Torcetrapib setback raises questions for Pfizer

Pfizer said it will halt all clinical trials for torcetrapib, the most highly vaunted drug in its pipeline, due to safety concerns. The crushing blow will force the firm to accelerate its cost-cutting measures, stock repurchases and acquisition activity and raises questions about the future of the company and the safety of other drugs in its class, analysts said. Pfizer said an independent review board monitoring studies of torcetrapib found an unexpected number of deaths—82 patients taking torcetrapib and Lipitor had died, compared with 51 taking only Lipitor. The FDA confirmed that the board notified Pfizer of the mortality finding early Saturday morning and that Pfizer told the agency its plan to halt the drug's development program later that day. Pfizer had been counting on torcetrapib to make up for several patent expirations, including the patent on the cholesterol-lowering drug Lipitor, Pfizer’s top-selling product with $12 billion in annual sales. Lipitor could lose patent protection as early as 2010. In a statement following the torcetrapib announcement, CEO Jeffrey Kindler said Pfizer’s plan for transformation will be expedited. Although he didn’t give any specifics, those plans could mean more belt-tightening. “We have begun a transformation that has been accelerated by this event. We’ve (already) announced the first step with a reduction in our sales force,” Kindler said during an appearance on the cable television network CNBC yesterday. Last week, Pfizer said it would cut its sales force by 20%, or 2,200 jobs. Barbara Ryan, an analyst with Deutsche Bank, told the Associated Press Pfizer may have to lay off as many as 10,000 people in the near future—about 10% of its workforce. Ryan added that she expects Pfizer to hike its annual dividend from 96 cents to $1.10 per share in the next few weeks in the hopes of putting a floor on the stock, which was battered by investors yesterday. Shares of Pfizer fell $2.96, or 10.6% to close Monday at $24.90 on the New York Stock Exchange. Torcetrapib was designed to raise HDL or “good” cholesterol. It was being tested for use in conjunction with Lipitor, and the company had hoped to file for approval in the second half of 2007. But it had a side effect of raising blood pressure. In a presentation to analysts last Thursday, Pfizer’s R&D chief, John LaMattina, spoke optimistically about torcetrapib, saying the ability to raise HDL, while lowering LDL cholesterol when given in combination with Lipitor, “should overwhelm” the blood pressure elevation. Pfizer officials promised investors a “broad and very diversified stream of new products in development” that will produce four new products a year beginning in 2011. The centerpiece was clearly torcetrapib, which the company hailed as “the most important new development in cardiovascular medicine in years.” “The R&D day was scheduled many, many months ago,” Kindler said during his CNBC appearance. “It was an opportunity to show our entire pipeline. We did talk about torcetrapib that day and we did express the enthusiasm that we and, candidly, scientists had for the promise that this treatment provided. Saturday morning, we received the very unexpected and surprising news that the independent safety monitoring board that was reviewing the trials had concluded that the trials had to be stopped. We did not anticipate that at all and we are very disappointed.” Besides the deaths, patients taking torcetrapib also showed an increase in angina, congestive heart failure and procedures to clear clogged arteries. The axing of torcetrapib also calls into question other drugs in the same class, known as CETP inhibitors. Last week, Pfizer mentioned two backup compounds to torcetrapib in its pipeline that haven’t displayed the blood pressure side effect. Roche is developing one slated for approval in 2009, and Merck is said to have one in its pipeline. Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, told the AP it is too soon to pronounce the entire class dangerous or if torcetrapib’s problems were unique. Pfizer said it still hopes to bring six new products to the market by 2010. To do that, it will have to supplement its pipeline. Kindler said that will mean aggressively pursuing business development and licensing efforts. Meanwhile, dual therapy for raising good cholesterol while lowering the bad—the same approach Pfizer was testing before it discontinued torcetrapib—appears to still be a viable treatment. Niaspan, marketed by Kos Pharmaceuticals, can do what torcetrapib aimed to. It raises good cholesterol without serious risks, and a large federal study is testing it with simvastatin, the active ingredient in generic Zocor for lowering bad cholesterol. Niaspan is an extended-release version of niacin, a type of B vitamin. The drug’s only side effect is flushing, a hot prickly sensation. It was launched in 1997. While torcetrapib’s demise doesn’t spell the end of dual cholesterol therapy, it may mean consumers face a delay in getting a new medicine that avoids flushing, although doctors say the effect can be minimized. Kos says it’s developing a modified version to prevent it. Merck is also testing an extended-release niacin combined with a prostaglandin blocker, a drug to prevent some of the flushing. The drug is designed to boost HDL. Drugs called fibrates also raise HDL, but they carry risks when combined with statins, according to the report. Some newer diabetes drugs may boost HDL, too. The Cleveland Clinic’s Dr. Steven Nissen, who led one recent study of torcetrapib, will present results of other studies on the Pfizer drug that may shed light on whether it was uniquely dangerous. “My suspicion is torcetrapib failed because of its mechanism of action,” Dr. Greg Brown of the University of Washington in Seattle told the AP. Brown is leading the big federal study of Niaspan plus the statin Zocor. Pfizer’s setback with the failed drug raises the safety bar for new agents to a very high level, another physician who has led a study of Niaspan plus a statin told the AP, “because deaths and heart attacks were significantly greater among those taking [it].”