2013118

1868

1871

David Chip
1956
1949

2007

50

300 cities
100 countries

Combining deep
employee expertise to
deliver critical information
in the financial, legal, tax
and accounting,
healthcare and science
and media markets.
4

I-III

Thomson Reuters Integrity

Genego Markush
IDRAC
Newport
Cortellis for Competitive Intelligence
Web of Knowledge
Thomson Innovation (

R&DNME
2000-2010
R&D expenditure

Development times

NME output

Sales

275

250

240.4

225

Indexed to 2000

200

175

162.8

150

125

121.9

100
2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010*

75

50
25
0
Year

*The development time data point for 2010 includes data from 2009 and 2010 only
Source: CMR International & IMS Health

65.6

22.10%

3.00%

18.90%

13.30%

4.40%
38.20%

Source: CMR, Thomson Reuters

: CMR international

II

III

: CMR international

12

Erectile dysfunction;
Pulmonary artery hypertension
13

14

Indication Discovery Unit

New Opportunities
Innovative Medicines Unit

Bayer Common
Mechanisms Research
Group

Biovista
Marco Polo Pharmaceuticals
Numedicus
15

BUT Repositioned drugs are

low risk not NO risk

2000
150-200

Reference: Ashburn and Thor : Nature Reviews

Drug Discovery August 2004 page 673
16

A:

B:

* Circle indicates relative pipeline size

Viagra

Revatio
Gemzar

Proscar

Evista

Rograine

1950-1960

1992Celgene

1998THALOMID

2006

3-5

19


Drug

Innovator

Mechanism

Original

Repurposed

Indication

Indication

Gemcitabine

Eli Lilly

Inhibition of DNA synthesis Antiviral

Anticancer

Raloxifene

Eli Lilly

Estrogen

Osteoporosis

Breast cancer

agonist/antagonist
Buproprion

GSK

Norepinephrinedopamine Depression

Smoking cessation

reuptake inhibitor
Dapoxetine

Eli Lilly

Selective serotonin

Analgesia

Premature ejaculation

Depression

Premenstrual

reuptake inhibitor SSRI

Fluoxetine

Eli Lilly

SSRI

dysphoria

Hydroxychloroqu Sanofi

Lysosomal alkalinization;

ine

TLR inhibitor

Doxepin

Bimatoprost

Boehringer

Serotoninnorepinephrine

Mannheim (Roche)

reuptake inhibitor (SNRI)

Allergan

Prostaglandin analog

Antiparasitic

Antiarthritic

Antidepressant

Antipruritic

Glaucoma

Eyelash growth

20

22

OR

OR

A
?

OR

Rask-Andersen, et al 2011
Dudley, et al 2011
Zhichao Liu, et al 2012

23

24

Network-based methods
Knowledge-based methods

Methods based on disease similarity

25

 2010 Thomson Reuters.

KNOWLEDGE-BASED

26


3:
2:

Linear pathways

4:
Normal pathway maps

5:
Disease pathway maps

Network expansion

1:
Disease
biomarkers

Myshkin et al, submitted

27

1:

Myshkin et al, submitted

28

 2:

Myshkin et al, submitted

29

 3:

BA

A
Myshkin et al, submitted

30

 4:
A

Myshkin et al, submitted

31

 5:
A

Myshkin et al, submitted

32

33


WNT signaling in
Hepatocellular
Carcinoma

34

Description

Tools

Information used

Via disease
biomarkers

Enrichment analysis by disease

ontologies

1) Disease biomarkers of
MetaBase
2) Drug information of Integrity

Via network
expansion

Network building, enrichment

analysis by disease ontologies

1) Protein interactions of
MetaBase
2) Disease biomarkers of
MetaBase,
3) Drug information of Integrity

Via normal
pathway maps

Conditional search of pathway

analysis databases, drug target
visualizations on maps

1) Normal pathway maps of

MetaBase
2) Drug information of Integrity

Via diseasespecific pathway

maps

Enrichment analysis by disease

specific pathway maps

1) Disease pathway maps of

MetaBase
2) Drug information of Integrity

Via linear
pathways

Queries to pathway databases

1) Linear pathways of
MetaBase
2) Drug information of Integrity

35

 2010 Thomson Reuters.

NETWORK-BASED
METHODS

36

Interconnectivity

Hidden nodes

(Hsu et al., BMC Genomics, 2011)

(Deszo et al., BMC Syst Biol, 2009)

