Healthy Skepticism Library item: 212

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Publication type: news

Landers P.
Drug Industry's Big Push Into Technology Falls Short : Testing Machines Were Built To Streamline Research -- But May Be Stifling It
The Wall Street Journal 2004 Feb 26

Full text:

A decade ago, pharmaceutical companies announced a revolutionary new way of finding drugs. Instead of relying on scientists’ hunches about what chemicals to experiment with, they brought in machines to create thousands of chemical combinations at once and tested them out with robots. The new technology was supposed to bring a flood of medicines to patients and profits to investors.

Today, some leading chemists are calling the effort an expensive fiasco.

Machines churned out chemical after chemical that didn’t produce useful results. And chemicals that seemed promising often turned out to have big flaws that traditional testing might have caught earlier on. Some drugs couldn’t dissolve in water or be turned into pills, for example.

Critics believe these problems help explain the pharmaceutical industry’s drought of new products. “That’s the secret of why they’re spending billions of dollars and getting nothing,” says James Hussey, a former Bristol-Myers Squibb Co. manager who now leads biotech company NeoPharm Inc.

Last year, the U.S. Food and Drug Administration approved only 21 new drugs, marking a steady decline since a peak of 53 in 1996. Many of the world’s largest drug companies failed to win U.S. approval for a single new drug in 2003.

The dearth of new products has forced companies to seek growth by heavily promoting their pills and extending product lines through minor modifications. The tactic has led to political criticism that the industry is making big profits without improving the public’s health.

Drug companies believe they have solved their technology troubles and expect a stream of new drugs after 2010. And many scientists don’t think machines are mainly to blame for the new-drug drought. They cite other factors, such as the complexity of the diseases being tackled nowadays and the FDA’s tighter standards for safety and efficacy.

Still, the story of chemistry technologies shows how hard it is to automate a process and keep room for serendipitous insight — which has been responsible for many great drug discoveries. Penicillin came from Alexander Fleming’s chance observation in 1928 that bacteria were absent around a certain mold in a lab dish. In the early 1970s, a Japanese scientist, Akira Endo, had a hunch that fungi could break down cholesterol. After testing 6,000 types of mushroom and mold by hand, he found one that did so — which led to the $22 billion class of anticholesterol drugs called statins.

Drug companies love such breakthroughs but hate their unpredictability.

Years ago, many pharmaceutical companies had large industrial-chemical or consumer-products businesses to smooth out the cycles of drug research. The industry shed those businesses over the years to focus on prescription medicines, which brought higher stock-market valuations.

But the rise of generic copycats meant companies must consistently bring new products to market or see sales dwindle.

This need explains the attraction of “combinatorial chemistry,” a new technology that burst onto the scene in the early to mid-1990s. The idea: Take a few basic building blocks of chemicals, and combine them in myriad ways. Rather than having chemists cook up each type of molecule by hand — which can take weeks — machines could create thousands of chemicals almost overnight by mixing and matching common building blocks.

From there, robots dropped bits of each chemical into tiny vials containing samples of a bodily substance involved in a disease — for example, the protein that triggers production of cholesterol. If the two reacted in the desired way, that was called a “hit.” This testing process is known as high-throughput screening.

The machinery seemed to offer a surefire way to find drugs. “Medicinal chemistry has undergone a revolution,” pronounced the Lancet, the prestigious British medical journal, in May 1995. At a conference in October of that year, Sir Richard Sykes, then chief executive of Glaxo Wellcome, said, “It is no longer necessary to rely on empirical research which may lead to something or nothing.”

Virtually every U.S. and European pharmaceutical giant tore up its labs to install the new machines, and many spent tens of millions of dollars in deals with small companies that specialized in the new technology. At Glaxo, Sir Richard spent more than $500 million to buy a combinatorial-chemistry company.

But the chemistry machines didn’t work as they were supposed to, many scientists now say. Carl Decicco, the head of discovery chemistry at Bristol-Myers, calls the first five or six years of the new technology a “nightmare.” Dr. Decicco says many chemists became fixated on creating thousands or millions of chemicals for testing without thinking about whether any of them could turn into a once-a-day pill. “You end up making things that you can make, rather than what you should make,” he says.

Often the machines would throw so many ingredients into their stews that the resulting chemicals were too “large” in molecular terms; they would work in the test tube but would get broken down too easily in the human stomach. In the days when a chemical took a week to make, chemists usually weighed such issues beforehand.

Robert Lipper, a Bristol-Myers scientist in charge of getting drugs ready for human trials, wrote an article for Modern Drug Discovery in 1999 describing how his staff had to wrestle with chemicals that were almost impossible to deliver in humans. The struggle often led to a “major drag on the development timeline,” he said. In one case, a drug that prevents infection showed good results in the test tube — but Dr. Lipper pointed out that the drug didn’t dissolve in water, the medium used in intravenous drips.

At Pfizer Inc., senior research fellow Chris Lipinski watched with dismay as machine-made chemicals failed to turn into drugs. “Garbage in, garbage out really applies to drug screening,” says Dr. Lipinski, who retired in 2002 after 32 years at Pfizer. He drew up a list of complex technical traits that often make chemicals hard for humans to absorb and persuaded Pfizer to reprogram its computers so chemists got a warning whenever chemicals violated the “Lipinski rule.”

