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Platform Technologies for
Drug Discovery
ASENT
February 2011
Daniel W. Gil, PhD
Vice President, BioScience
Allergan, Inc.
1
Platform vs. Disease-Focused Discovery
Platform
Disease
Target
Broad Modulatory
Pathway
Disease-Specific Pathway
Scientific Challenge
Subtype selectivity/
Targeted delivery
Pathway validation
Advantage
Leverage know-how and
risk across disease areas
Highly selective
Discovery Approach
Chemistry-driven
Biology-driven
2
Chemistry-Driven vs. Biology-Driven Discovery
PLATFORM
DISEASE
HTS
Evaluate Hits
Biological Target Validation
Indentify
Selective
Leads
HTS
In Vivo Testing to Validate
Biological Roles
Evaluate Hits
Optimize
Leads
3
Selecting Discovery Platform Technologies
Technology
Platform:
PG / prostamide
Pain
(neuro-pathic,
inflamGlaucoma
mation)
Specialties:
Ophthalmology
Dermatology
Neurology
Aesthetics
Urology
Gastroenterology
Endocrinology
Oncology,
Hematology
OB/Gyn
Primary Care
Cardiology
Psychiatry
Emergency
Medicine
Colon
Cancer
Alpha-2
Labor
induction/
prevention
Pain
(neuro-pathic,
inflamGlaucoma
mation)
Spasticity
Retinoids
Tourettes/
OCD /
psychosis
Psoriasis
Acne
Cancer
Diabetes
Often Platform Technology Has an
Unanticipated, But Welcome, Activity
Technology
Platform:
PG / prostamide
Alpha-2
Pain
Glaucoma
Specialties:
Ophthalmology
Dermatology
Neurology
Aesthetics
Urology
Gastroenterology
Endocrinology
Oncology,
Hematology
OB/Gyn
Primary Care
Cardiology
Psychiatry
Emergency
Medicine
(neuropathic,
inflammation)
Retinoids
Pain
Eyelash
Growth
Colon
Cancer
Labor
induction/
prevention Glaucoma
(neuropathic,
inflammation)
Tourettes/
OCD /
Spasticity psychosis Psoriasis
Acne
Cancer
Diabetes
Alpha2 Agonist Platform:
Marketed “Alpha2” Agonists Are Non-Selective
a
a1
a2
Marketed
“Alpha2”
Agonists
a1A a
1B
a1D
a2A a a2C
2B
Sedation
Blood
pressure
• Minimal therapeutic window for treatment of spasticity, pain, Tourette’s
• Glaucoma treated locally with eye drops
6
Utility of Marketed Compounds Is Limited
By CNS Side Effects
Sedation Assay
Chung Model
IP Clonidine in the SNL Model and the Sedation Assay
Sedation Assay: Total Activity Counts
2500
**
100
Sedation Assay
2000
Chung Model
80
*
1500
60
**
1000
40
500
**
0
0
20
40
60
80
Clonidine Dose (ug/kg IP)
100
SNL Model: % Allodynia Reversal
Clonidine and other
alpha2 agonists with
alpha2A activity do
not separate
analgesia from
sedation
120
20
0
120
*p<0.05, **p<0.01 vs. vehicle
7
Two Approaches to Selective Non-sedating
Alpha2 Agonists
a
a1
a1A a
1B
a2
a1D
a2A a a2C
2B
• Peripherally-limited alpha2 agonist
• Alpha2B-selective agonist
8
Peripherally-Limited Alpha2-Adrenergic
Agonist Reduces Sympathetic Outflow
AGN-203818 is effective on pain
exacerbated or triggered by stress
• Fibromyalgia 1-month phase II study:
α2 - clonidine
Improvements in pain and secondary
endpoints on the order of magnitude of
marketed drugs
• Functional Heartburn PD study:
Patients with visceral hypersensitivity to
esophageal balloon inflation studied in
single-dose crossover study
Peripherally-Limited Alpha2 Agonist Increased
Visceral Pain Threshold in FHB Patients
Volume (mL)
Mean Volume to
20Discomfort/Pain Threshold
(± SEM)
P = 0.057
N=18
15
20 mg dose resulted in mean
47% increase from baseline
discomfort/pain threshold
No sedative or cardiovascular
effects observed
10
5
Baseline Placebo
3 mg
20 mg
20 mg vs. placebo comparison is significant at
p<0.05 when adjusting for baseline volume,
weight or BMI
But, fibromyalgia and
gastrointestinal functional pain
disorders are not in Allergan
areas of commercial focus
10
Alpha2B Agonist Reduces Allodynia Without
Sedation In Rat Neuropathic Pain Model
AGN-196923 EC50 in nM
1A
2A
2B
2C
1679
NA
61
91
11
Alpha2B Selectivity Reveals Disease-Modifying
Activity in Neuropathic Pain Models
Prolonged alleviation of pain
sensitivity following cessation of
dosing in three models
AGN-196923 Chronic Drug Administration Via Osmotic Minipumps
120
n = 3 per group
****
100
**
**
80
60
**p< 0.01 vs vehicle
**
**
**
196923 pumps:
2.4 mg/kg/day
**
**
40
20
Vehicle pumps
0
0
5
10
30
25
20
15
10 pump
196923
5
Vehicle pump
0
Alpha 2B
**
**
Raw RQ (relative
quantitation)
% Allodynia Reversal
Pumps removed on day 7
Raw RQ (relative
quantitation)
Involves immune modulation
Alpha2B, but not 2A or 2C
receptors, present on T cells
15
20
25
35
30
25
20
15
10
5
0
Alpha 2A
30
Time (Days)
12
Summary
Selective drugs reveal unexpected therapeutic opportunities
for platform technologies
– Enable growth into new therapeutic areas
– Provide outlicensing opportunities
Platform technologies leverage drug discovery assets
– Chemical libraries
– Biological know-how
13