Andy Leadbeater

Head of Fungicide Technical R&D, Basel Switzerland

Introduction of new fungicides for Septoria Leaf Blotch Control

EPPO Workshop on azole fungicides and Septoria leaf blotch control, Rothamsted December 2010

2

2

0

14

Agriculture is innovation driven…

Source: Financial Times, Phillips McDougall

2

4

6

8

10

12

R&D investment as percent of sales by sectorPercent of

sales

8

6

4

2

3

Loss of active substances: Cereal fungicides example

Charts show percentages of EU-27 arable fungicide value

2002 2008 2014?

61%

31%

8%Triazole

Stro-

bilurin

Other

33%

49%

18%

• Strobilurin resistance

continues to grow

• Triazoles significantly

restricted by cut-off

criteria

• Still fewer “other”

alternatives available

Triazoles dominate

Strobilurin resistance

widespread

Strobilurins dominate,

followed by triazoles

Other Triazole

Stro-

bilurin

Reduced Yields

Loss of EU competitiveness

Greater reliance on grain

imports

4

Waves of new chemistry for sustainable disease control

• From broad spectrum and low resistance risk to highly specific and high

resistance risk

• Innovation key for solving continuous pathogen adaptation

• Mixtures: tool for resistance management program and disease control

security.

5

“Industry can come up with new solutions”.....

● Costs of new product discovery and development have risen by 39%

from 2000-2008

6

Costs of New Product Discovery and Development

32 41 42

30

44 3210

91118

20 3618

25

54

18

18

32

13

16

24

13

11

25

0

50

100

150

200

250

300

1995 2000 2005-2008

$M

Registration

Environmental Chemistry

Toxicology

Field Trials

Chemistry.

Tox/Env Chemistry

Biology

Chemistry

Development 146

Source: ECPA / Crop Life America 2010

Total $152 m

Total $184 m

Total $256 m

Development 67

Development 79

Research 72Research 94 Research 85

7

Will new chemistry be available to fill the gap?

Drivers for Innovation:

Rapid time to Market

•Increasing number, and complexity

of new testsStable development costs

Predictable review process

Return on R&D investment

•Significant uncertainty

•Erosion of data protection rights

•Increasing delays (average 6 years)

Need.. Have..

8

“Industry can come up with new solutions”.....

● Costs of new product discovery and development have risen

by 39% from 2000-2008.

● Number of molecules screened to bring 1 to market is

around 140,000.

● Number of years between first synthesis and market has

increased to 9.8 years.

● Increased registration requirements thus increase cost and

impact on development workload and time to market

negatively.

● New EU regulations raise the hurdles further for new

product innovation and are likely to reduce the chances of

success.

9

Year Fungicide

1940 - 1960 thiram, zineb, nabam, biphenyl, oxine copper, tecnazene, captan, folpet, fentin

acetate, fentin hydroxide, anilazine, blasticidin S, maneb, dodine, dicloran13

1960 - 1970 mancozeb, captafol, dithianon, propineb, thiabendazole, chlorothalonil,

dichlofluanid, dodemorph, kasugamycin, polyoxins, pyrazophos, ditalimfos,

carboxin, oxycarboxin, drazoxolon, tolyfluanide, difenphos, benomyl,

fuberidazole, guazatine, dimethirimol, ethirimol, triforine, tridemorph

24

1970 - 1980 Iprobenfos, thiophanate, thiophanate-methyl, validamycin, benodanil,

triadimefon, imazalil, iprodione, bupirimate, fenarimol, nuarimol, buthiobate,

vinclozolin, carbendazim, procymidone, cymoxanil, fosetyl-Al, metalaxyl,

furalaxyl, triadimenol, prochloraz, ofurace, propamocarb, bitertanol

diclobutrazol, etaconazole, propiconazole tolclofos-methy, fenpropimorph

29

1980 - 2000 benalaxyl, flutolanil, mepronil, pencycuron, cyprofuram, triflumizole, flutriafol,

