COVER STORY
TAKING COVER Agrochemical researchers can test potential new products directly on their "patients."
GROWING AGCHEM R&D Agrochemical researchers are maintaining their crop protection arsenals by using tools developed by the pharmaceutical industry PATRICIA L. SHORT, C&EN LONDON
R
ESEARCH IN AGROCHEMICALS USED TO BE SIMPLE:
"spray and pray," as one R&D director puts it. But that time is long gone in the $30 billion crop protection industry Pressuresfromregulators, shareholders, environmental activists, and consumers are driving companies in the business to product development that increasingly mirrors that of the pharmaceutical industry So it is not surprising to see the tools and techniques developed by drugmakers being used by agrochemical researchers. What's more, those researchers say, in many ways they are findwww.CEN-ONLINE.ORG
ing more success with the same tools than their counterparts in human health have. That's good news for the agrochemical industry Companies in the sector are counting on R&D to keep their pipelines of new products well-filled because, just as for drug companies, a full pipeline is key to the health and growth of the agchem industry For example, Bayer CropScience told investors earlier this month that it has doubled its forecast for sales of crop protection products containing new active ingredients. Previously, the target for sales of such products had been set at 1 billion euros— roughly $1.2 billion—per year, to be achieved by the end of 2006. Now, says Friedrich Berschauer, chairman ofthis BayC & E N / S E P T E M B E R 19. 2005
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COVER STORY er company, the company's target is 2 billion euros by the end of the decade. Similarly, BASF's Hans W Reiners, president of its agricultural products division, sees new products contributing sales of $2.2 billion by the end of the decade.
The big difference—and advantage— that David Lawrence, head ofresearch and technology at Syngenta, points out is: "We can test directly for the effect we want. We can test immediately on plants, fungi, and insects. "You can't do that in pharma." FOR AGROCHEMICAL companies, research Moreover, notes Bernward into new molecules means a substantial Garthoff, chief scientific officer commitment. Bayer figures that it costs for Bayer CropScience, agronearly $250 million from inception to chemical researchers get to doulaunch ofa newproduct, often 10 years lat- ble their fun: They can use the er—upfromroughly $60 million in 1990. two hemispheres to pack two Spending on initial chemistry is rough- seasons' worth of research into ly $80 million. Biology work, begun soon one year. On the other hand, Peter Eckes, BASF's senior vice presWEED WHACKERS ident for global research in the agriculturHerbicides dominate crop al products division, points out that drug protection chemical market researchers concentrate on the action of a substance in the human or animal patient Other Herbicides with absorption, distribution, metabolism, 5% 47% Fungicides 23%
LEADERS Nine companies report $1 billion or more in sales in crop science
Insecticides 25% SOURCE: Buckingham Research Group, New York City
after promising chemistry results, costs nearly the same amount. Follow-up toxicology and environmental analysis adds another nearly $85 million to the tab. Only after eight or nine years can a company submit registration documents to regulatory authorities. And only after regulators clear the product can it hit the market and begin to recoup those costs. For researchers at the six major agrochemical companies— BASF, Bayer, Dow Chemical, DuPont, Monsanto, and Syngenta—there are several fundamental differences between their industry and the pharmaceutical industry
COMPANY
COUNTRY
Bayer Syngenta Monsanto DuPont BASF Dow Chemical MakhteshimAgan Sumitomo Nufarm
2004 SALES3 ($ BILLION)
Germany Switzerland U.S. U.S. Germany U.S.
