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Horizons
DRUG DISCOVERY

New tools and business structures show signs of plumping early-stage pipelines

By Malorye Branca

 'Signs': GSK's Peter Goodfellow sees drug development beginning to reap the rewards of its efforts. 
November 15, 2003 | The breakthrough medicines promised by the genomics revolution are nowhere and everywhere at once. While several high-profile "genomic" drugs — those springing directly from gene databases — have been dropping out of development at biotechs with worrying regularity, in pharma, meanwhile, genomic technologies have become firmly entrenched.

"Everything we do is rooted in genomics," says Peter Goodfellow, former chair of genetics at Cambridge University and now senior vice president of discovery research at GlaxoSmithKline (GSK) in the U.K. Jim Fickett, global director of bioinformatics at AstraZeneca, concurs. "Genomics is now a necessary part of doing business at almost every stage," he says.

Most important, the long-awaited payoff that companies are seeking is becoming distantly visible in the pipelines.

For the past few years, some analysts have argued that genomics is actually slowing drug discovery. Reports by Lehman Brothers and McKinsey & Co.'s The Fruits of Genomics, released in early 2001, predicted that companies would need several years to take advantage of so many complicated new tools. The problem was compounded by unwieldy management structures and research groups at the big drug makers and exacerbated by a stream of mega-mergers, the most recent being Pfizer's joining with Pharmacia. (Pfizer CEO Hank McKinnell stated recently that there are "no large mergers to be expected in the near future.") Mega-companies need mega-profits, increasing the pressure on their pipelines.

GSK's thrashing with this problem has been more public than most. Tachi Yamada, chairman of R&D at GSK, caused a stir in early 2002 when he told the Financial Times, "There may come a time when we do not do any of that [research]." Yamada said GSK might spin out any of its six Centres of Excellence for Drug Discovery if they didn't produce well enough. These centers were formed after the merger of Glaxo Wellcome and SmithKline Beecham in 2000, as a way to re-inject innovation into the company's bulging research arm. Each center refines drug leads in a specific therapeutic area, such as psychiatry or infectious disease.

The New York Times reported recently that former GSK managers claimed the company's labs were virtually paralyzed by the post-merger reorganization. Peter Traber, previously senior vice president of clinical development and medical affairs at GSK, now president and CEO of the Baylor College of Medicine, even went so far as to say: "It's a disaster."

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But today, many big pharmaceutical firms, including GSK, believe they are finally improving productivity, after several tense years of backpedaling — spending more but getting less. Goodfellow says, "We are seeing signs that we have indeed increased both the speed-through of the process and the number of agents coming out."

"There is a clear hint that more compounds are moving into Phase I trials," says Paul Herrling, head of corporate research at Novartis.

This progress, very early in the pipeline, is attributable to both improved management structure and growing experience with the latest technology.

GSK, for example, has been "identifying all the areas amenable to high throughput," says Goodfellow, whose job is to find new compounds for the Centres of Excellence to follow up on. Some tasks are more difficult to automate than others, which has hampered expected efficiencies. For example, determining the 3-D conformation of proteins is far more difficult than routine DNA sequencing. As a result, determining which drug candidates to test against a new protein target is a big bottleneck.


Process Means Progress
GSK has taken several steps to expedite this process, including running ultra-fast "ligand fishing" expeditions. These net the company lengthy lists of structures, or ligands, that bind to popular targets, such as the notorious ATP-binding pocket of kinase molecules. That pocket is the focus of many new cancer-drug development programs. Having the information about the types of structures that do work should help GSK avoid testing more of the compounds that won't.

"Deciding where you want high throughput, and where [you don't], is very important," Herrling agrees. The Genomics Institute of the Novartis Research Foundation, located in San Diego and headed by Peter Schultz, was set up specifically to access and evaluate budding technologies.

Novartis is also proud that it skipped much of the early gene-hunting frenzy, immersing itself instead in understanding how genes work. Dalia Cohen leads the main functional genomics effort (see "Talent Fuels Drug Pipeline in Swiss Time," Jan. 2003 Bio·IT, page 63). "To be simplistic," Herrling says, "Dalia does the wet part and Peter [Schultz] the engineering." The activities of those two groups are increasingly converging.

Companies have also had to move up the new technology learning curve. Initial inexperience with microarrays, for example, resulted in bad data and bum steers. "The gene-expression data at AstraZeneca seem pretty reproducible now," Fickett says. "I don't see people reversing ideas about their results anymore, as used to happen."

At Wyeth, expression profiling with microarrays started out as a niche activity, then spread across the company, but is now specialized again. For a while, scientists were trying to "figure it out," says Charlie Richard, vice president in Wyeth's genomics department. "Now, it makes more sense to have a dedicated core group run the chips."

The application of DNA microarrays is also evolving. Used initially to validate and explore new gene targets, "we are now also using them in lead optimization," Richard explains. One task of Wyeth's new discovery medicine unit is to help smooth the transition of microarrays and other tools from discovery into clinical trials. Wyeth has consistently been at the forefront of this field — its scientists tested the first Affymetrix GeneChips, and it was the first large pharmaceutical company to subscribe to GeneLogic's gene-expression databases.

Another major bottleneck is assembling everything known about a genomic drug target, regardless of whether that information is produced inside or outside the company. "We have a major internal project in development around data integration and sharing," Fickett says. That includes aggressively pursuing new ways to mine the millions of scientific reports and papers in text databases (see "Digging into Digital Quarries," Oct. 2003 Bio·IT, page 38).

Pure genomic drug candidates may be scarce, but many compounds have received a boost from genomics, particularly in combination with traditional genetics. Patrice Milos, assistant director of pharmacogenomics and clinical biochemical measurements at Pfizer, points specifically to two drug candidates. One is a CETP inhibitor, which arose from the observation that people with mutations in that gene have high levels of HDL (good) cholesterol. The company's work on a CCR5 receptor inhibitor, meanwhile, grew out of studies of natural resistance to HIV infection. In both cases, genomic tools speeded the drug development process. Neither drug is approved yet, but their novel mechanisms have generated great interest.

For the most part, "genomics got us the targets," Milos says. Groups like hers now have to provide "real value" around those targets by clarifying their relationships to disease and animal models. In the next few years, new genomics-fed compounds will enter trials against cancer, osteoporosis, diabetes, and cardiovascular research. Close behind will be the tougher cases, such as schizophrenia, stroke, and Alzheimer's disease.

With a minimum of merger backlash, these would-be new drugs should move even more quickly than their predecessors. Still, the hardest part of the drug development process undoubtedly lies ahead. "We never really know how successful we've been until we get those new agents through to the market," Goodfellow says. Based on the number of drugs entering the pipeline, a wave is ahead in the next 5 to 10 years. But as Herrling cautions, that is contingent on "assuming the attrition rate of these compounds is not higher." * 

 International affairs: GSK's Tres Cantos facility in Spain now carries out ultra-high-throughput screening and high-throughput chemistry. 










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