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Cholesterol

Life Flow One
The Solution For Heart Disease

by
Karl Loren

January 24, 2000

Marketplace

The Birth of a Blockbuster:
Lipitor's Route out of the Lab

By RON WINSLOW
Staff Reporter of THE WALL STREET JOURNAL

ANN ARBOR, Mich. -- If not for the impassioned pleas of a biologist 11 years ago, the unusual genetic illness of a South African boy and a "left-handed" chemical, the titanic drug-industry tug of war over control of Warner-Lambert Co. probably wouldn't be happening.

All played crucial roles in the discovery and development of a superpotent cholesterol-lowering drug that is central to the Warner-Lambert battle that now pits Pfizer Inc. against American Home Products Corp. and Procter & Gamble Co. The drug, Lipitor, although available only since 1997, is already expected to become the biggest-selling prescription medicine in the world. By itself, Lipitor will generate profits that will assure its eventual owner strong financial growth and the funds to fuel new drug research for the next 10 years.

Indeed, Lipitor is already transforming heart care world-wide. Just one of five similar-acting drugs known as statins that reduce dangerous cholesterol levels in the bloodstream, Lipitor can do it more effectively than its rivals, and that will help it post world-wide sales of more than $5 billion this year, outpacing Merck & Co.'s Zocor and Bristol-Myers Squibb Co.'s Pravachol.

This spring, Lipitor is expected to be introduced in Japan's $2 billion statin market. And U.S. heart experts are discussing revisions of national cholesterol guidelines that some think will double the number of Americans regarded as prime candidates for statins to more than 25 million. Although a potent new rival could emerge from AstraZeneca PLC by 2002, many analysts believe that Lipitor is on a trajectory to become the first-ever drug to garner $10 billion annually.

Yet Lipitor very nearly didn't make it out of Warner-Lambert's labs here at the company's Parke-Davis research facility. How it was transformed from an initially unspectacular compound known as CI-981 to the most prized drug-company product ever illustrates the role chance and the dedication of a handful of people can play in a medicine's success.

During more than a decade of development before its launch in February 1997, the drug overcame a series of scientific and strategic challenges within Parke-Davis, almost any one of which could have derailed the compound. Then, in the home stretch toward approval by the Food and Drug Administration, marketing strategies by Warner-Lambert's chief competitors unwittingly laid the groundwork for Lipitor to become a sensation from the day it hit pharmacy shelves.

'Boggles the Mind'

"The number of factors, internal and external, that had to come together for the drug to be a success really boggles the mind," says Bruce D. Roth, a senior director and chemist at Parke-Davis who invented the molecule that became Lipitor.

One of the most boggling episodes -- in retrospect, at least -- came near the beginning. In the early 1980s, Dr. Roth and his colleagues were several months into the development of a different compound only to learn that Sandoz AG, the former Swiss drug company that is now part of Novartis, had obtained a patent for it. So they switched to a different molecule. Lipitor was actually Parke-Davis's Plan B.

Once scientists turned to Lipitor, the pivotal moment came in late 1989, when top executives at Parke-Davis met to consider whether to advance CI-981 into human trials. Scientists had by then spent eight years developing the compound, and there was a problem: In animal studies, it proved no better than competitors at reducing cholesterol. With one statin already on the market and three others in late-stage human studies, some officials argued that the potential payoff was too slim to justify further development.

But Roger Newton, a biologist who co-directed development of the drug with Dr. Roth, mounted an impassioned defense. "We'd spent a lot of years and blood, sweat and tears on this compound," he says. "Why would you spend all this money just to get to the edge of where you find out if it's viable?"

Indeed, scuttling CI-981 would have wasted an intense, two-year effort to come up with a process to manufacture the drug in commercial quantities. Dr. Roth's initial Lipitor molecule had what chemists describe as both left-handed and right-handed sides. But only the left-handed portion latched onto targets in the body, blocking enzymes and causing a reduction in cholesterol. The inactive, right-handed side amounted to a glove that wouldn't fit.

