Join Date: Jul 2001
Location: New Brunswick, NJ, USA
The case of the frailty drug: an example of how a drug company "cans" a promising drug
I am sorry for posting this long article but it illustrates the travails of drug companies in developing drug therapies. Pfiser is the richest and one of most successful drug companies in the world. They made Viagra which is making them a bundle. The company is plowing $5.3 billion a year into research and development. The decision to toss this drug (which actually is of interest for the spinal cord injury community), in my opinion, was a result of a decision based on looking for a blockbuster drug, not a drug that would do a particular thing. This drug may well be effective for something else.
Drug costs start in labs desperate for discoveries
SCOTT HENSLEY, The Wall Street Journal Â* Thursday, May 2, 2002
(05-02) 08:06 PDT (AP) --
NEW LONDON, Conn. -- William Landschulz, a Pfizer Inc. doctor, brimmed with anticipation as he strode through the company's research headquarters to a hastily called meeting last August.
Dr. Landschulz, a boyish 42-year-old endocrinologist, was leading the clinical trials for one of the most exciting drug candidates at Pfizer in years. Code-named CP-424,391, it was a once-a-day pill with the potential to be a fountain of youth.
By stimulating the pituitary gland, the experimental drug aimed to reverse the physical decline that comes with aging, to make old people feel young again and to keep legions out of nursing homes. The treatment, in which Pfizer had already invested tens of millions of dollars during nearly a decade of research, also had a shot at becoming the ultimate lifestyle drug for baby boomers by offering them vigor in old age instead of frailty.
Dr. Landschulz was optimistic about the early results of an ambitious clinical test. But the moment he entered the cramped, windowless conference room where several senior scientists had been analyzing the data, he knew the results were bad. "Only my boss looked at me," he recalls. "All the rest of them looked away."
What happened to Dr. Landschulz's frailty pill helps illuminate a big reason the price of drugs is surging: Despite the best science that money can buy, including the recently unlocked secrets of the human genome, discovering new medicines has become vastly harder. Researchers have unearthed many of the easiest cures and treatments, and drug makers have been largely unable to find replacements for familiar blockbusters that are losing their patent protection. Adding to the difficulty: the task of managing research operations that have ballooned after a wave of drug-industry mergers.
For Pfizer, the world's biggest drug company, the failure of the frailty drug was a deep disappointment. Even a thriving drug company counts on a small percentage of substances turning into spectacularly successful drugs to more than make up for the many costly busts.
Of the 18 major drugs that Pfizer markets for annual sales of $26 billion, eight bring in more than $1 billion each in sales annually and together account for 76 percent of total drug sales. They include the anticholesterol pill Lipitor, antidepressant Zoloft and the blood-pressure drug Norvasc. During the next five years, four of the eight will lose patent protection.
In the past three years, Pfizer has struggled to find replacements, launching only one new medicine on the U.S. market that was discovered by company researchers, a schizophrenia treatment called Geodon, with sales of $150 million in 2001. Its last blockbuster was Viagra, launched four years ago. Despite a strong first quarter, Pfizer warned last month of a sharp decline in profits for the current quarter. This year, the company expects to plow $5.3 billion into the hunt for new treatments, five times more than it did a decade ago. During the next five years, Pfizer expects to file for or receive U.S. marketing approval for 15 new medicines, 12 of which were discovered by Pfizer scientists.
The drug makers in the industry's main U.S. trade group as a whole spent $200 billion on research during the past decade, including more than $30 billion last year alone. Yet the 24 new drugs approved last year for marketing in the U.S. represented the lowest total since 1994, and very few of them, such as the novel cancer treatment Gleevec, appear to have blockbuster potential.
Drug companies point to the high rate of research failure as the reason why new drugs, particularly breakthrough medicines, are so expensive. With each step forward -- from first concept to test tubes, to animal experiments, then into human trials -- the cost of research increases astronomically. Failure late in the process, when investors are counting on a new product, can send a company's stock price plunging. That happened at Bristol-Myers Squibb Co. earlier this year when its much-anticipated blood-pressure drug Vanlev failed to live up to expectations in testing.
