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April 18, 2011

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

Germinating Pesticides
Chemical firms change course in the search for new products for
agriculture
Melody M. Bomgardner

Syngenta

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

These researchers do not work in the pharmaceutical industry, although they borrow the popular haystack
metaphor. Crop protection chemical scientists are also struggling to find new compounds to replace old
standbys. 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 experience—
and the gut instincts—of 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 agricultural
chemicals business has to confront a market that is essentially flat, with most of the growth now in genetically
modified seeds.

Nevertheless, leading firms including Syngenta, Bayer, BASF, DuPont, and Dow Chemical continue to spend
hundreds of millions of dollars looking for new molecules with crop protection activity. And executives say their
research efforts are still capable of producing blockbuster herbicides, insecticides, and fungicides—just not as
many as in the past.

“If we think back to those original ‘hard’ chemistries like DDT and chlorinated hydrocarbons that worked very
well, they were early products of modern synthesis chemistry,” points out Jay J. Vroom, chief executive officer
of CropLife America, an industry trade group. “But fast-forward to where we are today. It takes longer to
discover 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 from
new or existing classes of chemicals, have to fight to find a niche. If they can show a new mode of action or
apply a known one differently, they may find a place helping growers manage resistant pests. And as farmers
look for increased yields to take advantage of high commodity prices—whether the crop is for food, fuel, or
fiber—firms 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 in
2008 carried an R&D price tag of $256 million, up from $184 million in 2000, according to agriculture market
research firm Phillips McDougal. Today, Vroom reports, only one of 140,000 potential candidates survives the
wringer 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 growth—after removing currency effects and inflation—has been under 1% annually over the
past 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 this
been more evident than in the herbicide market. The adoption of seeds with genetically modified traits, which
began in 1996 with Monsanto’s 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 robust
16.6% 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 other
factor that’s occurred in the history of mankind,” Vroom declares. “People thought it was dramatic to shift from
hand weeding to a metal hoe, but I don’t think that change occurred as fast as adoption of Roundup-resistant
technology. For companies having great success in selling other herbicides, suddenly competing with Roundup
was a nightmare commercially.”

But the more than a decade-long dominance of glyphosate, the active ingredient in Roundup herbicide, is
finally fading because of the emergence of resistant weeds. Farmers who have depended on glyphosate almost
exclusively 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 new
herbicide specifically aimed at this sliver of the market. “We were one of the few companies that didn’t close out
herbicide research at end of the ’90s, although we did do it a little smaller scale,” recalls Jordi Tormo, head of
herbicide research at BASF.

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Kixor comes from a class of chemicals called benzoisothiazoles. It affects chlorophyll biosynthesis in broadleaf
weeds by inhibiting protoporphyrinogen IX oxidase. This mode of action is not new; predecessor products
existed for soil applications. BASF’s advance was to modify a side chain of an existing benzoisothiazole to help
it stick better to weeds’ leaves. “The side chain’s lipophilicity gave it better attachment to the target,” Tormo
explains.

Kixor provides excellent control of broadleaf weeds, he says, and some control of other weeds. Its major benefit
to 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 have
grown 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 older
imidazolinone and dicamba herbicides.

Similarly, Dow AgroSciences is looking to resurrect an old herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), as
part of a new trait program. And Syngenta and Bayer CropScience are working to develop soybeans resistant to
Syngenta’s 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 publicly
announced upcoming pesticides from the pipelines of Syngenta, Bayer, BASF, DuPont, and Dow shows only
two products that claim to include new active ingredients to control weeds. Syngenta’s bicyclopyrone, another
inhibitor of HPPD, aims to control both broadleaf and grass weeds that afflict corn and sugarcane. And this
year, Bayer will launch indaziflam to control grass weeds in specialty crops such as fruits, nuts, and olives. The
active 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. “It’s not easy going into the
lab 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 several
common herbicides. “Waterhemp is the perfect example,” Hartzler says. “It has confirmed resistance to five
different classes of herbicides, and we’re running out of options.” Waterhemp competes with soybean and corn
crops in the Midwest.

It’s not clear that new technology can help. BASF’s Tormo says the innovation behind Kixor’s side chain is an
example of a successful use of combinatorial chemistry and computer modeling to optimize a known class of
molecules. Meanwhile, genomics and metabolomics were supposed to turn up entirely new targets for pest
control. “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 easily
incorporated into computer models. Difficult-to-kill weeds have few metabolic “weak links” to attack. “That is
where you need expertise from chemists, biologists, and agronomists,” Tormo says.