penconazole, flusilazole, diniconazole, oxadixyl, fenpropidin, hexaconazole,

cyproconazole, myclobutanil, tebuconazole, pyrifenox, difenoconazole,

tetraconazole, fenbuconazole, dimethomorph, fenpiclonil, fludioxonil,

epoxyconazole, bromuconazole, pyrimethanil, metconazole, fluquinconazole,

triticonazole, fluazinam, azoxystrobin, kresoxim-methyl, metaminostrobin,

cyprodinil, mepanipyrim, famoxadone, mefenoxam, quinoxyfen, fenhexamid,

fenamidone, trifloxystrobin, cyazofamid (acibenzolar s methyl)

42

Key Fungicide Introductions

10

Year Fungicide

2000 - present picoxystrobin , pyraclostrobin, prothioconazole,

ethaboxam, zoxamide, fluopicolide, flumorph,

benthiavalicarb, iprovalicarb, mandipropamid, boscalid,

silthiofam, meptyldinocap, amisulbrom, orysastrobin,

metrafenone, ipconazole, proquinazid, penthiopyrad,

isopyrazam, ametoctradin

ca. 20

Future Many known pipeline products

● Industry continues to invest heavily into providing new innovative

solutions, despite increased costs and legislation. Sustainability is

essential to maintain this investment

Key Fungicide Introductions

11

Fungicide Mode of Action Groups Available for Resistance Management in Wheat (adapted from HGCA, 2010)

Rusts S tritici S nodorum Mildew Eyespot Ear Blight

DMIs Triazoles **** **** **** ** **** ***QoI Strobilurins **** * **** * * ***Amines Amines *** * ***Chloronitriles Chlorothalonil * *** ** *APDs Cyprodinil **** *** **Azanaphthalenes Quinoxyfen

Proquinazid****

Benzofenone Metrafenone * **** **Phenylacetamides Cyflufenamid ****Dithiocarbamate Mancozeb * ** ** *Carboxamides Various

(provisional)**** **** ? *** **** ?

performance of best fungicides in each class (adapted from HGCA 2010; modified)

**** excellent *** very good ** moderate * poor (**** resistance losses)

Septoria tritici: Very limited possibilities for resistance management

Powdery mildew: Good situation with > 6 modes of action

12

So What's New??

13

Bayer presentation IUPAC Congress Melbourn 2010

Classification: INTERNAL USE ONLY

14

New QoIs -The Strobilurin Family(FRAC Code 11)

Company Compound Launch

Syngenta azoxystrobin Sales 2008:

895 mio US$*

BASF pyraclostrobin Sales 2008:

670 mio US$*

Bayer CS trifloxystrobin Sales 2008:

474 mio US$*

Kumiai pyribencarb 2010

Shenyang pyrametostrobin Provisionally

approved

Shenyang coumoxystrobin ?

Shenyang pyraoxystrobin Provisionally

approved

Shenyang triclopyricarb ?

Shenyang dicloaminostrobin ?

* Phillips McDougall 2009

15

Summary (QoI / Strobilurins)

• No new breakthrough in the QoI area (new

compounds show limited biological potential)

• All new compounds seem to be x-resistant to the

market strobilurins

• New compounds might be only of local importance

e.g. China

16

Complex II Inhibitors – SDHI FamilyBoscalid (BASF) – the first broad spectrum SDHI

Chemical Group Pyridine carboxamide (bisphenyltype amide)

Mode of Action SDHI (complex II inhibitor)

Spectrum Alternaria (vegis), botrytis (grapes), sclerotinia (lawn,

oilseed rape and lettuce) and eyespot (cereals)

Characteristics Protective, persistent, crop enhancement effects claimed

Registration 2002

Sales First sales 2003

Reinhardsbrunn Symp April 2010

N

O

N Cl

Cl

H

boscalid

17

Historical Overview of SDHIs (source: BASF)

