Pfizer Makes $800 Million Bid To Reshape Heart-Care Market
Drug Giant Pins Its Hopes On Treatment That Boosts Levels of Good Cholesterol
By SCOTT HENSLEY and RON WINSLOW
Staff Reporters of THE WALL STREET JOURNAL
April 8, 2004; Page A1
Pfizer Inc. has climbed to the top of the global pharmaceutical industry on the shoulders of its blockbuster drug Lipitor, which lowers bad cholesterol. The company's hopes of staying there rest largely on a yet-to-be-proven pill that raises good cholesterol.
The drug giant is betting $800 million on human tests to find out if its experimental medicine torcetrapib will successfully fight disease in heart patients' arteries by increasing levels of HDL cholesterol. That sum is far more than Pfizer, or any company, has ever committed to spend on a clinical test to win regulatory approval, company executives say.
The big investment reflects the cost of Pfizer's aggressive new strategy for testing the drug, which includes sophisticated imaging to measure plaques within artery walls, and the company's high hopes for the medicine. If the tests ultimately show that the drug leads over time to fewer heart attacks and deaths, then torcetrapib is almost certain to emerge as a major new weapon in the battle against cardiovascular disease.
Today, doctors, patients and investors get the first significant peek at the potential for torcetrapib in a study appearing in the New England Journal of Medicine. The results are striking. Taken daily for a month, the drug boosted HDL, or good cholesterol, by 46%. When combined with Lipitor, the results were more dramatic: HDL rose 61%. Almost as tantalizing, LDL, the bad cholesterol, fell an additional 17% beyond the reduction achieved by Lipitor alone. Side effects in the study of 19 patients were mild.
The study was funded by Pfizer, a branch of the National Institutes of Health, the University of Pennsylvania and New England Medical Center. The appearance of the results in the prestigious, peer-reviewed journal shines a spotlight on the first pill that appears to significantly increase HDL. "There is little question that the drug raises HDL better than anything we have currently," says Daniel J. Rader, director of preventive cardiology at University of Pennsylvania School of Medicine, Philadelphia, and principal investigator for the study.
The much more important question is whether that matters. That's a question the $800 million tests, several times more expensive than the typical clinical trial, are designed to answer. HDL serves as the body's principal garbage truck for hauling away bad cholesterol, the main ingredient in artery plaques that rupture to cause heart attacks. But how HDL works is complicated, and it remains uncertain whether increasing HDL with a drug improves heart health. So far, "there is precious little evidence that raising HDL has a clinical benefit," Dr. Rader says.
Pfizer is betting that its studies will provide that evidence and persuade the Food and Drug Administration to approve the drug. The company can scarcely afford to lose the wager. Already, it faces growing challenges to its $10 billion Lipitor franchise from drug giants such as AstraZeneca PLC. Meanwhile some of its other big drugs -- antibiotic Zithromax and antidepressant Zoloft -- will soon lose patent protection and face competition from generics. If torcetrapib passes muster, Pfizer will take a highly unusual step to protect its franchises: The company intends to test and sell the new drug only in combination with Lipitor. Patients who use another cholesterol-lowering drug won't have access to torcetrapib.
Pfizer isn't the only company under pressure. Some of the industry's most popular cholesterol-lowering drugs will soon lose patent protection, threatening a $22 billion global market. Pfizer's push for an HDL treatment is part of a big scramble for new remedies that can make headway against cardiovascular disease, the world's leading killer, while fueling a new decade of earnings growth.
Despite the question marks around HDL therapy, many heart experts and rival companies agree with Pfizer that HDL is one of the next frontiers in heart disease. Until now, doctors have focused on lowering bad cholesterol using Lipitor and its rivals. In the past decade, these drugs, known as statins, have transformed cardiology, reducing heart attacks and deaths while becoming the best-selling medicines in the world.
