Zyprexa, interesting article here
<<By Jeff Swiatek
Indianapolis Star
May 28, 2000
In 1982, it was an unnamed compound in a flask that almost was cast aside out of scientific frustration.
Today, Eli Lilly and Co.'s Zyprexa is a superstar drug, with yearly sales of $1.9 billion and a 140-person product team tending to its every need.
The plain white tablet, which hit the market in 1996 and offers new hope to those afflicted with the mental scourge of schizophrenia, also has another credit coming to its name.
It's about to become Lilly's best-selling drug.
Zyprexa's rise to stardom at Lilly is unusual for a niche product. Unlike the antidepressant Prozac or antibiotic Ceclor, Lilly's current and former top-sellers, Zyprexa is hardly a pill for the masses. It sells to a relatively small patient group of schizophrenics and manic-depressives.
Even so, the pill's relatively high price of $5.50 to $8.50 a day (or $2,000 to $3,100 a year), limited competition and aggressive worldwide marketing by Lilly have propelled the drug's sales to blockbuster levels.
Last year, Zyprexa made up nearly 20 percent of Lilly's $10 billion in sales. Next year, the drug's sales are headed to $2.7 billion or higher.
That would top Prozac's sales, which last year dipped to $2.6 billion, according to Evaluate Plc, which analyzes the pharmaceutical industry.
Zyprexa comes just in time for Lilly. The Indianapolis drugmaker is desperate for a big moneymaker to replace Prozac, which loses protection from its main U.S. patent in 2003, allowing generics to steal its market share.
Zyprexa's rise has much in common with the famous antidepressant whose sales it's poised to surpass. Both are products of Lilly's neuroscience research, and both bring new treatments to troubling mental problems.
But while Prozac followed a long line of tranquilizers and other mood-improving medications, Zyprexa's discovery path was littered with disappointments.
"I don't think anybody realized . . . just how difficult it was going to be," said David Tupper, one of the three Lilly scientists in England credited with discovering Zyprexa.
The creation of olanzapine, as Zyprexa is known scientifically, proved to be a wrenching, 12-year period of ups and downs, with hopes raised, then dashed.
In the end, scientific perseverance paid off, but Tupper admits, "To be honest, there was a very large element of luck" involved.
Another kind of hunt
The discovery drama played out at Erl Wood, a former hunting lodge near London that Lilly remodeled into labs in 1967. During the 1970s and '80s, Erl Wood was the only site outside Indianapolis where Lilly did basic drug research.
In 1974, a handful of Erl Wood scientists became intrigued with trying to find a new schizophrenia drug.
One, Jiban Chakrabarti, attended a conference where he heard about the problems with clozapine. Introduced in 1960, clozapine helps many schizophrenics, but it can cause a deadly blood disorder that prompted its withdrawal from many world markets.
"I had a sixth sense, a feeling that something was missing in the molecular structure," said Chakrabarti, an Indian-born and -educated scientist who hired on with Lilly in 1966.
Chakrabarti hooked up with two junior researchers then in their late 20s, Terry Hotten and David Tupper. Both are Britishers who joined Lilly in 1969.
Their disease target was a mental illness that affects about 1 percent of the population. It hits people in their late teens or 20s, causing mental woes that can jumble emotions and thoughts for weeks or even months at a time.
Sufferers often hear voices, believe they're in a fantasy world, or withdraw from friends and family.
The three Erl Wood scientists had a simple hope: to tweak clozapine's molecular structure and eliminate whatever causes the blood disorder side effect.
By 1976, they had their first compound ready for testing. But it caused the same blood disorder.
It took six years for another compound to progress to toxicity testing. This one didn't cause the blood disorder, but it turned out to harm the liver.
For Tupper, who likes to fish the Thames valley, the search for a better clozapine was much like baiting a hook and waiting to see what bites.
"Really, it's not predictive what was going to happen," he said, recalling highlights of his work during a trans-Atlantic telephone call.
In fact, he said, team members never got their hopes up because they knew that, on average, only one in 10,000 lab compounds ends up a marketed drug.
"The expectation is that you will fail," Tupper said.
In 1982, failure seemed at hand. The team had painstakingly crafted 400 compounds over eight years, toying with their atoms and chemical structures, only to find the two best ones had failed.
The project would have ended there if the team hadn't squirreled away five other promising, but untested, compounds.
While awaiting the second set of test results, scientists created the extra compounds on the side, without the full blessings of their bosses.
"I won't say it was sneaky, but it wasn't totally 100 percent sanctioned," Tupper said.
Management agreed to let the team test the last batch of compounds, but added an ultimatum.
"It was, 'Thus far and no further. This is your last try, guys. If this one fails, that's it,' " Tupper said.
This time, the team had a winner. One of the final five compounds was olanzapine, whose safety and effectiveness quickly stood out in tests.
By the late 1980s, Zyprexa was winging it way to testing on humans.
The fast-track approach
Zyprexa had more going for it than good chemistry.
Lilly management decided about 1994 to try a new way to get drugs to market more quickly.
