Transcript Presentation

Platform Technologies for
Drug Discovery
ASENT
February 2011
Daniel W. Gil, PhD
Vice President, BioScience
Allergan, Inc.
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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
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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
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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
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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
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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
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 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
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Alpha2B Agonist Reduces Allodynia Without
Sedation In Rat Neuropathic Pain Model
AGN-196923 EC50 in nM
1A
2A
2B
2C
1679
NA
61
91
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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)
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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
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