Yet as many as half of all heart-attack victims have LDL levels that are considered normal. Often, those patients have low HDL. One of three components of a person's total cholesterol -- along with LDL and triglycerides -- HDL is the only one where, generally, more is better. Researchers now think HDL also may have anti-inflammatory effects on blood vessels, damp the aggressiveness of LDL's assault on the arteries and work in other ways to preserve the health of artery walls.
The American Heart Association estimates that more than 53 million U.S. adults -- about one-quarter of the population -- have low HDL. It is especially common among people who get heart disease earlier than usual and is one of a cluster of risk factors that predispose people to diabetes.
Exercise raises HDL, as do some foods, including whole-grain oat products and olive oil. And drugs based on the B-vitamin niacin, such as Kos Pharmaceutical Inc.'s Niaspan, boost HDL modestly -- but much less than torcetrapib has done in studies, and often with annoying side effects.
Potential Benefits
Low HDL "is extremely frustrating to treat," Dr. Rader says. But the potential benefits appear significant. Results from the half-century-long Framingham Heart Study show that for every milligram increase in HDL, the 10-year risk of a heart attack falls by 2% to 3%. If further clinical tests prove that torcetrapib prevents heart attacks and saves lives, Dr. Rader says, "it will be a major advance."
But simply boosting HDL may not be the full answer. Some research suggests that HDL that's too high doesn't decrease the risk of heart attacks. And some findings seem to show that it's the efficiency of an individual's type of HDL that matters, not just the amount. HDL therapy is likely "to be extremely useful and help us to add a big increment to our ability to reduce risk," says Richard Pasternak, director of preventive cardiology and cardiac rehabilitation at Massachusetts General Hospital, Boston. But HDL, or high-density lipoprotein, is more complex than LDL, or low-density lipoprotein, he says. "Higher isn't always better, and lower isn't always worse."
Pfizer acknowledges the skepticism in some quarters about HDL therapy and the challenges in developing an effective treatment. "Nobody knows what happens when you raise HDL," says Henry McKinnell, Pfizer's chairman and chief executive. "I happen to have a lot of confidence in this program, but you never know. This could show no benefit, which means we'd fold the tent on this one and go back and start on something else."
Four months ago, the New York-based drug maker underscored its faith in the idea by acquiring Esperion Therapeutics Inc., a tiny biotech startup, for $1.3 billion. Esperion has a burgeoning HDL-drug pipeline, including an intravenous drug that might be used to melt plaques in patients having heart attacks. Meanwhile, banking on success with torcetrapib, Pfizer broke ground last year on a $90 million plant in Ireland that will make a key ingredient in the drug. That brings the company's total wager on HDL therapy to well more than $2 billion.
Pfizer's interest in HDL treatments stemmed from the 1990 publication of a paper in the New England Journal of Medicine about a dozen Japanese families with genetically high HDL and no evidence of early heart disease. The company's hunt for an HDL drug proved tricky. In uncharted territory, the scientists used robots to sift for clues among 400,000 chemicals at Pfizer labs in Groton, Conn., and Nagoya, Japan. Early leads were either too weak or too toxic.
An inexperienced young chemist, Roger Ruggeri, just hired from Yale in 1992, was assigned to check a final list of 10 possibilities, as a prelude to discontinuing the project. Of the two chemicals Dr. Ruggeri chose to review, one turned out to be a red herring, the other appeared to work -- weakly latching onto a protein that shifts cholesterol from HDL to LDL. "It would have taken a golf-ball-sized dose," he says. But by adding a few fluorine atoms, which enhanced the affinity of the drug for the target protein, he boosted the chemical's potency 100 times. "It was a psychological breakthrough," he says.
The next problem was that the chemical was so greasy that Pfizer scientists were stumped on how to make a pill that would dissolve in the stomach. The solution found by Pfizer scientist Ron Clark was disarmingly simple: mix the drug with olive oil. An apocryphal account making the rounds at Pfizer has it that he bought olive oil at a local supermarket after late-night inspiration during the summer of 1994. The prosaic truth, Mr. Clark admits, is that he ordered the oil, along with other greasy solutions, from a chemical-supply catalog. Mr. Clark's formula worked well enough to test the drug in tubes of human plasma.
