Agrochemical Control: Screening, costs, efficacy and environment

1
Agrochemical Control Screening, costs, efficacy
and environment

• Dr Naomi Pain
• Fungicide Lead, Discovery Biology
• Jealotts Hill International Research Centre

2
Menu

1. Market drivers and demands
2. Business strategy
3. RD Adaptations
4. Future development of disease control

3
Menu

1. Market drivers and demands
2. Business strategy
3. RD Adaptations
4. Future development of disease control

4
Agrochemical industry sales performance 1980-2005
US millions
Source Phillips McDougall
5
Drivers for fungal control in agriculture Fungal
control is a core business sector.
Total value 2005 30.05bn

• Fungicide sector expected to provide most growth
  over next 5 years 4
• Fungal control essential for high yield and
  quality

Source Phillips McDougall
6
Fungicide introductions 1980-2005
Cyproconazole
Tebuconazole
Prochloraz
Myclobutanil
Kresoxim-methyl
Metominostrobin
Fenpropimorph
Tetraconazole
Picoxystrobin
Carpropamid
Fludioxonil
Dimoxystrobin
Pencycuron
Benalaxyl (Metalaxyl 1977)
Tolclofos-methyl
Prothioconazole
Difenoconazole
Fenpropidin
Epoxiconazole
Dimethomorph
Trifloxystrobin
Pyraclostrobin
Propiconazole
Flusilazole
Fluoxastrobin
Azoxystrobin
Famoxadone
Flutolanil
Quinoxyfen
Cyprodinil
Fluazinam
Boscalid
1980
1990
2000
2005
1995
1985
Data from Cropnosis (2006)
7
Drivers for fungal control Resistance

• Resistance drives need for product refreshment
• Can develop faster than RD can deliver new
  technologies
• Resistance management is then a major issue
• Different types of resistance development and
  impact so monitoring is important
• Azoles creeping tolerance
• Strobilurins sudden and total failure
• Example Septoria tritici resistance to
  Strobilurin fungicides in Europe.

Septoria tritici
8
Drivers for fungal control Resistance
St Septoria tritici Bgt Blumeria graminis

• Septoria tritici most significant wheat disease
  in Europe
• Yield losses up to 40
• Strobilurin fungicides widely used since late 90s
• Crop typically received 1 to 2 strobilurin sprays
  per season
• Resistance risk monitored since launch
• Mechanism understood
• Diagnostic test for G143A mutation
• First control issues in 2002, followed by rapid
  spread

Resistance in population
100
St Germany
St UK
80
St France
St IR
60
Bgt Germany
40
20
0
98po
99po
00po
01po
02po
03po
04po
03pr
04pr
3 years
9
Many fungicide classes for resistance management
rotations and mixtures
sterol biosynthesis in membranes (Triazoles/
Imidazoles, Morpholines/Piperidines)
mitochondrial respiration Complex 1 2, QoI
inhibitors (strobilurins) Uncouplers
amino acid biosynthesis (anilinopyrimidines)
cell division / mitosis (benzimidazoles) Protein
synthesis inhibitors (acylanilides)
Multi-site effectors (e.g. Chlorothalonil)

• Also..chitin synthesis, melanin biosynthesis
  and others

10
Drivers for fungal control Control programmes

• Products to fit within programmes are a key
  requirement
• Provides
• spectrum of control
• resistance management
• added value effects

Greening/Yield
Rust
D.tritici repentis
Septoria tritici
Multi-site
Strobilurin
Triazole
11
Drivers for agricultural fungal control New
disease issues

• New disease pandemics can occur
• Example Soybean rust (Phakopsora pachyrhizi)
• a billion opportunity in N S America that
  didnt exist 6 years ago.
• a virulent strain from the Far East first
  identified in 1902
• rapid defoliation and dramatic yield losses (up
  to 80).
• Rapid spread from Zimbabwe in 1998 to S. Africa,
  S. America and USA by 2004.
• Over-wintered in Southern US States in 2004-5

Fungicide treated vs. untreated soya in Brazil
12
Septoria tritici/Septoria nodorum shift

• In the mid 1980s, N Eu saw a shift in the
  relative abundance of the two wheat pathogens
  Mycosphaerella graminicola and Stagonospora
  nodorum
• Several hypotheses have been proposed
  introduction of foliar fungicides, cultivar usage
  etc.
• Bearchell et al (PNAS, 2005) studied the
  Broadbalk collection (wheat samples collected
  from 1843-2002) established a link with SO2
  levels