The challenges to developing Pfizer's frailty drug, which would have been a new class of medicine, were especially daunting. Last year, Pfizer Chairman Henry McKinnell cited the decade-long project as an example of the protracted, high-stakes research that only the biggest pharmaceutical companies can afford. The often-cited statistic that only one in 10 drugs in clinical trials goes into production actually understates the rate of failure: Pfizer says only one in many thousands of chemical compounds that its scientists discover make it to market.
The frailty-drug project began more than a decade ago when Pfizer decided to look for osteoporosis remedies, a new field for the company. Osteoporosis is a serious weakening of bones that comes with aging. Pfizer hired David Thompson, a seasoned researcher in the area from Merck & Co., to lead the effort with a multidisciplinary team of biologists, chemists and clinicians.
In early brainstorming sessions, Dr. Thompson and his colleagues observed that bones become weaker when the muscles that pull on them atrophy because of age or injury. Some research suggested that muscles shrink in old age because the amount of natural hormone that triggers their growth and is produced by the pituitary gland declines steadily after age 35.
So Dr. Thompson's team began searching for a chemical that could prod the pituitary, the peanut-sized gland located deep inside the brain, to produce. It would be a pill -- far more convenient than an injection -- that would boost the amount of growth hormone the pituitary squirts into the bloodstream but wouldn't otherwise change how the hormone was released. The researchers believed the restoration of youthful levels of growth hormone would increase muscle mass, reduce fat and improve people's ability to perform everyday tasks.
The team searched for clues in scientific papers and talked with academics. When they started, no one knew the identity or structure of the switch, or receptor, on the pituitary cells. Industry scientists typically probe such receptors as a shortcut to designing new drugs.
University researchers had identified particular small protein fragments called peptides that could stimulate the pituitary, though the exact mechanism was unknown. Dr. Thompson's team looked for a stable chemical that could do the same thing. In less than a year, he says, "we found a molecule we really liked" in the library of compounds that Pfizer maintains for its researchers.
Lab tests at Pfizer showed the favored chemical raised growth-hormone levels in young and old rats. The finding proved that while the pituitary secreted less growth hormone in old age, that didn't mean it couldn't be coaxed into producing more with the right chemical nudge. This proof of the key principle behind the drug was crucial in convincing management to proceed from research into the development of medicine that could be tested in humans.
Pfizer pushes its researchers to put compounds to definitive early tests. If a compound proves promising, the research team can nominate it for classification as a formal "drug candidate." At Pfizer, this rite of passage from research to development is signaled officially by a "Candidate Alert Notice" entered into the company's tracking system. But everybody in research refers to it as being "canned," which in this instance is a good thing.
David Clark, an organic chemist, chairs a committee of scientists who decide whether to approve drugs for heart disease, stroke, diabetes and obesity. A canned drug has already become a star. Fewer than half of the compounds investigated by Pfizer's discovery scientists in earnest make it this far. These successes are anointed with millions of dollars in funding to support clinical tests of safety and effectiveness.
About a sixth of Pfizer's portfolio of drugs in development were approved by Dr. Clark and his colleagues, including the frailty drug, which got the green light in December 1995. He was confident the frailty compound would succeed, ranking it among the top third of candidates at the time.
But even among the fortunate drugs that pass muster initially with Dr. Clark's committee, the odds remain stacked against their ever making it to market. Dr. Clark's group also guides the researchers, funds interim studies and establishes milestones for judgment. And at any point Dr. Clark's committee can kill the very projects it has approved. Last year, the committee terminated research on five of seven promising medicines it had previously "canned."
The growth-hormone project quickly surpassed all the researchers' expectations. From the time the project was canned, it took only nine months to develop a drug that was safe enough to test in humans -- a speed record for the research center in Groton, Conn., across the river from administrative headquarters in New London. The drug "had no bumps or warts," marveled Gordon Gruetzmacher, project manager for the frailty drug.
Though increasingly optimistic, Pfizer scientists and managers were sober about the challenges the potential new medicine faced -- especially the elusive nature of the condition it was intended to treat. Frailty, which they came to define as an "age-related decline in physical performance," wasn't a recognized disease, like osteoporosis or Alzheimer's.
