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The Search For Superdrugs


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THE SEARCH FOR SUPERDRUGS

As senior director of basic chemistry at pharmaceutical power house Merck & Co., Joshua Boger was an unlikely defector. With the No. 1 drugmaker's largest research budget, a staff of 60 top scientists, and a compensation package sure to make him a millionaire, Boger had one of the most coveted of drug industry jobs.

But three years ago, Boger left Merck, declaring it unable to exploit the advanced research techniques he deems vital for drug development. Now, he's running a new drug-design company called Vertex Pharmaceuticals Inc. with 25 like-minded scientists. And he has collected an eyepopping $47 million in backing, two-thirds of it from Japanese drug giant Chugai Pharmaceutical Co.

NEW WAVE. Boger is at the vanguard of a revolutionary approach to drug development. Few drugmakers admit it, but privately their executives say traditional research techniques just don't cut it anymore. The old way--screening thousands of chemicals in a hit-or-miss search--is inefficient and wastes time. That's why it can now cost more than $200 million to bring one drug to market.

Boger and others like him are carrying the flag for a new wave of R&D often called "rational drug design." Dozens of these entrepreneurs are consummating the long-awaited combination of biotechnology and chemistry--a union that promises to streamline and enhance drug development and reshape the biotech and pharmaceutical industries. This year, the first "superdrugs" from this marriage will enter human testing. "Everything is coming together," says Brook Byers, a biotechnology venture capitalist. "Chemistry and biology together will create the drugs of the `90s."

Super is the right term for these promised compounds. Superdrugs should be far more effective against disease and have fewer side effects than current drugs. The new approach should also lead to treatments for ills that today's drugs can't cure: Alzheimer's, cancer, heart disease, AIDS, rheumatoid arthritis, and multiple sclerosis. Within a decade, "all drug companies will use these tools," predicts Dr. Hans Mueller, president of Nova Pharmaceutical Corp.

Dozens of companies pioneering exotic-sounding approaches such as anti-sense technology, carbohydrate chemistry, and neuroscience, are exploiting some aspects of rational drug design. These startups bear little resemblance to either conventional biotech companies or traditional drug behemoths. Rational drug design requires a highly collaborative effort of biologists and chemists and masters of such high-tech arts as X-ray crystallography. This means the biotech companies that made a living by perfecting a single technology, such as gene-splicing, must broaden their focus. Bureaucratic, chemistry-based drugmakers must change, too--or sign up the rational drug companies as suppliers of R&D. Says Biogen Inc. Chairman James L. Vincent, a former president of Abbott Laboratories: "It takes a totally different culture to increase the rate at which new drugs are created."

To understand why requires a trip to the body's atomic level. There, millions of chemicals and cells interlock like pieces of a three-dimensional jigsaw puzzle. Every function, from blinking an eye to digesting a steak dinner, is caused by chemicals docking with cell receptors, a special protein "lock" on the surface of a cell. These chemicals have structures called ligands that serve as keys to open those locks. Only when that junction takes place can the chemical deliver its instruction to the cell. Drugs mimic this process by docking with receptors, whether it's to latch onto a cancer cell and kill it or to make cells stop producing a harmful protein.

For years, biotechnologists argued that the best new drugs would amplify the body's own disease-fighting chemicals. Copies of proteins, they thought, could be highly precise therapeutics. That approach produced some big hits: Sales of just five gene-spliced drugs--human insulin, human growth hormone, alpha interferon, TPA, and EPO--now exceed $1 billion a year.

But biotech drugs succeed against big odds. "It's like trying to open a door with a key mounted on the front of the Goodyear blimp," says Genentech Inc. scientist Michael C. Venuti. These huge molecules are delicate. If disrupted, they don't work. That makes them costly to manufacture and hard to administer: They're injected, because in pill form they're chewed up in the stomach. And their origins in nature make them tricky to patent.

TINY YIELD. The synthetic chemicals that are the staple of the pharmaceutical industry avoid many of these pitfalls. They are small molecules, given orally, and are inexpensive to make. But the challenge with these molecules, which are foreign to the body, is finding compounds that work. Chemistry-based companies rely on screening that exposes hundreds of thousands of chemicals to cells to see if they produce an effect. This generates a tiny yield: one success in 10,000 tries.

Now, the new breed of drug designers combines the best of both worlds. Instead of hit-or-miss screening, they use biotech to help them work backward from what biologists know about a disease and how the body fights it. With recombinant DNA and other genetic engineering feats, scientists make large quantities of natural proteins, then use them as research tools for designing better synthetic compounds.

Genentech's program to develop a drug called IIb/IIIa inhibitor is a case in point. Another Genentech drug, called TPA, prevents heart attacks by breaking up blood clots. But its violent action is the equivalent of ripping a scab off a wound. The body tries to form another scab to stop the bleeding--which can quickly lead to another clot. Now, scientists think they have a chemical that will help solve the problem. They have cloned the IIb/IIIa receptor found on blood cells called platelets. These receptors cause the platelets to stick together. Genentech is testing several small molecules designed to gum up the platelet receptors, cutting the chance of another clot. This drug could eventually be given by pill, so patients could take it regularly to prevent heart attacks.

The companies that are pursuing such approaches fall into two categories. Rational drug startups such as Arris, Vertex, Agouron, British BioTechnology, and Biocryst are trying to integrate biotech and chemistry into a broadly applicable drug design system (page 96). Dozens of other companies are incorporating elements of rational design in their own drug development programs.

