Staying the Course

Merck managers typically keep details of their R&D protocols close to the vest, but at their annual investors meeting last week, they confirmed rumors that they too are developing a CETP-inhibitor, the new class of anti-cholesterol drug whose fate has darkened since Pfizer pulled its much-hyped torceptrapib from Phase III trials two weeks ago.

In announcing that Merck had entered the CETP-blocker race, the president of its research laboratories, Peter Kim, was uncharacteristically blunt about its prospects. "There is no question that there remain doubts, and that those doubts have been reinforced," he said. "We--like everyone else now--are waiting to see what additional information comes in." The company's MK-0859 has just completed an eight-week Phase IIb trial that showed no cardiovascular or blood pressure side effects.

When pressed by an analyst, Kim acknowledged that he was one of the early skeptics of CETP-inhibitors. CETP, or cholesterol ester transfer protein, is involved in converting "good" HDL cholesterol into "bad" LDL cholesterol. But studies suggest that it also has a cardio-protective function, and that inhibiting it might produce defective HDL. Pfzer's large scale study--which saw a 50 percent greater mortality rate when torceptrapib was combined with Lipitor (atorvastatin)--has raised red flags among researchers, who now fear but that the entire approach causes more harm than good.

"You really have a big unknown," Kim said. "It is a field that is moving forward in terms of the characterization of HDL cells that are produced." Pfizer had been criticized for focusing its science on torceptrapib's ability to raise HDL rather than outcome studies on whether the drug could prevent heart attacks.

Yet with the statin market crowded with brand and generic products, companies are still banking on HDL to breathe new life into the category.

"Raising HDL is a big field," said Allan Haberman, principal of Haberman Associates, a consulting firm that specializes in science and technology strategy. "People are certainly trying to do something beyond niacin," a popular HDL-raiser.

Other leading CETP-inhibitor contenders include Roche, which is developing JTT705, and Avant Immunotherapeutics, which has an anti-CETP vaccine on deck, according to Haberman.

Another approach to raising HDL involves the protein APOA-1, a major component of HDL. Pfizer-owned biotech Esperion Therapeutics is working on a recombinant version, but trials have been stalled by the expense and difficulty of making the large-molecule product. Novartis and Bruin are collaborating on a Phase I small-molecule drug that uses amino acid peptides to mimic APOA-1's effect.

All of these programs are likely to continue--cautiously--because of scant understanding of the category. "People have been arguing about this for some time," Kim said. "We have no idea what target is being hit by torceptrapib. And when you don't know what's being hit, all bets are off."