-sized pill to benefit.
Stumped, Pfizer was preparing to pull the plug on its project. Other companies had already quit.
"I never told the team to stop, but I certainly questioned how much longer we could afford to continue," said Thomas Beyer, Pfizer's vice president of cardiovascular metabolic disease discovery. "No matter how compelling the science is, if you can't transfer that to a pill, you're wasting your time."
But before giving up for good, Pfizer assigned chemist Roger Ruggeri, then 31, to investigate avenues that had initially seemed less promising. Ruggeri methodically swapped atoms on the target molecule, mixing batches of chemicals, and then running tests to measure the new molecules' effect on CETP. The work was similar to a game of Battleship, where a player shoots blindly in a grid pattern, hoping to hit something that will guide a tighter search.
Ruggeri said he saw the task as scut work and not promising. "I was not looking fondly on this assignment, but I was just out of grad school and postdoc, so I tried very hard and was very much wanting to get in and make something happen," he said.
The breakthrough came in August 1994, a year after Ruggeri started working on the project. One morning a protein test showed that introducing a new atom dramatically boosted the molecule's potency. The numbers were so good that at first, no one at Pfizer believed them.
"It was such a profound change in activity that we immediately thought it had to be wrong," Ruggeri said. "We got new material, and we redid the test very carefully, and it happened again. It was incredibly elating."
A team leader returned from his summer vacation to find a copy of the latest test results taped to his computer terminal. He thought it was a joke.
Even after the positive test results on the compound, called torcetrapib, were proven, the researchers had to figure out a way to deliver the experimental drug into the bloodstream. Biologist Ronald Clark found the right medium by experimenting with olive oil. Next came tests in mice and monkeys. Pfizer went public with its discovery in 1997, when it filed a patent for the new compound.
"It wasn't until 1999 that we finally tested it in man," Clark said.
Early clinical trials for torcetrapib show that Pfizer's new treatment raises good cholesterol between 16 percent and 91 percent, the company said. Part of the gamble for Pfizer is whether the trials will definitively prove that using its drug to raise good cholesterol will reduce the incidence of heart attacks and disease. So far, the approach holds promise. "Both the animal studies and the epidemiological studies suggest that raising good cholesterol will be effective," said Brewer, the NIH researcher. One potential downside is the possibility that raising good cholesterol too much could worsen buildup in arteries, he said. Finding the right balance is key, Brewer added.
At Pfizer, Beyer said the research remains risky despite its promise. The company is testing the drug in double-blind phase III clinical trials -- which compare the drug's effectiveness against a placebo. A phase III trial, if successful, is the last step before a company submits an application for a drug's approval to the FDA.
"This is still a billion-dollar gamble," Beyer said.
Christopher Rowland can be reached at crowland@globe.com.