In the early days of automation, it was hard to separate hype from reality. Schering-Plough Corp.‘s vice president of chemical research, John Piwinski, recalls visiting one well-known combinatorial-chemistry entrepreneur to discuss a partnership. “I remember he showed us a jar and said, ‘There’s five million compounds in here,’ “ says Dr. Piwinski.

But the entrepreneur couldn’t explain how he’d solve key technical issues about testing the chemicals, and Schering-Plough declined to do a deal. Schering-Plough ended up signing on with another hot start-up, Pharmacopeia Inc., in late 1994.

Those most opposed to combinatorial chemistry and high-throughput screening believe it eliminates chances for serendipity. In 1991, Schering-Plough scientists were looking for a drug that would block a certain cholesterol-producing enzyme in the body. They noticed in a test on hamsters that one molecule, while failing to block that enzyme, nonetheless lowered cholesterol.

If a robot had tested the molecule in a test tube, it would have caught the failure but missed the serendipitous side result. Thanks to careful observation, the Schering-Plough scientists stumbled onto a new approach for reducing cholesterol. After some hand-tweaking by chemists, the molecule turned into Zetia, a drug approved by the FDA in 2002. It is expected to bring billions of dollars in revenue for Schering-Plough, which is otherwise bereft of major new products.

Arvid Carlsson, the 2000 Nobel laureate in medicine for his discoveries about the neurotransmitter dopamine, spent decades researching drugs in psychiatry. “That is what the modern pharmaceutical industry throws out:

intuition and intellectual creativity,” says Dr. Carlsson. “It replaces intellectual creativity with a robot — a highly sophisticated robot, admittedly — but a robot can never have intuition.”

In hindsight, the quest to create millions of chemicals was based on a misconception about what scientists now call the chemical space. The number of theoretically possible drug-like chemicals is estimated to be at least 10 to the 40th power — one followed by 40 zeros. Just as the universe consists mostly of empty space dotted with an occasional galaxy, the “space” of all these potential chemicals is mostly useless to humans.

That’s why recent screening efforts focus on the kinds of chemicals that have a shot at doing something in humans. Pfizer says it has spent more than $600 million at labs around the world to ensure that the chemicals in its libraries are more diverse and drug-like. The company is using techniques other than combinatorial chemistry to build up its libraries, and incorporating checks such as the Lipinski rule.

Martin Mackay, a senior vice president at Pfizer’s research labs, said recent data show a higher percentage of compounds at Pfizer are making it through each stage of testing, suggesting that the effort to improve the technology is working. “The proof of the pudding will be in 10 years’ time,” he said. “We’re very confident.”

Even so, the machines don’t always produce the quality that researchers achieved in the old days. The robot screeners can work only with liquids, so the huge chemical libraries created by the mix-and-match machines are often placed in dimethyl sulfoxide, a standard solution used to store chemicals. But some chemicals settle as a solid at the bottom of the solution, much as sand settles at the bottom of a glass of water. Or the solution may break down the chemical stored in it. So when the drug-testing robot reaches into the solution, it may come up with a drop of useless soup.

In traditional labs, chemists could store a chemical as a powder if they thought it would break down in dimethyl sulfoxide. Bristol-Myers has returned to that approach and now stores most of its chemicals as powders, according to Dr. Decicco. Machines put the powders into solution just before the screening.

A study led by David Newman of the National Cancer Institute concluded that combinatorial-chemistry machines had failed to create a single FDA-approved drug through the end of 2002. Dr. Newman says a separate study of 350 cancer drugs now in human trials found only one that originated in the chemistry machines, although the machines helped improve some drugs that were found by more traditional means.

Many observers believe the introduction of new technology in the 1990s helps to explain today’s drought of new drugs, which take years between discovery and approval. “Ten years later, we’re seeing the effects. The output has decreased tremendously,” says Michael Fernandes, a consultant who used to work in drug development at Wyeth.

Others play down the link to the new machines. They note that many of the diseases being tackled today, such as Alzheimer’s and AIDS, are tougher to study because they can’t be reproduced in mice, traditional test subjects. Also, the FDA has raised standards for safety and efficacy.

Some scientists believe the industry has solved the machines’ early problems and pipelines might be bulging a decade from now. “I anticipate that we will see a renaissance of new compounds coming onto the marketplace,” says Richard Gregg, vice president of clinical discovery at Bristol-Myers’s research labs. “It took a while to learn how to use all these new technologies.”

Bristol-Myers says it has tried to create a better mix of high technology and old-fashioned lab work. Its research center in Wallingford, Conn., has a screening machine capable of testing a million chemicals at once, taking as little as 10 microliters of each chemical — about a hundredth part of a drop of water. Other rooms in the same building hold scores of mice so scientists can quickly test the “hits” in animals. John Houston, vice president of applied biotechnology, says that avoids a problem he has seen at other companies where scientists spend months or years refining a compound in a test tube only to find it doesn’t work in living things.

At Schering-Plough’s main research lab in Kenilworth, N.J., chemist Johnny Zhu shows off a machine that allows him to make several dozen variations of a chemical, all in the liquid state. The number is much smaller than older machines produce, but Dr. Zhu says he can hand-pick the combinations and get higher quality.

Schering-Plough says one of its most exciting drugs in human trials, which attacks the AIDS virus through a new mechanism, emerged from robot screening. The robot found that a molecule long ago discarded as an Alzheimer’s treatment successfully hit the new AIDS target.