Crop Protection Overview CENews Apr 18 2011

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April 18, 2011Volume 89, Number 16pp. 13 - 17DOI:10.1021/CEN041211100807

Germinating Pesticides

Chemical firms change course in the search for new products foragriculture

Melody M. Bomgardner

Syngenta

There is an industrywhere research directors describe their work as finding a needle in a haystack. In thisindustry, the introduction of new high-throughput screening devices and sophisticated chemical modelingmore than a decade ago promised to bring a host of new active ingredients to light. Alas, the so-called advancesonly made the haystack larger.

These researchers do not work in the pharmaceutical industry, although they borrow the popular haystackmetaphor. Crop protection chemical scientists are also struggling to find new compounds to replace oldstandbys. As in the drug industry, finding a truly new mode of action is rare, and bringing new products to

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market costs more than ever before. Some research executives report going back to relying on the experienceand the gut instinctsof scientists who work in the lab and in the fields to decide which candidates to develop.

Discovering new products is not the only challenge facing developers of crop protection chemicals.Pharmaceutical companies can at least depend on healthy sales growth for their products, but the agriculturalchemicals business has to confront a market that is essentially flat, with most of the growth now in geneticallymodified seeds.

Nevertheless, leading firms including Syngenta, Bayer, BASF, DuPont, and Dow Chemical continue to spendhundreds of millions of dollars looking for new molecules with crop protection activity. And executives say theirresearch efforts are still capable of producing blockbuster herbicides, insecticides, and fungicidesjust not asmany as in the past.

If we think back to those original hard chemistries like DDT and chlorinated hydrocarbons that worked verywell, they were early products of modern synthesis chemistry, points out Jay J. Vroom, chief executive officerofCropLife America, an industry trade group. But fast-forward to where we are today. It takes longer todiscover and develop new chemistry. The easy-to-discover, low-hanging fruit have already been found, he says.

For every plant pest or disease, some kind of a solution already exists. So new products, whether made fromnew or existing classes of chemicals, have to fight to find a niche. If they can show a new mode of action orapply a known one differently, they may find a place helping growers manage resistant pests. And as farmerslook for increased yields to take advantage of high commodity priceswhether the crop is for food, fuel, or

fiberfirms can successfully market products that promote plant health and stress tolerance.

It is difficult to recoup the huge R&D costs that go into a new product. An agricultural chemical introduced in2008 carried an R&D price tag of $256 million, up from $184 million in 2000, according to agriculture marketresearch firm Phillips McDougal. Today, Vroom reports, only one of 140,000 potential candidates survives thewringer of hundreds of screens for efficacy and safety to make it to market.

The value of the global agricultural chemicals market last year was $38.3 billion, Phillips McDougal estimates.But real-dollar growthafter removing currency effects and inflationhas been under 1% annually over thepast five years. That translates to a nominal annual growth rate of 4.2%, according to Matthew Phillips,principal of the firm.

Part of the reason for the slow growth is the proliferation of genetically modified crops, and nowhere has thisbeen more evident than in the herbicide market. The adoption of seeds with genetically modified traits, which

began in 1996 with Monsantos Roundup Ready soybean, has significantly stunted the demand for chemical-based pest control. In contrast with anemic chemical growth, market growth in biotech traits has been a robust16.6% annually over the past five years, Phillips McDougal estimates.

The Roundup Ready trait has probably been the greatest shift of the herbicide market than any single otherfactor thats occurred in the history of mankind, Vroom declares. People thought it was dramatic to shift fromhand weeding to a metal hoe, but I dont think that change occurred as fast as adoption of Roundup-resistanttechnology. For companies having great success in selling other herbicides, suddenly competing with Roundupwas a nightmare commercially.

But the more than a decade-long dominance of glyphosate, the active ingredient in Roundup herbicide, isfinally fading because of the emergence of resistant weeds. Farmers who have depended on glyphosate almostexclusively will have to manage weed resistance by applying herbicides with different modes of action.

With the active ingredient Kixor, introduced in the U.S. last year, BASF is the first company to produce a newherbicide specifically aimed at this sliver of the market. We were one of the few companies that didnt close outherbicide research at end of the 90s, although we did do it a little smaller scale, recalls Jordi Tormo, head ofherbicide research at BASF.




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Kixor comes from a class of chemicals called benzoisothiazoles. It affects chlorophyll biosynthesis in broadleafweeds by inhibiting protoporphyrinogen IX oxidase. This mode of action is not new; predecessor productsexisted for soil applications. BASFs advance was to modify a side chain of an existing benzoisothiazole to helpit stick better to weeds leaves. The side chains lipophilicity gave it better attachment to the target, Tormoexplains.

Kixor provides excellent control of broadleaf weeds, he says, and some control of other weeds. Its major benefitto farmers, however, is that it can control broadleaf weeds that are resistant to glyphosate.