1999 S.tritici
1970 S. nodorum
13
Fusarium Head scab

• Of increasing importance in UK and N Eu
• F. graminearum is increasing in prevalence
  (previously F. culmorum was dominant species in
  UK)
• Variety
• No/minimum tillage
• Maize rotation
• Temperature
• Increased awareness of mycotoxin contamination
  Deoxynivalenol (DON) and Zearalenone (ZEAR)
  limits imposed in Eu in July 2006

14
Regulatory environment brings challenges

• Re-registration requirements in EU have forced
  rationalisation of product portfolios
• Regulatory packages have become more complex
  resulting in increased development costs and
  timelines
• Environmental Science and risk assessment is
  critical to the selection of modern agrochemical
  development candidates
• Development of novel assays can predict
  tox/ecotox issues
• Impact of use rate, crop uses etc.

15
Agribusinesss focus on regulatory science brings
rewards
16
Menu

1. Market drivers and demands
2. Business strategy
3. RD Adaptations
4. Future development of disease control

17
Market drivers and challenges

• Continued demand for products
• Novel modes of action/chemistries
• Regulatory requirements
• Increased data provision
• Emphasis on safer compounds
• RD cost increases

18
RD Productivity OK, but steadily declining rate
of blockbuster introduction in the Ag industry
Number of blockbusters (gtUS 100m peak sales)
launched per year (rolling average)
Rolling average in respective preceding
10-year period Source McKinsey
19
Economic pressures industry response

• Efficiency improvements and cost savings
• Blockbuster strategy
• Improved product life cycle management

20
Agrochemical Industry consolidation
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Novartis
Ciba
Syngenta
Sandoz
Merck
Zeneca
ISK Biosciences
Bayer
Bayer
Aventis
Rhone-Poulenc
Hoechst
Schering
Monsanto
Monsanto
DuPont
DuPont
Shell
AHP
Cyanamid
BASF
BASF
Dow
Dow
Rohm Haas
21
Menu

1. Market drivers and demands
2. Business strategy
3. RD Adaptations
4. Future development of disease control

22
High throughput screening (HTS) used to find
starting-points

• Miniaturisation and automation has enabled
  high-throughputs at low cost and low ai amounts
• Increased access to new potentially-active
  chemicals available in small quantities
• Library Synthesis
• Natural Products

23
Sources of new molecules are continuously
required combinatorial chemistry plays a key
role

• Usually carefully selected to represent millions
  of virtual compounds in chemical space
• Lead explosion libraries designed using
• knowledge of target protein and active leads
• Computer modelling to maximise novelty and
  diversity
• Builds past experience into future design

24
Agribusiness RD can screen pathogens in
realistic HTS assays

• Many crop targets are obligate plant pathogens
• This test designed for mildews
• Miniaturised, with results in 5-7 days

Infected leaf
Mildew controlled

• Other technologies build on the fundamental
  advantage of in planta assays.
• Cascade moves to representative tests quickly,
  then to field.

25
Genomic technologies for target validation ?
novel MoA

• Essential genes can be identified by knock-outs
  etc
• But mimics 100 inhibition for 100 of the time.
• Not all these will be druggable!
• Some pathogens are difficult to transform so
  models are often used
• Protein over-expression and rational design is
  feasible but costly.
• in vitro to in vivo translation can be problematic

High-throughout protein crystallisation
26
Genomics technologies support characterisation
eg. Mode of Action
Fungicide test chemicals 1 2 3 4 5
6 7 8 9 10 11 12 13 14 15
16 17 18 19 20 21 22 23 24 25 26
27 28 29 30 31
Increased gene expression
Decreased gene expression
Known genes for fungal sterol biosynthesis
Known mode of action
NEW mode of action
Genes
Genes not associated with known modes of action
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Efficacy and development

• efficacy data in local markets generated
• Major focus on environmental impact
• Sophisticated modelling
• Precise mitigation possible

• Toxicology in humans is predictive using models
• Delivery to the active site is important
• Major formulation investments

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Delivery to the active site

• Agribusiness invests heavily in formulation
  science both for first launch and project
  life-cycle management.
• Example Adjuvant RD to improve activity by
• increasing droplet spread
• increasing leaf uptake

No adjuvant
Novel adjuvant
Standard adjuvant
With adjuvant
No adjuvant
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Agricultural formulations can be very
sophisticated
New surface properties
First generation

anionic

• Improved handling
• Targeted activity
• Differentiated products
• New markets
• Extended patent protection

lipid
cationic

Triggered release
trigger ruptures weak link for fast release at
right place / time
30
Menu

1. Market drivers and demands
2. Business strategy
3. RD Adaptations
4. Future development of disease control

31
Plant defence mechanisms may offer options for
the future

• Research on signalling pathways used by plants to
  recognise invading pathogens and mount a response
  provides new options.
• Basic mechanism of this Systemic acquired
  resistance is

• 1. A local infection creates a signal in the
  plant
• 2. The signal moves within the plant
• 3. The signal induces the synthesis of salicylic
  acid
• 4. Salicylic acid binds to a receptor
• 5. The receptor induces a cascade of effects
  resulting in long-lasting defense

Resistance
Signal
Induction
32
Chemicals can induce natural plant defense
mechanisms

• BION has no fungicidal activity
• It mimics salicylic acids role in natural plant
  defense mechanisms.