$7.4 7.3 5.5 4.8 3.4 3.4
Israel Japan Australia
1.5 1.4 1.0
a Crop science products. SOURCE: Buckingham Research Group; company data
excretion, and toxicology (ADME/Tox) studies. Agrochemical researchers, however, must go one step further into the environmental impact of the substance. Within theframeworkof those funda-
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mental differences, however, there actually are many similarities, Garthoff says. "When I moved from pharma to agrochemicals, the surprise was that it was not that different," he recalls. "I spent 18 years in pharma and almost 12 years in agrochemicals. They are quite similar; the basics are the same." Dan Kittle, vice president of R&D at Dow AgroSciences, agrees. "Research strategies are virtually identical," he says. "We use the same tools, but on an ag budget." However, as Kittle points out, when and if a pharmaceutical active ingredient is successful, the company developing it can enjoy tremendous success. "The investment/reward ratios are different," he explains. "But that's understandable. I'd pay a lot more to have my daughter treated than my field of soybeans." THE TRUE TEST of the closeness between agrochemical and pharmaceutical R&D, Kittle adds, comes down to staff. "I compete with the pharma folks toe-to-toe for chemists, biochemists, molecular designers, and so on." Pat Confalone, DuPont Crop Protection's vice president of global R&D, believes that his industry's main change in recent years has been the increased use of new discovery platforms. High-throughput screening remains a way of finding leads, but other approaches include combinatorial chemistry, directed library designs, patent and literature scouting, natural product extracts, and structure- or mechanism-based design. Any survey of the agrochemical industry's greatest need, Confalone says, will arrive at one conclusion: "Like any other R&D-intensive business, we need a great lead compound—that's the beginning of any dedicated discovery program. If you look back 10 years, it was leads. Ifyou look back 20 years, it was leads. So the major discovery platforms employed today are all designed to identify new lead compounds." High-throughput screening, however, does have some drawbacks, says Lawrence, whose career wends back to ICI, which owned the Zeneca agrochemical business that became part of Syngenta. At ICI, he recalls, "We started high-throughput screening in 1983. At the time, we were doing more in agrochemicals than in pharma. Then genomics came in, and combinatorial chemistry, and automation, which enabled us to do more."
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"Six or seven years ago, we would have said we were going into the exploitation ofthis enhanced high-throughput screening technology," Lawrence says. "But we had less money to spend on it than on pharma, so we couldn't go for the bignumbers." By Lawrence's reckoning, though, that was okay "In our experience, chemical library technology is quite restricted to the kind of molecules you can make. \bu do a skeleton and a lot of analogs, but the diversity isn't all that big. There is ahuge potential, and libraries only scratch the surface." Syngenta responded by stepping awayfromreally high throughput to about 1 million compounds per year, and he says, "We've stepped back evenfrom,say, half a million. Throughput occupied our time but didn't give us product." Instead, Syngenta has put more emphasis on designing molecules for the effects its researchers want. "We are using genomics to understand what is happening when we get the hits. We do that through automation and whole-organism tests. That seems to be working for us," Lawrence says. The trick, he adds, "is to find a molecule with an edge that can replace some-
tests is helping screen more compounds and make decisions faster. This has boosted the throughput of in vivo organism-based screeningbyafactorof 10. It has also enabled the company to look at more diverse compounds. One result: BASF claims that some 70-80% of the compounds it decides to pursue will make it to market. Eckes is also enthusiastic about in vitro technology "We are looking at genomics to identify new modes of action," he says. "In this respect, crop protection probably is more advanced than pharma. We can do targeted creation of antisense plants—introducing antisense genes in a plant, gene by gene. %u can down-regulate one gene and look at the effect on the plant." A successful new product in the pharmaceutical industry has a short, fast, high peak of profitability, then abruptly drops off as it comes off patent, Garthoff points out. Agrochemicals, on the other hand, follow a shallower, wider curve. "Ybu never have the sharp peak," he explains. "We have a longer penetration period. We have to cover all the different crops, for example." And that is why he adds, aproducer tries to identify as early as possible a new mech-
Just as for drug companies, a full pipeline is key to the health and growth of the agchem industry.
PESTS BE GONE It takes the human touch to evaluate the performance of new chemicals. thing that has been around for years." It should, he says, be an improvement in basic factors such as activity, potency, and safety But it should also be an improvement in convenience,fittingwhat a customer really wants. At BASF, Eckes says, miniaturization of
anism specific for one family of insects, perhaps, but extending to several. "The broader the spectrum, the better," he says. One area of significant difference between agrochemical and pharmaceutical research remains the frequency of collaborations with outside companies and institutes.
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