Kixor is used to kill weeds in fields prior to planting, a step called burndown. But with glyphosate, farmers havegrown accustomed to killing weeds after the crops have begun growing, including those that hide within the

crop rows. So BASF also has in its pipeline new seeds with traits that make them resistant to olderimidazolinone and dicamba herbicides.

Similarly, Dow AgroSciences is looking to resurrect an old herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), aspart of a new trait program. And Syngenta and Bayer CropScience are working to develop soybeans resistant toSyngentas herbicide mesotrione and other 4-hydroxyphenyl-pyruvate-dioxygenase (HPPD) inhibitors.

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These programs aside, not many major new products are in the works for weed control. A review of publiclyannounced upcoming pesticides from the pipelines of Syngenta, Bayer, BASF, DuPont, and Dow shows onlytwo products that claim to include new active ingredients to control weeds. Syngentas bicyclopyrone, anotherinhibitor of HPPD, aims to control both broadleaf and grass weeds that afflict corn and sugarcane. And thisyear, Bayer will launch indaziflam to control grass weeds in specialty crops such as fruits, nuts, and olives. Theactive ingredient inhibits cellulose biosynthesis in the grasses, according to regulatory filings.

But neither active ingredient exploits a new physiological target in weeds. In fact, although researchers have

discovered at least 22 modes of action to control weeds, no new ones have been found in the past 20 years,according to Robert Hartzler, a professor of weed science at Iowa State University. Its not easy going into thelab and finding new ways to kill plants, he says.

One result of the dearth of new modes of action is that weeds have had time to develop resistance to severalcommon herbicides. Waterhemp is the perfect example, Hartzler says. It has confirmed resistance to fivedifferent classes of herbicides, and were running out of options. Waterhemp competes with soybean and corncrops in the Midwest.

Its not clear that new technology can help. BASFs Tormo says the innovation behind Kixors side chain is anexample of a successful use of combinatorial chemistry and computer modeling to optimize a known class ofmolecules. Meanwhile, genomics and metabolomics were supposed to turn up entirely new targets for pestcontrol. But it is difficult to translate theoretical target activity into field activity, Tormo observes.

Weed physiology can adapt to, and in some cases thrive on, weather and soil conditions that are not easilyincorporated into computer models. Difficult-to-kill weeds have few metabolic weak links to attack. That iswhere you need expertise from chemists, biologists, and agronomists, Tormo says.

The outlook is brighter for insecticide development. Although sales of genetically modified cotton and cornengineered to produce theBacillus thuringiensis (Bt) toxin have sold briskly, DuPont and Dow have found newmarket niches worth exploiting.

At DuPont, as at BASF, researchers have moved away from a heavy dependence on modeling. Ten years ago,when the burden of wading through ever-larger libraries of molecules threatened to drag down the process oflaunching new products, the company began to reengineer, says Julia Wheeler, R&D director for cropprotection. The company decided to look first for opportunities in the marketplaceproducts that would appealto both farmers and regulatorsbefore investing in new leads.

We are still using high-throughput screening to focus quickly on active molecules. We do use genomics andunderstanding how molecules work to drive our optimization technology, Wheeler acknowledges. As forcombinatorial chemistry, we are not employing it to a great extent now.

The first product to benefit from DuPonts new focus is the insecticide Rynaxypyr, which the company launchedin 2008. It was discovered via the old technology-first process, but as a candidate, it stood out as a winnerunder the new market-based criteria. And it did find a ready market: In only its third year, Rynaxypyr broughtin $400 million in sales.

Rynaxypyr is a member of the anthranilic diamide chemical class. It boasts a new mode of action in its controlof pests in the order Lepidoptera, including many species of cutworms, leafworms, and hornworms. The activeingredient binds to insect ryanodine receptors, which modulate the release of calcium ions to control muscle




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contraction. When the receptor is bound, the channel stays open and calcium is depleted. Insects treated withRynaxypyr stop eating, become paralyzed, and die.

Wheeler lists several reasons that Rynaxypyr fit DuPonts market-centric approach. It controls important pests,has a new mode of action, is the first in a new class of pesticides, and displayed early signs from the farmcommunity that it would be an attractive investment for DuPont.

Rynaxypyr also looked good from a regulatory perspective. It is potent at very low doses compared with other

common insecticides, and its high level of specificity means it is less harmful to beneficial organisms such aspredatory insects and parasites. Because it works differently from current insecticides, growers can addRynaxypyr to programs designed to prevent the emergence of pesticide-resistant insects.