Dr. Roth and his colleagues worried that this would leave their synthetic compound less potent than rivals from Merck and Bristol-Myers, which are natural molecules with no inactive components. Moreover, a lot of inactive material could cause unwanted side effects and even jeopardize approval at the FDA. "It forces patients to metabolize 50% of material that is of no value to them," Dr. Roth explains.

'Right Relationship'

In collaboration with other scientists, Dr. Roth fashioned a version of the molecule that was only left-handed, but it proved especially tricky to produce in large batches. "The chemistry needed to get the right relationship of the atoms was just coming available," says Jim Zeller, a chemist in the company's Holland, Mich., facilities, where the scale-up work was done. He and his colleagues spent months experimenting with various processes, but they kept getting side reactions that produced right-handed gloves.

Finally, after a global search for equipment, the scientists hit pay dirt by running their reactions at liquid-nitrogen-cooled temperatures lower than minus 80 degrees Celsius. A manufacturing process that took three weeks from raw materials to end product yielded a compound that was 100% left-handed gloves.

Ultimately, though, the decision to move forward with CI-981 was based on less esoteric factors. Lopid, the company's top-selling drug at $600 million in annual sales, was about to come off patent. The market for statins was expected to be so big that even if this one got just a 10% share, it could become Warner-Lambert's top seller. And, other than a new antibiotic and an experimental treatment for Alzheimer's disease, the pipeline was anemic. Says Donald Black, vice president of clinical research: "We were desperate."

But desperation turned to elation after the first tests of the drug on 24 employee-volunteers. At 10 milligrams, LDL, or bad, cholesterol dropped 38%. That was as good as or better than competing compounds at their recommended maximum doses. At 80 milligrams, LDL dropped 58% -- about 40% more than any other statin at any dose.

"You could tell immediately that this was something really different," says Dr. Black. "This was the real deal."

Based on those results, Dr. Black devised an all-or-nothing strategy for the trials needed to win FDA approval: Parke-Davis would test 10 milligrams as a starting dose and 80 milligrams for patients with especially high cholesterol. "It allowed you to go for a strategy that essentially took the competition out," says Ronald M. Cresswell, who recently retired as head of Parke-Davis. "You were going to beat them at LDL even at your lowest dose."

But there wasn't any assurance at the time that the market would want a supercharged low-dose pill. Indeed, because of studies in the 1980s linking low cholesterol with an increased risk of death from non-heart-related illnesses, many doctors in the early 1990s were wary of aggressive treatment. Dr. Cresswell himself was modestly reducing his own LDL levels by taking a Merck statin then and says his heart doctor told him the market didn't need a more potent pill.

The 80-milligram strategy was risky too. If it turned out to have unacceptable side effects, it could taint the drug even at low doses and leave the company with only a 10-milligram tablet to take to the market.

But results of larger studies vindicated Dr. Black's strategy. In October 1994, he and his colleagues made the first public presentation of human trial data of the compound -- now known as atorvastatin -- at a scientific conference in Montreal. The results were so stunning a senior Merck official stood up to suggest the drug be called "turbostatin."

'You've Got a Winner'

Even Dr. Cresswell's cardiologist would come around. In 1995, Dr. Cresswell enrolled in a special clinical program to get the drug before the FDA had approved it and, at 20 milligrams a day, his LDL fell from 160 to 90 -- below the 100 goal for people with heart ailments. "I faxed my results to him," Dr. Cresswell recalls. "I got faxed back: 'You've got a winner.' "

But other challenges loomed. Scientists wondered how they could persuade the FDA that the compound deserved "fast-track" review, a status reserved for products that fill an unmet medical need and can shorten the time to market by at least six months. The problem: By mid-1994, four other statins were already on the market.

So the company approached two South African doctors who had a group of patients with a rare genetic disorder that impaired their ability to clear cholesterol from their bodies. For children born with two copies of the defective gene -- one from each parent -- the condition is particularly severe: a cholesterol level of 600 or more, compared with about 200 for the average adult. Such children typically suffer heart attacks or have bypass surgery by their teens. "If we can't do anything," says Frederick J. Raal, head of the lipid clinic at Johannesburg General Hospital, "the average age of death is about 14 years."