Network
analysis
Random Walk

Overconnectivity

(Koehler et al., Am J Hum Genet, 2008)

(Nikolsky et al, Methods Mol Biol, 2009)

Neighborhood scoring
(Krauthammer et al., PNAS 2004)

Network Propagation
(Vanunu et al., PLoS Comput Biol, 2009)

:
->

P21: 206 interactions
in 16,000 proteins db

Under-connection

Expectation

Over-connection

3 interactions for P21

P21: expect 5 interactions

in 320 proteins dataset

9 interactions for P21

:
->
hidden nodes

Differentially Expressed Genes

Topological scoring algorithm: clinical program for

treatment of previously untreatable cancer patients with
combinations of off-target drugs based on individual
gene expression profiles

41

 2010 Thomson Reuters.

METHODS BASED ON
DISEASE SIMILARITY

42


Mental disorders

Neurodegenerative

Neoplasms

Autoimmune diseases
Inflammatory diseases

Obesity; Diabetes II; etc

Cardiovascular


Mental disorders

Neurodegenerative

Neoplasms

Autoimmune diseases
Inflammatory diseases

Obesity; Diabetes II; etc

Cardiovascular

47

II III

(N = 15,000)

N = 100

1000 15000

IP

Integrity, GeneGo and Cortellis for CI

0 and 18:
Is the drugs target a known target for the disease?
Is the drugs target a known biomarker for the disease?
Is the target part of the disease interactome?

Is the drugs target expressed in skin?

Is the drugs target in a disease-associated pathway?
Is the drugs target associated with disease-tissue expression patterns?
Is the drug compounds structure predictive of efficacy using QSAR
bioinformatic models?
Does the drug have IP protection for dermatology indications?
What clinical trial data is available supporting use in dermatology
indications?
What animal model data is available supporting use in dermatology
indications?
49

15,000 )