Created by two Harvard University business professors, the fast-track approach was tried out first on Zyprexa.
"We'd really been pushing them on it for some time," said Steven C. Wheelwright, who developed the approach with colleague Kim Clark.
The approach called for a "heavyweight team" of top company experts to concentrate solely on getting one tested drug at a time to market. That was a radical change from Lilly's old approach of assigning its employees several drug launches at once.
Not everyone at Lilly liked the idea.
"The rest of the Lilly organization's resentment towards the teams, because of their free access to resources and senior management attention, was palpable," Wheelwright wrote in a 1999 case study of the Lilly heavyweight teams.
The 100-person Zyprexa team, created in January 1995, was also referred to as Lilly's "Manhattan Project" for its massed resources and daunting task it took on, said Dr. Gary D. Tollefson, who headed the team and is president of neuroscience products.
The resentment would soon fade.
In less than nine months, the Zyprexa team pulled together the federal application to market Zyprexa. It ran to 1,100 volumes of 350 pages each and required a truck to haul to the offices of the U.S. Food and Drug Administration in Rockville, Md.
For the first time on an FDA drug application, the team also submitted full records on CD-ROM discs to make it easier for FDA reviewers to read the mounds of data on computer.
In other firsts for Lilly, the team also applied simultaneously for the rights to market Zyprexa in 19 other Western nations and, soon afterward, in 60 smaller countries.
The team also began hiring a sales force and stockpiling Zyprexa at a Lilly manufacturing plant in Puerto Rico.
The drug's packaging carried any of three different brand names, since Lilly didn't know which of its three requested names the FDA would approve. The other two names were Zyprex and Olansek.
The team was able to move fast because it was less encumbered by corporate bureaucracy. "Our credo was, 'If we say we are going to do something, we're going to do it,' " said Tollefson.
Investing so much in marketing a drug before it's even approved was risky, but Lilly felt Zyprexa's good showing in patient trials would make FDA approval close to a sure thing.
To motivate the team, leaders circulated a letter to Lilly from a patient with schizophrenia. She'd been helped by Zyprexa during a patient experimental trial. But the trial had ended, and she was forced to use other drugs while Lilly sought approval to sell Zyprexa.
"I feel terrible now," the woman's letter said. "These other medicines are not enough to give me the benefit I received from the olanzapine. Please hurry."
Tollefson said the letter encouraged team members to work harder because it "brought the human side to the work they were doing."
Mother Nature almost foiled the team's credo.
In early September, three weeks before the expected FDA approval of Zyprexa, Hurricane Hortense hit Puerto Rico, battering the island where the drug was being made and stored.
"We heard the plant had been devastated," Tollefson said.
In fact, the plant survived intact, thanks in part to a few Lilly engineers who volunteered to stay inside during the storm, running the building's emergency power system and repairing leaks.
The gamble on the new, fast-track approach paid off. FDA approval came Sept. 30, 1996.
The heavyweight team managed to cut about 18 months off Lilly's normal development time for a major new drug.
At Erl Wood, approval was marked by "a little gathering in the cafeteria. Very modest," Tupper said. The Indianapolis heavyweight team convened for a similar celebration.
A day after the FDA approval, the first olanzapine tablets, bearing the approved name of Zyprexa, were flown to Indianapolis, where the first prescription was filled.
No other company had ever gotten its drug to market so quickly after an FDA approval.
Within three weeks, Zyprexa was approved for sale in much of the rest of the world. Prozac needed three years to attain similar worldwide approvals.
Zyprexa showed that Lilly can "come out of the starting blocks faster" with new drugs, said Bob Kirby, a drug stock analyst for Edward Jones investment firm in St. Louis.
"It raises the bar" for the rest of the pharmaceutical industry, he added.
The fast-track project brought "dramatic leaps in speed and quality" to drug development at Lilly, says the Harvard case study.
Lilly now uses heavyweight teams for all its upcoming drugs.
Keeps getting better
And Zyprexa continues to add to its stature.
As of December 1999, Zyprexa was the second most widely prescribed antipsychotic, with 28 percent of the U.S. market. Risperdal, an antipsychotic launched in 1993 by Johnson & Johnson subsidiary Janssen Pharmaceutica, had a 34 percent share.
Recently, Zyprexa won federal approval to be marketed for manic- depression, doubling the size of its potential market.
As for those who discovered Lilly's new star drug, Tupper and Hotten continue to work at Erl Wood. Chakrabarti retired in 1989 and lives five miles from Erl Wood, stopping in occasionally for lunch.
Last month, the three were awarded the prestigious Discoverers Award, given by Pharmaceutical Research and Manufacturers of America to those who've created significant new medicines.
On his way to California to accept the award, Tupper met two schizophrenia patients who've been helped by Zyprexa. He said it was the first time he met someone afflicted by the disease he spent more than a decade trying to outwit in his laboratory.
"It's kind of neat," Tupper said of the meetings. "To actually realize what you've done made a difference to somebody, it's quite a thrill.">>
starnews.com |
