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Pfizer's Secret Weapon

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In a skunkworks 100 miles north of Pfizer’s R&D mothership, Alan Proctor’s team forges “the drug discovery paradigm of the future.”

 

by Adrienne Burke

 

Striding along the Charles River on a breezy, blue-sky, August afternoon, Alan Proctor recalls the early days of his drug-research career when he worked in a lab with an ocean view. “I would be standing there looking out and all of a sudden the solution to the problem I’d been locked on would just come to me,” says Proctor, a 27-year Pfizer veteran who is now the company’s vice-president for US discovery, genomics, targets, and cancer research.

There are no data to back him up, he concedes, but Proctor says he has a “gut belief” in going outside of the lab for inspiration. Once, to get creative juices flowing around Pfizer’s sprawling R&D campus in Groton, Conn., he invited local artists to exhibit their work in the facility’s miles of corridors. The idea took hold and earned him a reputation company-wide as an out-of-the-box thinker.

Proctor’s latest scheme has pushed the Pfizer envelope much further and taken him and his staff not just out of the box, but out of the state.

Two years ago Pfizer’s Discovery Management Committee saw “the genome project coming at us like a locomotive at full speed,” says Proctor. Throughout its history, the pharmaceutical industry has developed drugs for a field of about 500 known targets. Now, sequences of the human and other medically relevant genomes are expected to provide as many as 10,000 new drug targets.

“The tried and true method is one target, one drug candidate, one drug to treat one disease,” Proctor explains. “Well, the genome is coming, so that approach just isn’t going to work.”

His solution: set up a shop to figure out how to integrate data and disciplines such as informatics, engineering, chemistry, and molecular biology in order to devise a new “parallel-processing approach to drug discovery.”

Proctor envisioned an environment where scientists could work without being distracted by the everyday demands of drug discovery. Instead of drugs, their work product would be change. The concept was antithetical to the culture of the 150-year old pharmaceutical company, and unlike anything any of its competitors have done to date. Proctor laughs when he recalls first pitching it to CEO Bill Steere. “He kind of looked at me like, ‘You’ve got some credibility with me, Alan, I don’t believe you actually said that.’”

Nevertheless, Proctor says it wasn’t a hard sell. Like every pharmaceutical company, Pfizer is bracing for a genome-data-induced overhaul of its traditional procedures. It is open to far-out fixes.

Within two months Proctor got the go-ahead to take a long-term lease on a 100,000-square-foot building in Cambridge, Mass., and undertook a $25 million renovation project to turn the outpost, the former headquarters of a failed biotech company, into Pfizer’s Discovery Technology Center.

George Milne, president of strategic and operations management and Proctor’s Groton-based boss, says the Cambridge center represents about four percent of Pfizer’s total expenditures on drug discovery — which would put its annual budget in the $30 million range. The center, with capacity for a staff of 140, is small and nimble by design, he says, but adds, “It will get whatever resources it needs to do this integration job and to be a great conduit in terms of technology.”

Milne says Proctor has a “naturally peripatetic mind” and is open to new ideas, but is also familiar enough with the Pfizer machine to know that “you don’t want to have a palace in which these technologies all run.”

In other words, Proctor’s success will be measured according to the number of new drugs to which his team contributes. “This place isn’t going to survive five years if we don’t stay connected to Pfizer,” says Proctor. “If we don’t discover new chemical leads and verify new targets for the discovery projects, we will have failed. But, he adds, “if that’s all we get done, we will have failed.”

Though he predicts that the effects of its work won’t be felt around the global organization for another three to five years, Proctor says the center has already had a “bumper-crop year.” By studying them in parallel, his staff has been able to validate 20 genes in the phosphodiesterase (PDE) family for disease relevance using drug-like small molecules. (The PDE family includes targets for Viagra and asthma drugs.)

From idea-stage to validated lead, the center’s innovative method of analyzing the genes as a group got results “a couple of years” faster and with one-fifth the personnel than a traditional research program could have, says Proctor’s assistant director, Jeff Hanke.

Milne says Pfizer researchers perk up at the news. Their productivity is measured in terms of discovering drug candidates, he explains. “You are seeing guys in the laboratory saying, ‘Hey, step aside, we want this stuff in our lab.’ When you see people snarling about stuff like that, it’s good news, right?”

Slow or Stealthy?

Ask any industry observer to name the pharmaceutical company with the biggest lead in genomics, and Pfizer is not likely to roll off their tongue. Analysts cite SmithKline Beecham’s prescient 1993 database deal with Human Genome Sciences, Bristol- Myers Squibb’s innovative genomics subdivision, or Merck’s early establishment of a genome research institute. Pfizer, many say, has been late to the game.

Pfizer managers argue that they deserve more credit. Their company was first in 1994 to subscribe to Incyte’s LifeSeq database. And among the big pharmas, they maintain, Pfizer was also first to see the wisdom in establishing functional genomics partnerships with academic researchers, and first to set up camp in the genomics hotbed of Cambridge. They also like to point out that Pfizer invented high-throughput screening at least three years before competitors caught on. Says Milne, “We’re making a business of going out and figuring out hot ideas, and other people then mimic that.”

Proctor says, “We’ve been characterized as being slow to come to genomics, but I think we came to it thoughtfully. Some companies, as soon as the technology became established, immediately set up a 100-person department. We carefully found our way.”

Without getting inside Pfizer’s competitors, it’s impossible to judge just how innovative the approaches being developed at the Discovery Technology Center will be. After all, every pharma has access to proprietary genome data, and every one has massive libraries of compounds. Milne says Pfizer has spent $180 million on technology partnerships that have secured it access to the most cutting-edge technologies. But when Pfizer entered into its $17 million partnership last year with the ultra-high-throughput instrument-maker Evotec, Novartis and SmithKline Beecham were already customers. Aurora, another screening technology company with which Pfizer signed a $50 million contract in 1999, also has deals with American Home Products, Bristol-Myers Squibb, Glaxo Wellcome, and Merck.