S
C
H
O
O
O
H
3
S
O
H
N
N
Salicylic acid
BION

• MESSENGER is a 403aa protein isolated from a
  plant pathogen.
• It elicits resistance to pathogen attack by
  activating the systemic acquired resistance
  pathways in plants.
• Registered and sold in the USA

Both provide broad spectrum effects (fungi,
bacteria, viruses) Both requires application
prior to pathogen attack.
33
GM technology has successfully exploited plant
defence mechanisms but not commercialised
anything yet

• Example Broad-spectrum fungal control in carrots

Alternaria dauci
Cercospora carotae
34
Conventional Breeding

• Some varieties do have increased horizontal
  resistance
• Wheat variety shift for greater Septoria
  resistance
• Quality and yield have been major drivers for
  breeding programmes
• Disease resistance breeding has had a tendency to
  focus on major R-genes
• Easier to screen for
• Generally not robust
• Pyramiding is required
• Marker assisted selection and mapping of
  resistance loci is aiding speed of programmes and
  retention of traits

Puccinia striiformis
Xanthomonas oryzae
35
Conclusion

• Accelerated breeding approaches (MAS etc) are
  starting to increase the level of resistance in
  commercial varieties. Limited by native gene
  pool
• New approaches (GM, Systemic Acquired Resistance)
  have not yet proved competitive with small
  molecules
• Unlikely that these approaches will replace
  fungicide use, but scope to combine strategies
  and gain synergy
• There remains a need for innovation in disease
  control

36
THANK YOU
Acknowledgements Mike Bushell, Martin Battersby,
Fergus Earley, Paul Worthington, Ulrich Gisi,
Paul Hendley, Amita Patel, Jonathan Shoham
37
Drivers for fungal control A core business
sector
Effects of Potato Late Blight (Phytophthora
infestans) exemplifies why agricultural fungal
control is so important to global agriculture
38
Drivers for agricultural fungal control
Resistance
Effect of one seasons strobilurin use on
resistance frequency
Frequency of G143A mutation
Less than 0.1
Between 0.1 and 10
pre 2004 treatment
post 2004 treatment
Between 10 and 20
More than 20
39
Progress of soybean rust, Brazil 2003
1st May
6th May
13th May
27th May
40
Drivers for agricultural fungal control New
disease issues

• Soybean rust economic impact
• Brazil 2004 4.5 M tonne losses costing 2B.
• USA potential losses - 2B/year?
• Correct timing of fungicide application is a
  challenge.
• Demands specialised monitoring techniques.
• The disease is controlled by systemic azole
  fungicides.
• Strobilurins add to the long-lasting effect and
  increase yield

41
View of Pharma from David Horrobin

• Billions invested in hi-tech approaches CADD,
  Combichem/HTS, genomics
• Bigger haystacks not more needles?
• HTS could it be that there is something wrong
  with the technology in principle and that target
  choice and configuration is fundamentally flawed?
• In Pharma Previous success based on crude whole
  animal or organ biology screens helped avoid the
  in vitro in vivo conversion issue
• Must get back to study of the whole organism

Sources Nature Reviews (2003) 2, 151-15 Nature
Biotechnology (2001), 19 1099-1100 J Royal Soc
Medicine (2000), 93, 341-345.
42
Shift in Agrochemicals

• We have the advantage of using whole organism
  screens
• Increased emphasis on more relevant screening
  organisms even at the expense of through put
• Data quality constantly being improved to
  increase confidence and allow decision making at
  an earlier stage ? increased efficiency
• Targeted use of genomics/in vitro technology to
  assist lead characterisation

43
Product life-cycle management a key feature of
agribusiness strategy

• Generics have ca 30 market, more in some local
  areas
• Longer product life cycles before compounds
  become generic
• Economies of scale
• Cost of goods critical for profitability in Ag
• Big investment to compete globally
• Complexity of supply chain
• Working capital
• Costs of continuous re-registration
• Many mixture products offer large farmer benefits
• Broad product range is essential to these offers
• Best mixtures often have a proprietary component