The Quest to Boost Good Cholesterol

Dr. Steven Nissen, 61, has built a prominent career as chief cardiologist at the Cleveland Clinic. He has run trials that helped some lifesaving drugs win approval from the Food & Drug Administration. And he voiced doubts that proved prescient about other experimental medicines.

But Nissen's hunches don't always hit the mark. Twice, he tested new drugs designed to keep heart disease at bay by boosting "good cholesterol," and giant drugmaker Pfizer bet upwards of $2 billion that they would succeed. The strategy may yet bear fruit, but neither of these two drugs made it onto the market—leaving Pfizer with no heart medicine to replace its current $11.4 billion blockbuster, Lipitor, which faces generic competition in 2011.

Undaunted, Nissen is now running clinical trials on a third treatment—this one from Resverlogix, a small Canadian company with no commercial products. If its medicine, RVX-208, succeeds in reversing buildup of harmful plaque in blood vessels, it may grab a "substantial" portion of the $35 billion market for cholesterol drugs, says Simos Simeonidis, an analyst with Rodman & Renshaw in New York.

Nissen says he's "cautious but optimistic" about RVX-208. "Hope springs eternal," he says. "We need to keep trying to find an HDL-raising strategy that works."

Lipitor and RVX-208 work in very different ways. The former belongs to a class of drugs called statins, which lower production of so-called bad cholesterol, or LDL, by blocking an enzyme in the liver. RVX-208 helps the body make more of the good kind of cholesterol, which excels at removing its evil twin from plaque in arteries.

Studies have shown that people with naturally elevated HDL are less likely to suffer heart attacks or die from cardiovascular disease. Nissen and Resverlogix are hoping that artificially raising HDL will have the same effect. It's not a sure bet. People who take the B vitamin niacin, for example, often show higher HDL levels, but it's not clear this cuts heart-attack risk, says Stephen Kopecky, a cardiologist at the Mayo Clinic in Rochester, Minn.

Heart disease is the leading cause of mortality in the U.S., resulting in 632,000 deaths a year, according to the Centers for Disease Control & Prevention in Atlanta. In many cases the culprit is the buildup of fat, cholesterol, calcium, and other substances—collectively known as plaque—in blood vessels that supply oxygen to the heart.

Nissen is determined to find new weapons to fight this process, in part because LDL-zapping statin drugs are an imperfect fix. They only reduce the risk of heart attack and stroke by 25% to 35%, according to Nissen, who has no financial stake in Resverlogix. "We could put statins in the water supply and heart disease would still be the leading cause of death in the developed world," he says.

Yet the track record for HDL boosters is dismal. In 2004, Pfizer paid $1.3 billion to acquire Esperion Therapeutics. The prize was an HDL-boosting drug similar to RVX-208. A report Nissen published in 2003 showed the medicine reduced plaque in early-stage testing. But it proved difficult to produce, and Pfizer ended up selling it to another drugmaker last December for just $10 million, plus additional payments should the drug hit certain clinical and sales milestones.

Pfizer also spent $1 billion on the compound torcetrapib, designed to raise good cholesterol by blocking an enzyme that breaks it down. Pfizer at one point projected $13 billion in annual sales for torcetrapib as the successor to Lipitor. But it halted development of the drug in December 2006 when results showed that, far from lowering the risk of death, the drug raised it by 60%. Pfizer shares plummeted the first trading day after the announcement, wiping out $21 billion in market value. It was a blow for the team at the Cleveland Clinic, too. "Nissen kind of got burned," says Kopecky.

Early trials of RVX-208 last summer went well, and a second phase of testing has begun involving about 400 patients. If these trials succeed, CEO Donald McCaffrey says he'll start a third and final round of testing, aiming to file for regulatory approval in 2015.

Resverlogix is in "detailed discussions" with several companies seeking to partner or license its medicine, says McCaffrey, though he declines to give names. Simeonidis, the analyst, says Pfizer, Merck (MRK), Novartis (NVS), and Roche are all plausible collaborators—or buyers. Prospective partners "may want to wait to see more data," he says. "Then again, there's such a huge potential they may be willing to take a flyer."

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