Mr. Clark taped a chart of the results to the computer monitor of his boss Mark Bamberger, who was vacationing at the time. His first morning back, Dr. Bamberger glanced at the chart and figured it was a joke. "The results were too good to be true," he says. Further experiments confirmed the approach. Pfizer chemists eliminated the need for oil by preparing a fine mist of torcetrapib, then drying it to create tiny particles that could make their way into the bloodstream. After animal testing, the first dose of torcetrapib was given to humans in 1999. Preliminary studies for effectiveness began the following year.
Assuming torcetrapib clears safety and effectiveness hurdles, Pfizer has an unusual marketing plan: The drug will be sold only as part of a combination pill with Lipitor. The idea is that the new pill will provide a one-two punch that would lower LDL and raise HDL simultaneously, preventing more heart attacks and deaths than statins alone.
If successful, the strategy would also help fend off rivals such as AstraZeneca's new and powerful statin Crestor, which lowers LDL even more than Lipitor does, and diminish the impact of impending competition from generic versions of statins now sold by Merck & Co. and Bristol-Myers Squibb Co. The vast majority of patients who would be candidates for HDL treatment would also be on a statin. But patients who take a statin other than Lipitor wouldn't be able to get access to torcetrapib.
"Not being able to give the drug with any statin limits [a doctor's] flexibility somewhat," says Dr. Rader, who led the study published today.
Besides Crestor, Lipitor will soon compete against a combination cholesterol reducer called Vytorin, a mixture of Merck's statin Zocor and Schering-Plough Corp.'s novel cholesterol blocker, Zetia. Sales of these medicines as separate pills topped $5 billion last year. By 2006, Zocor and Bristol-Myers's Pravachol will have lost patent protection, opening the way for cheap generics.
High Hurdles
The hurdles to regulatory approval for Pfizer's new drug will likely be quite high. For starters, Pfizer will test a combination of 60 milligrams torcetrapib and various doses of Lipitor against Lipitor alone.
In addition, statins were approved based on their ability to lower LDL -- and only later were shown to prevent heart attacks, strokes and other problems. For the new pill, simply increasing levels of HDL isn't expected to pass muster at the FDA. Yet proving the drugs would save lives can take five years and tens of thousands of patients.
Pfizer says regulators have agreed to assess the new pill on its ability to affect cholesterol and reduce the size of plaques inside arteries over two years, an effect that Pfizer hopes would eventually reduce heart attacks and deaths. Ultrasound images will reveal whether dangerous plaques have regressed as a result of treatment. That's an important shortcut to market. Pfizer will follow patients for up to five years or run additional studies to look for changes in rates of cardiovascular illness or death.
Last October, Pfizer started the final round of the pivotal clinical studies needed to win approval for the combination pill. Researchers will collect blood from 13,000 patients and test it for the amount and kind of cholesterol present. But the acid test, which will eat up much of the $800 million, will be what the imaging tests reveal about the inside of the arteries in some 3,000 patients. "What we'd like to show here is an effect significantly greater than Lipitor alone," says John LaMattina, Pfizer's head of research and development.
That's a high bar. Statin therapy has substantially reduced incidence of major heart problems among patients across all levels of risk. Proving that the HDL booster provides an added meaningful benefit is a daunting challenge. If the results break Pfizer's way, torcetrapib could create a franchise to rival those for medicines that lower blood pressure or bad cholesterol, already strong suits for the company. "If the theory proves out, we own cardiovascular risk protection for a good period of time," Mr. McKinnell says.
Write to Scott Hensley at scott.hensley@wsj.com and Ron Winslow at ron.winslow@wsj.com
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