Who really has the lead in genomics “will be hard to know until the drugs hit the clinic,” remarks Robert Hazlett, vice president and large cap pharmaceutical analyst at investment bank Robertson Stephens. “Pfizer may be playing catch-up, but the technology is evolving so rapidly, that they might not be penalized. Being late might just mean you’ve bought the right technology at the right time,” he says.

With the largest R&D budget in the industry — $4.7 billion calculated after its merger this summer with Warner Lambert — and executives whose flexible management style has made the company a media darling in recent years, Pfizer stands as good a chance as any big pharmaceutical company to gouge the genome for products.

Biotechy Feel, Big Pharma Funding

Its off¯site location has kept the DTC out of Pfizer’s mainstream, but Proctor’s intent was never to keep the skunkworks a secret. Its Memorial Drive address places the center within a mile of Harvard University, Harvard Medical School, MIT, and Boston University. Milne, who talks about creating work environments where “people’s brains rub against each other,” is a big believer in networking. And he and Proctor share the notion that university scientists could be a ticket to genomic success.

Since 1996, Pfizer has nurtured more than 20 relationships with academic discoverers of early stage targets. Lab space for the Drug Finders, as academic allies are called, was first to be retrofitted at the new center.

And Cambridge is a cornucopia of the sort of talent Pfizer is especially lacking: informaticists and computational biologists. One-quarter of the open slots at the new facility are in those fields. To draw them in, the center sponsors a computational biology fellowship at MIT, and dedicates lab space to incubating an MIT instrumentation spin-off company. Says Hanke, “We’ve built quite a few bridges with Harvard, Harvard Medical School, and MIT. There are educational initiatives, science fairs, scholarships. We’re getting into the community and participating. As a consequence, what comes back is tremendous.”

Eighty percent of the center’s staff thus far has been drawn from the neighborhood. It’s easy to see how new graduates are lured. The place has an atmosphere akin to Starbucks, with sleek furniture, curved walls, soothing colors, and plenty of natural light. The modern, open layout and casual décor is designed to encourage mingling and a flow of energy, Hanke says. Scientists are even allowed to write on the walls: windows that divide offices and lab space double as scratch pads.

A help-wanted ad entices bioinformaticists, cell biologists, and lab automation technicians to jobs that offer “the high visibility and responsibility available only in a small, entrepreneurial organization” and the “support of one of the world’s largest and most respected pharmaceutical enterprises.”

Says Hanke: “We’re entrepreneurial, we’re biotechy, we’re new, we’re different, we’re going to change the drug discovery paradigm. Students and postdocs love that.” They also like working at a place where they could follow their own idea through to the stage at which it becomes a drug, he says.

Feeding the Beast

“We like to think of ourselves as feeding the voracious appetite” of the Pfizer engine, says Stephen Faraci, who, with Hanke, assists Proctor running the DTC.

Faraci, energetic and fast-talking, describes how the Cambridge center will work with several outside vendors — known internally as the Big Six partners — to rapidly validate small molecule drug leads and turn them over to Pfizer scientists worldwide. “Incyte and Celera equals targets, Aurora and Evotec equals screening, ArQule and Neurogen equals compounds that become rapidly synthesized to leads,” Faraci explains. “We’re putting together the drug discovery paradigm of the future.”

The DTC shares access to data, technology, and compounds from the Big Six partners with all of Pfizer Central Research. An Evotec 1,536-well plate assayer and high-throughput screening system resides on the Groton R&D campus.

And on this particular day, an Aurora assay development system has just been installed in a sunny, class-100,000 clean room in the corner on the second floor. On the ground floor, a construction crew makes a racket with power tools and hammers, readying another space the length of the entire building to house Aurora’s huge 3,456-well ultra-high-throughput screening system.

From the get-go, Faraci predicts that the instruments will enable the center to screen about one million compounds every two weeks — a major leap since a decade ago when Pfizer was on the cutting-edge screening 5,000 compounds a week using well plates. What’s different now, besides throughput, is that the compounds are being screened against gene families.

“In a way, this is a brave new world. Do I think they’re going to work?” Faraci asks, holding up a 3,456-well plate. “Yes, they will work. Are they going to have their problems? Yes, they will. Look how small this is!” he exclaims, pointing to one of the needle-sized wells.

But Proctor thinks they can burn through assays even faster: “The equipment we’re putting in is certainly capable of hundreds of thousands a day once you’ve really got it humming. Then it’s just a challenge to eke a little two-fold improvement out of that.” That’s for Faraci to deliver, he says.

My mantra is one million assays a day; that’s my dream, within two years,” Proctor adds, cheerfully admitting that he gets a kick out of pushing the brink of failure.

It’s a characteristic that even drives his wife nuts, he says. To illustrate he relates, “I like to cook, but I don’t like to plan a normal simple menu that you know will be a cinch and gives you time to socialize. I like to plan a 14-course Chinese meal for 20 people. When I get to the point that I think it’s possible, it’s just putting another meal on the table.”

That anecdote makes Proctor’s next remark not at all surprising. His peripatetic mind is already on the horizon. “We’re moving closer and closer to my next vision, which is for a giant database in which we have every gene of the human genome annotated with pharmacological activity data about millions of compounds. We would be able to screen every gene against every compound in the Pfizer universe and be able to utilize the data. I think the tools to do that will be at our fingertips in five years.”

That project, he says, he’ll build in Palo Alto.

 

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