Market entry of selected fungicidal SDHI´s & their main targets

1969

O

SN

O

19811974

carboxin

(Uniroyal)

fenfuram

(Shell/Bayer CS)

O N

O

benodanil

(BASF)

N

O

I

mepronil

(Kumiai)

1986

flutolanil

(Nihon Nohyaku)

1997

thifluzamide

(Monsanto/Dow)

furametpyr

(Sumitomo)

2003

boscalid

(BASF)

N

O

O

N

O

O

F

F

F

N

N

N

OCl

O

S

N N

OFF

F

Br

Br O

F

F

F

N

N

Cl

Cl

O

seed disinfection

(& foliar spray) rice diseases specialty crops

2010 – 2012

penthiopyrad

(Mitsui) S

N

N

N

O

CF3fluopyram

(Bayer CS)N

O

CF3

N

Cl CF3

bixafen

(Bayer CS)

N

N

N

O

CHF2

Cl

Cl

F

isopyrazam

(Syngenta)N

N

N

CHF2

O

fluxapyroxad

(BASF)

N

N

N

O

CHF2

F

F

F

sedaxane

(Syngenta)

N

N

N

CHF2

O

penflufen

(Bayer CS) N

N

N

O

F

cereals

18

SDHI - Mode of Action

IComplex

III IV

Complex IIinside

outside

NADH+H+ NAD+

2 e-

½O2 + 4 H+ H2O2 H+

ADP + Pi ATP

3 H+

3 H+

2 H+

-

Q

2 H+2 H+

Citrate Cycle

AcetylCoA

Citrate

Fumarate Succinate

Oxalacetate

SDHIs Strobilurins

Mitochondrial

Membrane

Complex II (Succinate Dehydrogenase)

Respiration Inhibitor - SDHI

19

SDHI„s bind to the UQ pocket of SQR of the complex II

Isopyrazam

N

O

NN

F

F

H

O

O

O

On

O

O

O

OSuccinate Ubiquinone

Septoria tritici SDH inhibition

-2 2 4

-50

50

100

150

Boscalid

Penthiopyrad

Fluopyram

SYN 520 (9:1)

Bixafen

Log (nM) AI

isopyrazam

2x e-

● Essential TCA cycle reaction

● ...can be blocked

20

Efficacy of Isopyrazam for control of Septoria tritici

0 10 20 30 40 50 60 70 80 90 100

Untreated

EPZ 1.0

IZM 1.0

IZM 1.0+ EPZ 0.5

Variety: DUXFORD LSD: 19.30

Application: GS30-31 (22/04), GS39-41 (14/05) ,

% Septoria tritici on leaf 2 (58 DAA2)

Source: AGRISEARCH, UK

21

Isopyrazam for control of Septoria tritici

0 20 40 60 80 100

Untreated

EPZ 125g

IZM 125g

EPZ 90g+Bravo 500g

IZM 125g+EPZ 90g

Location: Terrington, UK

Variety: Consort LSD: 10.83

Applic: GS31/32 (28/04), GS39-45 (21/05)

% Septoria tritici on leaf 2, 54DAT2

Rates: gai/ha

22

Improved yields from SDHI chemistry

8 8.5 9 9.5 10 10.5 11 11.5 12 12.5 13 13.5 14

Untreated

EPZ 125g

IZM 125g

EPZ 90g +Bravo 500g

IZM 125g + EPZ 90g

Yield (t/ha)

Location: Terrington, UK

Variety: Consort LSD: 0.97

Applic: GS31/32 (28/04), GS39-45 (21/05)