DRUG
DRUG ID PHASE
TARGET
UNIPROT
3_1 Integrity
3_2 Integrity
Targets
3_2 MetaBase
Biomarkers
Validity
3_3 Neighbor
biomarkers
3_3 Neighbor
Integrity
3_3 Neighbor
Integrity
Targets
3_4 Skin
MetaBase
Biomarker
Validity
3_5
Expression
Pathway
3_6
biomarkers
Expression
genes
3_7 QSAR
genes
Total Score
TOTAL
(+)-alpha-DHTBZ
739953 Phase II Synaptic Vesicular Amine
Q05940
Transporter (VAT2)
0
0
0
0
0
0
0
0
0
0
0
PROJECT
(+)-alpha-Dihydrotetrabenazine
739953 Phase II Synaptic Vesicular Amine
Q05940
Transporter (VAT2)
0
0
0
0
0
0
0
0
0
0
0
RANK
DRUG ID DRUG
SCORING
(+)-alpha-DTBZ
739953 Phase II Synaptic Vesicular Amine
Q05940
Transporter (VAT2)
0
0
0
0
0
0
0
0
0
0
0
1
392619
Apremilast
18
(-)- Cytisine
274951 Launched Nicotinic beta2 receptor P17787
0
0
0
0
0
0
1
0
0
0
1
2
424112
AN-2728
18
(-)- Cytisine
274951 Launched Nicotinic alpha4 receptorP43681
0
0
0
0
0
0
0
0
0
0
0
3
90998
Tranilast
17
(-)-(S)-Bupivacaine hydrochloride
220671 Phase III Kv1.5
P22460
0
0
0
0
1
0
1
0
0
0
2
4
91601
Danazol
17
(-)-(S)-Pindolol
270881 Discontinued
5-HT1A receptor
P08908
0
0
0
3
0
0
1
0
1
0
5
5
213242
Enbrel
17
(-)-(S)-Pindolol
270881 Discontinued
beta-Adrenoceptor (nonspecified
P25962 subtype)
0
0
0
0
0
0
0
0
1
0
1
6
230874
Onercept
17
(-)-4'-O-Methylnyasol 449465 Not Determined
Phospholipase C gammaP19174
1 (isoform a) 0
0
0
0
0
0
1
1
1
1
4
7
415533
AN-0128
17
(-)-BCH-10652
260444 Phase III Gag-Pol
P04585
0
0
0
0
0
0
0
0
0
0
0
8
198460
Remicade
16
(-)-BCH-189
184356 Launched Gag-Pol
P04585
0
1
0
0
0
0
0
0
0
0
1
9
204973
Ariflo
16
(-)-Catechin gallate 322601 Not Determined
Fatty acid synthase
P49327
1
0
0
3
1
0
1
1
0
0
7
10
255014
Humira
16
(-)-Catechin gallate 322601 Not Determined
Fatty acid synthase (bacterial)
P49327
1
0
0
3
1
0
1
1
0
0
7
11
264195
Cimzia
16
(-)-Catechin gallate 322601 Not Determined
Beta-site APP-cleaving enzyme
P56817 1
0
0
0
0
1
0
1
0
0
0
2
12
278534
Delmitide
16
(-)-Catechin gallate 322601 Not Determined
Beta-site APP-cleaving enzyme
P56817 1 isoform
0 455 0
0
0
1
0
1
0
0
0
2
13
287321
KF-66490
16
(-)-Cetirizine dihydrochloride
269103 Phase III Interleukin-8 precursor P10145
0
0
0
3
1
0
1
1
2
0
8
14
334585
Simponi
16
(-)-Cetirizine dihydrochloride
269103 Phase III 5-HT2A receptor
P28223
3
0
0
0
0
0
1
0
1
0
5
15
438575
AP-214
16
(-)-Cetirizine dihydrochloride
269103 Phase III Histamine H1 receptor P35367
0
0
0
0
0
0
1
1
2
0
4
(-)-Cetirizine dihydrochloride
269103 Phase III Nicotinic alpha7 receptorP36544
0
0
0
1
1
1
0
0
0
0
3
(-)-CG
322601 Not Determined
Fatty acid synthase
P49327
1
0
0
3
1
0
1
1
0
0
7
(-)-CG
322601 Not Determined
Fatty acid synthase (bacterial)
P49327
1
0
0
3
1
0
1
1
0
0
7
(-)-CG
322601 Not Determined
Beta-site APP-cleaving enzyme
P56817 1
0
0
0
0
1
0
1
0
0
0
2
(-)-CG
322601 Not Determined
Beta-site APP-cleaving enzyme
P56817 1 isoform
0 455 0
0
0
1
0
1
0
0
0
2
(-)-Cromakalim
91271 Phase III Potassium Channels (nonspecified
B7U540 subtype)
0
0
0
0
0
0
0
0
0
0
0
90998: 3,4-DAA, NU-3450, Rizaben, SB-252218,
Tumor necrosis factor alpha (TNF-alpha)
(-)-DAPD
257988 Phase II Gag-Pol
P04585
0
0
0
0
0
0
0
0Tranilast
0 - Launched
0
0
(-)-DDMS
295115 Phase II Sodium-dependent Noradrenaline
P23975 Transporter
3
(NET)
0
0
0
0
0
1
0
0
0
4
OVERVIEW
(-)-DDMS
295115 Phase II Serotonin transporter (SERT)
P31645
0
0
0
0
0
0
1
0
0
0
1
Kissei has developed and launched tranilast in Japan and South Korea for the treatment of allergic rhinitis, asthma and atopi c
(-)-Desoxyepothilone B251562 Discontinued
Tubulin
P04350
0
0
0
0
0
0
0
0dermatitis.1Kissei, in collaboration
1
2 GlaxoSmithKline (GSK; formerly SmithKline Beecham), was additionally developing tranilast
with
prevention
(-)-DMS
322560 Phase II Sodium-dependent Noradrenaline
P23975 Transporter
3
(NET)
0
0
0
0
0
1
0(as Rizaben)
0 for the potential
0
4 of restenosis following percutaneous transluminal coronary angioplasty (PTCA). Tranilast
had been filed in Japan for restenosis by 1997 but Kissei was reported to have made the decision to withdraw its Japanese filing for
(-)-DMS
322560 Phase II Serotonin transporter (SERT)
P31645
0
0
0
0
0
0
1
0tranilast for0restenosis0by November12001 following GSK's decision to discontinue development of the drug for restenosis in July
(-)-dOTC
260444 Phase III Gag-Pol
P04585
0
0
0
0
0
0
0
02001. In December
0
0 it was reported
0 that Kissei decided to withdraw its Japanese filing for tranilast for restenosis following
2001,
(-)-DRF-2725
275437 Discontinued
PPARalpha
Q07869
1
0
0
1
1
1
1
1GSK's decision.
1
0
7
is 0also investigating
(-)-DRF-2725
275437 Discontinued
Peroxisome proliferator-activated
P37231 receptor
1 gamma
0 (isoform
0 2) 1
1
1
1
0Nuon Therapeutics
2
7 tranilast for the potential treatment of rheumatoid arthritis, multiple sclerosis and pain.
(-)-EGCG
183411 Phase II VEGFR-2 (FLK-1/KDR) P35968
0
0
0
3
1
0
1
1
2
0
8
(-)-EGCG
183411 Phase II Fatty acid synthase
P49327
1
0
0
3
1
0
1
1
0
0
7
(-)-EGCG
183411 Phase II Fatty acid synthase (bacterial)
P49327
1
0
0
3
1
0
1
1PATENT0 STATUS
0
7
SUPPORTING DATA
(-)-EGCG
183411 Phase II PDGFR (nonspecified subtype)
P09619
0
0
0
3
1
0
1
1
1
0
7
Drug shown to be safe and tolerable in restinosis, but no
(-)-EGCG
183411 Phase II Transcription Factor AP-1
P01100
(nonspecified0 subtype)
0
0
1
1
1
1
1
2
0
7
evidence of efficacy.
(-)-EGCG
183411 Phase II NF-kappaB (NFkB)
P19838
0
0
0
1
1
1
1
1
1
0
6