Phillips, the consultant, considers Rynaxypyr the best technology around for controlling Lepidoptera pests.Still, DuPont had to choose its markets carefully to ensure the best chance for success. Its a great example ofthe shift in the market and research focus due to genetically modified crops, Phillips says. In the past, thebiggest insecticide market was cotton, but control of Lepidoptera on that crop is now dominated by seedengineered to express Bt. Instead, he points out, DuPont is targeting fruit and vegetable growers.

Dow AgroSciences pipeline also includes a pesticide that works differently enough to be useful in controllingresistant insects. It plans to launch sulfoxaflor in 2012 for use against sap-feeding insects in cotton andvegetables. Those insects, which include aphids, are not controlled by Bt crops.

Dow says its new active ingredient, a member of a new class of chemicals called sulfoximines, interacts withinsect nicotinic acetylcholine receptors. Many common insecticides also target these receptors, but Dow claimsits different mode of action kills insects that are resistant to current products. The company figures that thelack of a ready biotech solution combined with the threat of resistant pests creates a $2 billion opening for itsnew product.

Another multi-billion-dollar market for crop protection chemicals is fungicides, in part because they do nothave to compete with genetically modified crops. But the bigger reason is that, in addition to fighting disease,they have been shown to benefit plant health.

Like its rivals DuPont and Dow, Syngenta continues to spend heavily to add to its portfolio, and fungicides areplaying a larger role. In 2010, the Swiss firm spent more than $1 billion on R&D. In the meantime, it has turnedto an older product, azoxystrobin, to drive revenue growth. Its researchers have found that when farmers applythe fungicide, even in the absence of fungal diseases, crops benefit from more vigorous growth and higher

yields.

Fungicides have had an important role historically, but there are a lot of new uses due to plant performancebenefits, particularly in corn, soy, and wheat, says Eric C. Tedford, Syngentas technical brand manager forfungicides.

Plants stay green longer, and they can better use the suns energy, which goes into the corn kernel, soybeanpod, or grain of wheat, Tedford explains. He says treated plants use water more efficiently and show improvedcarbon dioxide absorption during photosynthesis. In addition, fungicides improve plant performance bycontrolling low-level fungal diseases in crops that do not show symptoms of disease, he claims.

Syngenta is taking advantage of that potential. In 2010, the company sold $1 billion in azoxystrobin fungicidesunder the trade name Amistar. When crop prices are high, farmers are making more money, so they can affordto purchase more chemicals. They embrace anything to improve yield, Phillips explains.

The market opportunity has also triggered activity in new product development. Syngenta, Bayer, and BASFall have fungicide products coming out. If you look at the rate of new product introductions and their value, it isthe fastest growing category, Phillips says. Indeed, C&ENs analysis of corporate pipelines shows 13 upcomingfungicides, at least eight of which feature new active ingredients.

Syngenta also plans to introduce a different type of product to help farmers maximize yield potential. Invinsa, asprayable formulation of 1-methylcyclopropene, came out of a research partnership with Rohm and Haas, nowpart of Dow Chemical. Rather than protecting plants from pests, it works by protecting them from stress causedby periods of hot, dry weather.




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BASFLEAF LAB Researchers use automated devices, such as this leaf cutter, in their search for new fungicides.

It prevents the plant from recognizing the stress hormone ethylene, which it produces as a result of drought,high temperatures, or injuries, Syngenta brand manager Bernd Druebbisch explains. He says field trials haveshown Invinsa can mitigate the impact of moderate stress for five to eight days.

If the application is done at the right time, the product could carry the crop over the stress period, to when therain comes back, Druebbisch says. Then the plant would continue to grow normally without much effect onyield potential.

Similarly, Wheeler says DuPont is looking outside of the traditional pesticide categories to develop newproducts. Some parts of the answer include the protection of crops, clearly, but were looking at ways it can bedone in a more productive way to increase the robustness of crops, as well as increase yields and profitability.

Overall, however, the number of agriculture chemicals in the pipeline is down from past levels. CropLifesVroom lays some of the blame on increasingly stringent regulations. It doesnt come down to whether aproduct can ultimately be used safely but whether the market for the product can continue to justify theaddition of ongoing costs for safety testing, he says.

Phillips argues that the problem goes deeper than costly regulatory filings. In a market that is not expanding, hesays, only a few top firms can afford to put multiple products into development. To my mind, its thecompetitive environment between companies. What you can afford to do in a challenging environment is a keypoint.

At DuPont, such considerations now come into play much earlier in the R&D process than in the past, Wheelersays. When we began to reengineer our organization, processes, and technology, we asked, Whats happeningin the marketplace, and how do we know? she says. If we can meet the needs of customers and the demandsof society and regulators out into the future, then new products and new discoveries can be very profitable forthe farmer and the industry.




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Chemical & Engineering NewsISSN 0009-2347Copyright 2011 American Chemical Society

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Crop Protection Overview CENews Apr 18 2011