Previously, the doctors had tried Merck's Zocor -- the most powerful statin then on the market -- on these patients with little effect, but they agreed to try Lipitor.

Among 10 such children in the clinic was a youngster named Andre who had a cholesterol level of 1,100, "the highest I'd ever seen," Dr. Raal says. Like others, he had tell-tale signs of the condition: tiny lumps of cholesterol deposits just under the skin between his fingers and around his knuckles.

Within a month of starting on Lipitor, the children's cholesterol started coming down. Andre's dropped to about 700; that of others, who didn't start so high, fell much lower. "It was the first time we found a medication that was really working in this group of patients," says Dr. Raal. It wasn't always enough. Andre died late last year of a heart attack at age 10, four years after he began taking the drug. "We never got his cholesterol to anywhere near normal," Dr. Raal says. But several other young patients continue to do well.

The South Africa results were enough for the FDA to put Lipitor on priority review. The company enrolled the last patient in its major trial in October 1995 and filed for approval in June 1996. Six month later, Lipitor was cleared to begin sales.

Yet, in the months leading up to approval, top Warner-Lambert officials were still uncertain about what they had. The company had recently emerged from an FDA-ordered halt to the manufacture of several old-line drugs because of quality problems. Cognex, its once-touted Alzheimer's disease drug, had failed to match blockbuster sales expectations.

Meantime, sales of Merck and Bristol-Myers were beginning to soar. Both had recently completed large-scale, long-term studies showing use of their drugs reduced deaths and heart attacks among high-risk patients. Warner-Lambert had no data to support such claims. Selling what was vulnerable to being branded a niche product against two marketing powerhouses seemed daunting.

More Skeptics

Wall Street was skeptical, too. Dr. Cresswell says he and Warner-Lambert's then-chairman Melvin Goodes, who was also on Lipitor after having taken a Merck pill for years, sought to drum up enthusiasm by regaling analysts with their own before-and- after cholesterol numbers. But investors continued to question its prospects.

These were among the factors that led the company, shortly before FDA approval, to seek out a marketing partner for Lipitor. Out of several companies that expressed interest, Pfizer, highly regarded for its marketing, was chosen.

It wasn't until the product-launch meeting staged in a big auditorium atop San Francisco's Nob Hill early in 1997 that Warner-Lambert's mindset about Lipitor seemed to change. Roger Newton, the drug's ardent champion, Dr. Black, its chief strategist, and Dr. Cresswell spoke to an increasingly enthusiastic hall in an atmosphere that resembled a rock concert.

Then the price was announced. Instead of demanding a premium reflecting Lipitor's superior potency, the Warner-Lambert-Pfizer partnership had decided to go for a knockout punch by pricing it lower than Merck's top seller, Zocor. "The roar almost lifted the roof off the place," says Dr. Cresswell.

The market soon became enthusiastic too. Thanks in part to Merck's and Bristol Myers's own big studies, doctors began to embrace the statins. Lipitor, with its low-dose power and competitive price, hit the market just as worries about going too low on cholesterol were giving way to the belief that lower is better.

"Merck and Bristol-Myers spent 10 years educating doctors to get them to use their drugs," says Kevin Graham, a cardiologist at Minneapolis Heart Institute, Minneapolis. "But Lipitor, at lower doses, is a much better deal. It's kind of a marketing coup."

All of this comes with plenty of irony for Warner-Lambert. In the mid-1990s, the company was on every stock analyst's list of likely takeover candidates amid a consolidating pharmaceutical industry. Inside the company, Lipitor came to be viewed as the only hope for Warner-Lambert to remain independent. Now, it's the reason the company is all but certain to be acquired, and it's triggering a reshaping of the entire global pharmaceutical industry.

Why is it so powerful? The scientists who developed it credit the left-handed glove, along with an attribute that wasn't apparent in any of the early studies: It has a much longer half-life than its competitors, meaning it lingers in the body much longer to do its work.

"The beauty of this is it shows that serendipity is still left in science," says Dr. Newton, now chief executive of Esperion Therapeutics Inc. of Ann Arbor. "You have to follow your nose and your instincts. You create your luck."

Write to Ron Winslow at ron.winslow@wsj.com

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