DRUG PROFILES

See next slide for supportive evidence of role in derm

indications.

50
50

Has active method of use patent for atopic dermatitis.

GSK

GSK

38

CFTR
(97
14)

CFTR
15% ()

Source: GeneGo
52

GSK

Cystic Fibrosis
CFTR

70000


37

CFTR
CFTR cAMP
CFTR

Does GSK or anyone else have assets
which can be repositioned as CFTR
correctors?

53

56

McGills CFTR trafficking assay

CFTR


(15%),
15

57

matrix

58

1000

11,000
2,300

-
3-5
-

59

,
,

60

Iressa
Herceptin

1994
2003
NSCLC
All NSCLC patients

IND

88 100,000

1992
1998
HER2-positive breast cancer
HER2-overexpressing patients
(25-30% of breast cancer market)
34 100,000

(Source: ACS; US incidence)

NSCLC
EGFR
mutation-positive NSCLC
EGFR mutationpositive
None incorporated initially
2006Genzyme EGFR
mutation

8.5

2016

2015

2014

2013

2011

2012

2010

2009

2008

2007

2016

2015

2014

2013

2011

2012

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2006

200

2005

400

2004

600

2003

800

7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
2002

Global sales ($m)

1000

2000

Global sales ($m)

1996DAKO
Hercep

Herceptin HercepTest

70

2001

HER2positive

2000

61

:
- 250 cell
lines
- Measured
IC50

- XY
?
-
MetaCore
IDH1
BTC

Gene ID

IC 50

BTC

EGF

SPP1
SPP1

GLUD1
GRB14

BMPR1B
BMPR1B

IGF1R
IGF1R

Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung
Lung

Cell Line

204475_at
205479_s_at
206538_at
222100_at
242141_at
204858_s_at
216551_x_at
211121_s_at
207113_s_at
201746_at
210371_s_at
200970_s_at
222631_at
202804_at
239035_at
214093_s_at
216268_s_at
206870_at
241412_at
240294_at
209541_at
203685_at
215025_at

Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver

Liver
Liver
Liver
Liver
Liver
Liver
Liver
Liver

IC50 or
pathwayselected list

SNP

Patient samples



Metoo
Me better
New-in-class

spinout
CRO CRAMS

64

65

GeneGo (a systems biology

solutions provider)
Cortellis for CI

MetaBase
Thomson Reuters Derwent
World Drug Index
MDL Drug Data Report, MDDR
(together with Accelrys)

MetaCore
MetaDrug

66



http://ip-science.thomsonreuters.com.cn/freeresources/lifesciencesreport/

http://weibo.com/u/3204664833

http://ip-science.thomsonreuters.com.cn/productraining/
67

Yin.li@thomsonreuters.com
0105760126118911813699
http://science.thomsonreuters.com.cn

68

Useful reading and references

Ashburn and Thor : Nature Reviews Drug Discovery
August 2004 page 673
http://www.dddmag.com/article-drug-repositioning.aspx
http://www.dddmag.com/innovative-strategies-fordrug.aspx
http://www.genengnews.com/gen-articles/drugrepositioning-gains-in-popularity/3263/?page=1

69