Transcript Kitasato3Oct2002v2 - kitasato

The human approach to target
validation and drug discovery
Dr. Alastair J. Riddell
Chief Executive Officer
Pharmagene
3rd October, Tokyo
Presentation outline
 Introduction to Pharmagene
 The Integration of Pharmagene’s products and services
—
—
TargetEvaluator™, Phase ZERO ™, Indication Switch ™
Into the new Custom Validation Programme
 Pharmagene Therapeutics
—
—
—
Cystic fibrosis
Irritable bowel syndrome
Migraine
Pharmagene’s human tissue resource

Established relationships with suppliers in UK,
NL and US


clinical history with each sample
no reliance on single supplier of tissue types
 Dynamic and expanding resource
—
—
> 500,000 samples from >5,000 donors
80% living, 20% autopsy
 Legal & ethical integrity
—
—
tissue accepted only after informed consent
donor anonymisation
 No supply to third parties
 Biomaterials received and processed 24hours
a day, 7 days a week using SOP’s
 Managed by in-house Consultant Pathologist
Global customer base
US
Europe
Japan
Bayer (CT&CA)
Allergan
Cubist
J&J
Bristol-Myers Squibb
GlaxoSmithKline
Merck Sharp & Dohme
Pfizer
AstraZeneca
Roche
Boehringer-Ingelheim
Bayer (UK)
Janssen (J&J)
Amersham
Ferring
Oxford BioMedica
Vernalis
Kyowa Hakko Kogyo
Sankyo
Bayer Yakuhin
Daiichi
Taisho
T*
Ono
0060504L
4
A solution provider..
Genomic
Information
Target
Validation
Compound
Screening
Compound
Validation
Pharmagene
Indication Switch ™
Pharmagene
TargetEvaluator™
Cellular localisation
(mRNA and protein)
Pharmagene
Phase ZERO™
Pharmagene
Custom Validation Platform
Pharmagene
Custom Validation Platform
A staged integrated approach..
Stage 1
Expression
Analysis
Stage 2
Protein
Localisation
Stage 3
Cell-based
Assay
Development
Stage 4
Functional
Analysis
Pharmagene Validated Drug Target
Custom Validation Platform - overview
Targets
Stage 1
Expression Analysis
Directed access to
TargetEvaluator
Antibody localisation studies
Target analysis in specified
tissues and Pathologist report
Stage 2
Protein Localisation
For Target or ligand :
Ligand studies in target
tissues
Pharmacology in peripheral
and CNS tissue
Stage 3
Cell based assay
development
Stage 4
Functional Analysis
Validated Target
Cell based Assays
Demonstrate functional
response on target activation
Custom Validation Platform
 Human tissue based
 Custom design to allow validation of targets, compounds or both
 Multiple stages with the ability to stop at any stage
 Regular discussion between both parties
 Flexible deal structure, based on success
Pharmagene Therapeutics
In-house programmes
Pharmagene Therapeutics
 Current research areas
Respiratory
– Gastrointestinal
– Cardiovascular
– Inflammatory diseases
Multiple targets identified and undergoing validation
Intellectual property portfolio expanded in all areas
–
—
—
 Three lead programmes
Cystic Fibrosis
(PGN0052)
– Irritable Bowel Syndrome (R1)
– Migraine
(R4)
All with novel mechanisms of action
–
—
R52 ligand as a treatment for CF
10000
Control (n = 17)
CF (n = 24)
Copy number
8000
*
6000
4000
4x
2000
0
Tertiary Bronchus
3ry
bronchus
& lung
parenchyma
Significantly up-regulated in
bronchus from CF patients
R52 riboprobe in-situ hybridisation in tertiary bronchus
sense
donor 1
donor 2
donor 3
antisense
R52 Ab Immunocytochemistry in CF Tertiary Bronchus
100mg/ml
+ 100x blocking peptide
IgG control
x200 mag
R52 and ion flux in bronchus
amiloride 10 mM (apical)
R52 ligand 3 mM (apical)
ATP 10 mM (apical)
Isc (2µA)
0
5
10
15
20
Time (min)
25
30
35
Cystic Fibrosis – PGN0052, an Indication Switch
 Cystic Fibrosis is a monogenic disease attributed to a defect in a
chloride transport mechanism