For instance, many old-line biotech companies now see that small is beautiful. "If you want to be a big player, you must have small molecules," says Nova's Mueller. Chiron Corp. has set up a company called Protos to pursue small-molecule projects. Biogen is testing a version of the leech venom hirudin as a small-molecule anticoagulant. Immunex Corp. is working with Sterling Drug Inc. on rational drug-design projects, too.

Meantime, small molecules may help give new life to monoclonal antibody drugs. Antibodies were to be magic bullets that could home in on diseased cells and kill them. But the Y-shaped antibodies are huge and hard to work with. Cytogen Corp. and others are trying to make synthetic molecules that mimic the part of the Y that is the targeting portion of the antibody. Linking those to a drug could create guided missiles to deliver medicine to cells.

As rational drug design picks up momentum, many medical startups don't want to be called biotech companies anymore. A dozen or so companies that are zeroing in on drugs to fight nervous-system disorders have used biotech to unravel brain function. But they'll likely use chemical synthesis to create their drugs. Alkermes' first product, for instance, is likely to be a small molecule. "Chemistry is the cornerstone of the company," says President Richard Pops.

Another hot area for small molecules is carbohydrate research. Sugar molecules play a vital role in cell adhesion, which lets inflammatory chemicals migrate to a site in the body and damage it--as in rheumatoid arthritis. A critical step in the process appears to be the binding of carbohydrate ligands to certain cell receptors. So, companies such as Cytel, Glycomed, Biocarb, and Alpha-Beta Technology are pursuing drugs that interfere with that binding.

'ANTISENSE.' The ultimate arena for biotech-chemistry synergy could be "antisense technology." The double-helix ribbon of DNA gives cells their genetic instructions. At least half a dozen companies, including Gilead Sciences, Hybridon, Isis, Genta, and Synthecell, are trying to develop short strands of DNA-like chemicals that would short-circuit harmful genetic messages. The approach is speculative. But such drugs would "so narrowly target a disease they wouldn't interfere with anything else in the body," says Nigel L. Webb, chairman of Hybridon Inc.

Many drug companies were cool to biotech, though Schering, Merck, Eli Lilly, Hoffmann-La Roche, and Ciba-Geigy made early investments. Now, they may have a leg up on their traditional rivals in rational drug design. Still, scientists who have left large companies often claim that the giants don't really know how to exploit the rational drug approach. "Big-company researchers are overwhelmingly threatened by new technology," says Henry Nordhoff, a former executive at Pfizer Inc. who now heads startup American Biogenetic Sciences. "You've got to teach elephants to dance."

Indeed, drug design "seems like a very sequential process," says Klaus Mueller, head of Roche's New Technologies Group. But in rational drug design, an interdisciplinary team of scientists must continually share information. Most large drug companies have entrenched bureaucracies that keep scientists in different disciplines separated. Roche, in fact, reorganized Mueller's group in Switzerland recently to better integrate biotech and chemistry teams.

The pharmaceutical industry's recent productivity track record shows the need for such moves. A recent analysis by health care consultants The Wilkerson Group found that R&D spending by major international drug makers as a share of revenues has doubled since 1980. Yet the number of new drugs introduced has declined steadily since 1960. "The knowledge explosion in biology" could help reverse that trend, says Robert J. Easton, president of Wilkerson.

NO GUARANTEES. Big drugmakers tend to agree. Roche bought 60% of biotech leader Genentech last year partly to exploit the potential synergies of Genentch's gene-splicers and Roche's small-molecule experts. And in the past two years, larger drug companies have invested more than $200 million in technology-rich startups pursuing superdrugs.

There's no guarantee that rational drug design will restore the drug industry's R&D productivity. Richard A. F. Dixon, scientific director of Texas Biotechnology Corp. in Houston and another Merck veteran, predicts it will take years to refine superdrug technology. But Vertex' Boger hopes to have his first AIDS drug in testing by late next year, while Agouron plans to test a rationally designed psoriasis treatment by this fall. Genentech hopes to begin testing its IIb/IIIa inhibitor by mid-1992.

Boger is confident that small, nimble companies such as his will do best in this new type of drug design. But whether the startups remain independent and thrive is less important than the potential their technology offers: It's almost certain to beat opening the door to a cell with a key on the front of a blimp....AND IN THE FUTURE

STEP 1 BIOTECH Scientists pinpoint proteins that are central to a disease. By

genetic engineering, they make copies of them and probe how they react with

cells

STEP 2 PROTEIN CRYSTALLOGRAPHY

Researchers grow crystals that reveal the 3-D structures of the proteins. An

X-ray beam bombards the crystals, and a computer assembles the refraction

patterns to show where each atom is placed

STEP 3 COMPUTER MODELING

Computer programs create 3-D images of the molecular structure of the protein.

This helps chemists identify on which part of the cell a drug might work

STEP 4 CHEMICAL SYNTHESIS The drug is designed on a computer, which can also

run a simulated test of it. This improves the chances of arriving at the best

chemical compound but may be repeated many times before testing establishes

that the synthetic drug indeed works

DATA: AGOURON, BW

RAY VELLA/BW

Joan O'C. Hamilton in San Francisco, with Geoffrey Smith in Boston, John Carey in Washington, Joseph Weber in Philadelphia, and bureau reports


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