The outlook is brighter for insecticide development. Although sales of genetically modified cotton and corn
engineered to produce the Bacillus thuringiensis (Bt) toxin have sold briskly, DuPont and Dow have found new
market 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 of
launching new products, the company began to reengineer, says Julia Wheeler, R&D director for crop
protection. The company decided to look first for opportunities in the marketplace—products that would appeal
to both farmers and regulators—before investing in new leads.

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

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

Rynaxypyr is a member of the anthranilic diamide chemical class. It boasts a new mode of action in its control
of pests in the order Lepidoptera, including many species of cutworms, leafworms, and hornworms. The active
ingredient 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 with
Rynaxypyr stop eating, become paralyzed, and die.

Wheeler lists several reasons that Rynaxypyr fit DuPont’s 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 farm
community 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 as
predatory insects and parasites. Because it works differently from current insecticides, growers can add
Rynaxypyr 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. “It’s a great example of
the shift in the market and research focus due to genetically modified crops,” Phillips says. In the past, the
biggest insecticide market was cotton, but control of Lepidoptera on that crop is now dominated by seed
engineered to express Bt. Instead, he points out, DuPont is targeting fruit and vegetable growers.

Dow AgroScience’s pipeline also includes a pesticide that works differently enough to be useful in controlling
resistant insects. It plans to launch sulfoxaflor in 2012 for use against sap-feeding insects in cotton and
vegetables. 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 with
insect nicotinic acetylcholine receptors. Many common insecticides also target these receptors, but Dow claims
its different mode of action kills insects that are resistant to current products. The company figures that the
lack of a ready biotech solution combined with the threat of resistant pests creates a $2 billion opening for its
new product.

Another multi-billion-dollar market for crop protection chemicals is fungicides, in part because they do not
have 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 are
playing a larger role. In 2010, the Swiss firm spent more than $1 billion on R&D. In the meantime, it has turned
to an older product, azoxystrobin, to drive revenue growth. Its researchers have found that when farmers apply
the 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 performance
benefits, particularly in corn, soy, and wheat,” says Eric C. Tedford, Syngenta’s technical brand manager for
fungicides.

“Plants stay green longer, and they can better use the sun’s energy, which goes into the corn kernel, soybean
pod, or grain of wheat,” Tedford explains. He says treated plants use water more efficiently and show improved
carbon dioxide absorption during photosynthesis. In addition, fungicides improve plant performance by
controlling 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 fungicides
under the trade name Amistar. “When crop prices are high, farmers are making more money, so they can afford
to 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 BASF
all have fungicide products coming out. If you look at the rate of new product introductions and their value, it is
the fastest growing category,” Phillips says. Indeed, C&EN’s analysis of corporate pipelines shows 13 upcoming
fungicides, 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, a
sprayable formulation of 1-methylcyclopropene, came out of a research partnership with Rohm and Haas, now
part of Dow Chemical. Rather than protecting plants from pests, it works by protecting them from stress caused
by periods of hot, dry weather.

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BASF
LEAF 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 have
shown 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 the
rain comes back,” Druebbisch says. “Then the plant would continue to grow normally without much effect on
yield potential.”

Similarly, Wheeler says DuPont is looking outside of the traditional pesticide categories to develop new
products. “Some parts of the answer include the protection of crops, clearly, but we’re looking at ways it can be
done 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. CropLife’s
Vroom lays some of the blame on increasingly stringent regulations. “It doesn’t come down to whether a
product can ultimately be used safely but whether the market for the product can continue to justify the
addition 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, he
says, only a few top firms can afford to put multiple products into development. “To my mind, it’s the
competitive environment between companies. What you can afford to do in a challenging environment is a key
point.”

At DuPont, such considerations now come into play much earlier in the R&D process than in the past, Wheeler
says. “When we began to reengineer our organization, processes, and technology, we asked, ‘What’s happening
in the marketplace, and how do we know?’ ” she says. “If we can meet the needs of customers and the demands
of society and regulators out into the future, then new products and new discoveries can be very profitable for
the farmer and the industry.”

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More On This Story

• Germinating Pesticides
• Life After Roundup
• Going Mainstream

Chemical & Engineering News

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