—
Fatal disease with few effective pharmacological treatments
 R52 is a well known hormone receptor for a hormone that
stimulates chloride transport
 TargetEvaluatorTM revealed the
expression in the lung
novel
discovery
of
R52
 TaqMan RT-PCR studies showed R52 up-regulated 4-fold in
tertiary bronchus of CF
 Phase
ZERO technologies demonstrated that PGN0052
stimulates chloride transport in tertiary bronchus of the lung
 PGN0052 programme is being progressed to enter the clinic in
Q4 2002
Irritable Bowel Syndrome - R1
- New Lead Discovery from Indication Switch
 Significant unmet medical need and
commercial opportunity
 5-Hydroxytryptamine (5-HT) has long
been implicated in IBS
—
—
Large investment by Pharma in
5HT3 antagonists & 5HT4 agonists
(Lotronex & Zelmac)
Current drugs have not delivered
success
5-HT2B antagonists as a treatment for IBS
GI tract
Borman et al. Br J Pharmacol (in press)
0060504L.ppt
18
5-HT2B receptor protein expression
Protein dot blots with 5-HT2B Ab
Tissue
Whole
Mucosa
Smooth
muscle
Taenia
Coli
Ileum
NA
Colon
• Protein localised in colon smooth muscle
Borman et al. Br J Pharmacol (in press)
Irritable Bowel Syndrome - R1
 Pharmagene
Target
EvaluatorTM
revealed
expression of 5HT2B receptor in human colon
C
significant
NP
L
 Immunocytochemical stains revealed the highest
concentration of the receptor in nerve plexi and longitudinal
smooth muscle
Functional evidence for 5-HT2B receptors in colon
Smooth muscle pharmacology
Electrically-induced
contractions of colonic
strips
• Effect blocked by the potent, selective
5-HT2B antagonist, RS-127445
100-fold
RS-127445 100nM
• In human colon, 5-HT causes smooth muscle hypersensitivity, and this
effect is mediated by 5-HT2B receptors
Borman et al. Br J Pharmacol (in press)
Irritable Bowel Syndrome - R1
 Pharmagene
Target
EvaluatorTM
revealed
expression of 5HT2B receptor in human colon
significant
 Phase ZERO technologies established a novel role for the
5HT2B receptor
—
Enhances the contractile response of human colon to nerve
stimulation
 Selective antagonists at 5HT2B receptor represent a
completely novel mechanism of action for potential treatment
of IBS (example RS 127445)
 Pharmagene has identified two entirely novel lead series with
enhanced performance over RS 127445. Early stage lead
compounds identified.
 Optimised leads ready for licensing H1 2003
Migraine - R4 - New Lead Discovery
 Significant advances in the treatment of migraine
 However, side-effects of current therapies mean continuing unmet
medical need and commercial opportunity
A
M
P
P
B
40mm
Human cerebral arterial vascular tree
Measuring the function of human
cerebral artery in vitro
Migraine - R4 - New Lead Discovery
 Pain of migraine associated with dilation of the cerebral arterial
vasculature
 Circulating levels of PGE2 reported to be increased in migraine
 Detailed pharmacological studies of the human cerebral artery in vitro
revealed dilator effect of PGE2. This response is mediated by the EP4
receptor
 Pharmagene has a granted UK patent for the use of EP4 antagonists to
treat primary headache disorders
 Collaboration with Argenta to identify selective EP4 antagonists
through an intelligent screening approach
 Optimised leads ready for licensing by end 2003
Pharmagene Drug Discovery
 Based on an integrated human approach
 Validated by global customer base and growing revenues
 Most customers are repeat and long term
 The integrated technologies have produced novel in-house
therapeutic opportunities
 Lead candidates ready for licensing over next 1-2 years in
—
—
—
Irritable Bowel syndrome
Migraine
Cystic Fibrosis