The news came to Pfizer's chief scientist, Dr. John L. LaMattina, as he was showering at 7 a.m. on Saturday: The company's most promising experimental drug, intended to treat heart disease, caused an increase in deaths and heart problems.
Eighty-two people had died so far in a clinical trial, versus 51 people in the same trial who had not taken it.
Within hours, Pfizer, the world's largest drug maker, told more than 100 trial investigators to stop giving patients the drug, called torcetrapib. Shortly after 9 p.m. Saturday, Pfizer announced that it had pulled the plug on the medicine entirely, turning the company's nearly $1 billion investment in it into a total loss.
The abrupt decision to discontinue torcetrapib was a shocking disappointment for Pfizer and for people who suffer from heart disease. The drug, which has been in development since the early 1990s, raises so-called good cholesterol, and cardiologists had hoped it would reduce the buildup of plaques in blood vessels that can cause heart attacks. On Thursday, Pfizer's chief executive, Jeffrey B. Kindler, said publicly that the drug could be among the most important new developments for heart disease in decades and that the company hoped to get Food and Drug Administration approval for it in 2007.
"I'm terribly disappointed," said Dr. Steven E. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic and lead investigator of an earlier torcetrapib clinical trial. "This drug, if it worked, would probably have been the largest-selling pharmaceutical in history."
For people with heart disease, torcetrapib's failure means that progress might be slowing after two decades of substantial advances against the disease. Medicines to lower blood pressure and bad cholesterol are already effective and widely used, yet heart disease remains the biggest cause of death in the United States, killing 911,000 people in 2003, according to the American Heart Association.
Because the torcetrapib-related deaths occurred during a clinical trial, before the drug reached the market, Pfizer will not face the product liability lawsuits that have dogged Merck over its painkiller Vioxx. Patients in clinical trials must sign waivers confirming that they understand the risks that they face when they take unapproved medicines in clinical trials.
Scientists had seen torcetrapib as the vanguard of a new wave of medicines that would give physicians new ways to reduce heart disease by raising good cholesterol, following the success of medicines called statins, which work by inhibiting the production of so-called bad cholesterol. These drugs, which include Pfizer's Lipitor, are among the best-selling drugs in the world, with billions of dollars in annual sales.
Now Pfizer, and independent cardiologists, must determine whether torcetrapib's failure indicates that all medicines to raise good cholesterol will have similar problems, or if the problem was specifically related to some defect in torcetrapib.
For Pfizer, torcetrapib represented a potential blockbuster medicine that could have generated several billion dollars in sales annually. Those revenues are crucial for Pfizer, which is fighting to keep its revenues from declining as it loses patent protection on best-selling drugs such as Zoloft, an anti-depressant, and Zithromax, an antibiotic.
The problem comes at an especially bad time for the company, whose new chief executive, Kindler, heavily promoted torcetrapib's prospects, most recently Thursday at a conference for investors that Pfizer hosted at its giant research center in Groton, Conn.
Pfizer shares, which have been among the worst-performing of any major drug company over the last five years, will probably open sharply lower today.
Pfizer, which has 106,000 employees and about $50 billion in annual sales, is still highly profitable, but it will lose patent protection on its best-selling drugs over the next five years. And despite a $7 billion annual research budget its near-term pipeline of new drugs is nearly empty.
The Food and Drug Administration said it endorsed Pfizer's decision to end the trial and believed the company had acted properly. Torcetrapib's failure is disappointing, but developing new drugs is risky and difficult, said Dr. Robert Meyer, director of the agency's office of drug evaluation.
"Research is research," Meyer said. "If you knew the answer, you wouldn't be doing it."
Still, Pfizer's abrupt announcement will raise questions both on Wall Street and within the drug industry about the company's scientific prowess.
The discontinuation of torcetrapib is the second major failure in the Pfizer's development program in less than a week. On Tuesday, Pfizer said it would no longer collaborate with Akzo Nobel, a European company, on asenapine, a drug for schizophrenia that was also an important part of its new drug pipeline.
Finding new medicines is crucial for Pfizer, which in 2004 began to lose monopoly protection on several of its best-selling drugs, opening them to cheap generic competition. In 2010, Pfizer faces the loss of patent protection on Lipitor, the world's top-selling medicine, with $13 billion in annual sales.