A drug to treat the chronic condition, like many the industry is now tackling, would require lengthy and especially expensive clinical studies because its effects might be subtle and take months or years to understand. To make sure that an experimental drug deserves such a sizable investment, Pfizer blends marketing with R&D early on. A marketing specialist works with each drug team to ascertain commercial merit. In particular, will the drug meet a compelling unmet medical need and will Pfizer be able to differentiate its medicines from those of its competitors?
For the frailty drug, researchers believed they would have to show that it could do more than boost hormone levels or even muscle growth. Early talks with the Food and Drug Administration confirmed the higher standard. Insurers, too, would need evidence that the frailty drug would be worth their expense.
To persuade regulators and insurers to embrace the drug, the Pfizer team aimed to prove beyond a doubt that elderly people who took it could walk faster and longer and avoid the kinds of falls that force many of them into nursing homes.
Such a drug also could appeal to a younger, healthier but worried market, people who might use the medicine as a lifestyle enhancer, like Viagra, decades before they faced a real danger of frailty. For Pfizer, a medicine to stave off the ravages of old age, unlike an antibiotic taken for a week, could provide a long-term revenue stream: "People will take it for 20 or 30 years -- it'll be like a vitamin," predicted John LaMattina, a senior research executive, early last year.
In late 1996, the frailty drug hit its first setback when an otherwise healthy man participating in a small safety study in the Netherlands developed a mysterious, mild rash. The test was halted while the team investigated. The cause was never found, though the leading theory remains that he had a reaction to laundry detergent or hand soap. After a few months, the team concluded that the drug was safe enough to continue.
Pfizer recognized the growth-hormone workers as the best research team of 1996 for their trail-blazing accomplishments. And they continued on the fast track, initiating in late 1997 a larger clinical test of the drug, involving 114 people who randomly received one of four different doses or a placebo for a month. At this stage, the researchers sought to substantiate the safety of the drug and to pinpoint the best dose to use in subsequent tests of effectiveness.
To their happy surprise, the scientists found that even a one-month regimen with the experimental drug produced measurable growth of muscle. "It was great," Dr. Gruetzmacher recalls, "We didn't expect an increase in less than six months."
Though encouraging, the results didn't prove the drug was working. The test could have been a fluke. Besides, increases in muscle mass, even if they were real, wouldn't convince regulators to approve the drug, everyone had previously agreed. After lengthy discussion, the team decided to propose a six-month trial of the drug to Dr. Clark and his committee for approval and funding.
But the scientists realized that showing that the drug halted or reversed aging would take months or even years. Dr. Clark pushed the research team to reconsider its time frame and "go for the home run" by pursuing a longer and much more expensive test that could detect subtle improvements in patients' ability to function.
The team took six months to design a trial that would provide a definitive answer on whether the drug worked. They eventually proposed a two-year study in elderly patients that would measure muscle and some biochemical markers in the bloodstream. They also would test the subjects' walking speed and endurance and their ability to get in and out of a chair.
Dr. Clark's management committee agreed to fund the study in about 350 patients, much larger than usual for such an early stage. To hedge the outsize bet and ensure that the project was on track, the study included interim analyses at six and 12 months.
Last summer, three senior managers unconnected to the project, including a statistician, were chosen to review the data after six months. As outsiders, they were expected to be unbiased, and they would share their findings with only a few senior managers.
In less than a week, they had reached their conclusion and called Dr. Clark. He decided to break the secrecy and inform the research team of the news.
The patients taking the frailty drug had gained some muscle mass -- but less than 3 percent more than the placebo group, which had also experienced muscle increases. There were no safety problems with the drug. But the study was stopped within a month because the drug appeared ineffective.
Nobody is quite sure why. One theory is that the patients selected for the study may have been too healthy, so there was less room for improvement in the treated group. Another idea is that the drug caused the pituitary gland to release growth hormone in a way that was out of tune with the body's system for using it.
In the end, Dr. Clark's committee "took pity on us," Dr. Landshulz says, and allowed the team one last chance to salvage the medicine. They were permitted to collect and analyze data on the group of early patients in the study who had taken the drug for a year -- just in case its effectiveness emerged later than six months.
That was a long shot, everyone agreed, but worth the modest incremental expense. The final analysis was completed this spring, and the results were the same.
Later this month, Dr. Clark's committee will review the file one last time and officially lay to rest the frailty drug, which Pfizer says cost the company $71 million to research and develop.