Rates: gai/ha

23

Isopyrazam

Exciting New Chemistry

IZM, 125 ga/ha

Untreated

24Efficacy advantage

Source 23 trials various

Advantage 1l/ha high

performing triazole

Advantage

isopyrazam

Trials show outstanding brown rust control with

isopyrazam

25

Resistance risk assessment for SDHI fungicides

● Single site inhibitors

● Mutations in the target genes (sdh genes) lead to resistance

● Compound risk is „medium to high“

● Putative resistance risk

- Mycosphaerella graminicola: medium to high

- Pyrenophora teres: medium

- Rhynchosporium secalis: low to medium

- Puccinia recondita: low

- Ramularia collo-cygni: medium

● SDHIs should always be applied in mixtures or alternations with an appropriate partner i.e. one that is active in its own right against current field populations of the target pathogen at the applied dose

Source: Sierotzki et al, Reinhardsbrunn 2010

26

Monitored species / SDHIs and reported cases of resistance

Pathogen Field Sensitivity Pathogen Field Sensitivity

A. alternata R (US), Pistachio E. necator S

B. cinerea R (in grapes and

strawberries, apple storage

etc.)

S. sclerotiorum S (R, single isolate from OSR

in 2008 but not re-found

(FRAC))

C. cassiicola R (cucurbits, Japan) M. fijiensis S

P. xanthii R (cucurbits) V. inaequalis S

P. leucotricha S

M. graminicola S

P. teres S

R. secalis S

R. collo-cygni S

Tapesia spp. S

M. nivale S

U. nuda S?

27

SDHI Sensitivity Monitoring

● 2010 monitoring in cereals (all FRAC Working Group companies) show

a continuing fully sensitive situation for SDHIs against all pathogens

including M graminicola.

● All values are within the estabished baseline sensitivity range. No

change for isopyrazam since 2004 (start of monitoring).

C

28

SDHI FRAC Working Group recommendations

SDHI Guidelines – Cereals 2011

● Apply SDHI fungicides always in mixtures applied as tank mix or as a co-

formulated mixture

● The mixture partner:

- should provide satisfactory disease control when used alone on the

target disease

- must have a different mode of action

● Apply a maximum of 2 SDHI fungicide containing sprays per cereal crop.

● Apply the SDHI fungicide preventively or as early as possible in the

disease cycle. Do not rely only on the curative potential of SDHI

fungicides.

● Strongly reduced rate programs including multiple applications must not

be used. Refer to manufacturers’ recommendations for rates.

29

Summary (Broad spectrum Compounds/SDHIs)

● Boscalid is so far the most significant SDHI in

market, in many crops, also used in cereals.

● Penthiopyrad, bixafen, fluopyram, isopyrazam,

fluxapyroxad are broad-spectrum, high potential

SDHI fungicides expected to be significant in the

market. For seed treatment sedaxane and

penflufen are expected.

● Bixafen, isopyrazam, penthiopyrad, fluxapyroxad

used in mixtures with other fungicides expected to

be important in cereals based upon published

information

30

WHAT'S NEXT AFTER THE SDHIs?

31

What's next?

● Company published pipeline information shows a number of potential

new fungicides, of undisclosed chemistry and mode of action

● These fungicides may or may not be novel in terms of mode of action

● Based upon investor presentations alone these seem to be quite some

time away from market at present (6-9 years??)

● There is no guarantee that these willl pass regulatory hurdles and will

make it to the market.

● Key message – Industry is continuing to innovate but hurdles are high

and it seems we will have to wait a while before the next wave of modes

of action for cereals after the SDHIs hits the market.

32

Conclusions – New Fungicides for Septoria Control

● There are few modes of action available for M. graminicola

control.

● The "next generation" of cereal fungicides is based around

SDHIs.

● A very good number of high performing SDHIs will be launched

and will need to be managed well to ensure longevity. Triazoles,

chlorothalonil etc will be essential for resistance management.

● Chemistry / MOA following the SDHIs, is not yet clear.

● New EU regulations raise the hurdles further for new product

innovation and are likely to reduce the chances of success..

● R&D search criteria will be changed, hazard criteria designed in

earlier in the process (will tend to reduce success)

● Drive to lower performing but lower hazard solutions (not lower

risk!) e.g. biologicals