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Big Loss for Pfizer Big Gain for Heart Patients

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The New York Times
December 4, 2006

The news came to Pfizer’s chief scientist, Dr. John L. LaMattina, as he was showering at 7 a.m. Saturday: the company’s most promising experimental drug, intended to treat heart disease, actually 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. Just last 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 may 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. Merck withdrew Vioxx, a best-selling arthritis drug, after evidence emerged that it could cause heart strokes and heart attacks. Patients in clinical trials must sign waivers confirming that they understand the risks 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, drugs like Lipitor that 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 tens of 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.

Pfizer had been three years into a late-phase clinical trial of torcetrapib involving 15,000 patients when Dr. LaMattina, the Pfizer scientist, fielded the call early on Saturday. Dr. Steven W. Ryder, a senior Pfizer scientist overseeing the development of the company’s most important experimental medicine, told Dr. LaMattina that the independent researchers monitoring the torcetrapib trial — who were the only ones privy to the results — had called Friday evening to recommend that it be halted.

The independent monitors called regularly on the first of each month to give a progress report. This time, however, the results stacked up irretrievably against the drug’s safety, and the monitors had determined that the numbers could not possibly reverse themselves in torcetrapib’s favor.

Not only were there 31 more deaths among the people taking torcetrapib, but similar discrepancies were seen in the number of patients suffering heart failure and other problems, giving the company no choice but to stop development.

Dr. LaMattina quickly called Jeffrey B. Kindler, Pfizer’s chief executive, to tell him that the researchers thought the trial should be stopped. By 8 a.m., Pfizer’s senior leaders were talking over the results on a conference call.

Less than three hours later, the executives decided to stop the trial. By Saturday afternoon, the company began to notify the 100 hospitals and medical clinics on three continents that were running it. That night Pfizer put out a press release announcing the news.

For Pfizer, torcetrapib represented a potential blockbuster medicine that could generate 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, Mr. Kindler, heavily promoted torcetrapib’s prospects, most recently on 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.

Pfizer’s decision to abandon torcetrapib throws into question the theory that using drugs to raise good cholesterol, known as HDL, will benefit patients. Some scientists worry that the drugs cause the body to produce a form of HDL that may actually be harmful.

The problem, though, could be specifically related to a defect in torcetrapib, which is known to raise blood pressure, a serious side effect for a heart medicine. Other experimental drugs that raise good cholesterol, including two in very early stage clinical development from Pfizer and another from Roche, do not seem to have similar effects.

As is customary, Pfizer had hired a board of independent scientists to monitor the torcetrapib trial, which had been scheduled to end in 2009. The trial, called Illuminate, compared 7,500 patients taking a combination of torcetrapib and Lipitor, Pfizer’s best-selling statin, with a similar number of patients taking only Lipitor. The patients had diabetes or cardiovascular disease, making them more likely to have heart attacks or strokes than the general population.

Each month, the independent scientists reviewed data from the trial comparing the effects of the two treatments. To protect the trial’s integrity, people inside Pfizer were not allowed to see the data.
Pfizer had hoped the trial would show that people taking the combination pill would be significantly less likely to suffer deaths or heart problems than those taking Lipitor alone. Instead, it showed the opposite.
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,” Dr. Meyer said. “If you knew the answer, you wouldn’t be doing it.”

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.

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.

Michael Krensavage, an analyst at Raymond James, a financial services firm, said that torcetrapib’s failure would force Pfizer to accelerate its plans to lay off employees and reduce costs. “More job cuts are on the way,” he said.

Mr. Kindler said he was surprised and disappointed at the findings. Torcetrapib’s failure highlights the risks that drug makers face as they try to develop new and important medicines, he said in a telephone interview yesterday. “This is a very high-risk business,” he said.

Still, the company is financially strong and expects to report higher profit in both 2007 and 2008, mainly due to cost-cutting, Mr. Kindler said.

Dr. Meyer of the F.D.A. said that torcetrapib’s failure did not mean that similar medicines under developed should be abandoned.

“If another drug raised HDL but didn’t affect blood pressure, that might be suitable,” Dr Meyer said. “The finding certainly raises concerns and would make everybody appropriately cautious, but it’s not enough to say this class is at a dead end.”

Gardiner Harris contributed reporting from Washington.

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