Merck Research Labs Imaging Research West Point, PA

Molecular Imaging in Drug Discovery and Development
Low
Merck Research Labs
Imaging Research
Rikki N. Waterhouse, Ph.D.
Associate Franchise Director
Imaging Deptartment
High
West Point, PA
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Why do Drugs Fail in Clinical Trials ?
Industry: Survival by Phase
Phase 1
Phase 2
Phase 3
Registration
100%
90%
1 in 5
70%
60%
50%
40%
30%
20%
10%
1999–01
1998–00
1997–99
1996–98
1995–97
1994–96
1999–01
1998–00
1997–99
1996–98
1995–97
1994–96
1999–01
1998–00
1997–99
1996–98
1995–97
1994–96
1999–01
1998–00
1997–99
1996–98
1995–97
0%
1994–96
Success Rate
80%
Year of Entry into Phase
Source: 2005 Global R&D Performance Metrics Programme: Industry Success
Rates Report, CMR International, May 2005, p. 7
For 11 compounds entering Phase 1 clinical study
only 1 will be approved (POS: 9%)
MRL Imaging
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Why do Drugs Fail in Clinical Trials ?
• Lack of Efficacy
– Concept flawed
– Wrong doses used
– Wrong PK/PD
profile
• Side-Effects
– Mechanism based
– Compound specific
– Prevent target therapeutic
dose being reached
– Unacceptable risk to
benefit
Can Imaging Help ?
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Time & Expense in Drug Discovery:Slides
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Many projects turn out to be conceptually flawed
$500- 800 MM
$$$
Regulatory Approval
Laboratory
Clinic
Start Clinical Studies
Clinical Trials
Over with New
Compound
Research
Toxicology
Identify
Targets
1
2
Find
Leads
Refine
Leads
Fail
3
4
Copyright © 2003 Merck & Co., Inc., Whitehouse Station
, New Jersey, USA, All Rights Reserved
5
6
7
8
Time (Years)
Development
9
10
11
12
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5
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Molecular Imaging
Classical Imaging (eg CT, x-ray, MRI)
Visualization of gross anatomy – Diseased tissue detection based on morphological
alterations or abnormalities
- In general, diagnostic & non-specific
Molecular Imaging (PET & SPECT, MRS, Optical)
Cell/Molecular
Biology
Evaluation of specific biochemical
processes at the cellular and subcellular levels in living organisms
Chemistry
Pharmacology
Medicine
Physics
Engineering
IT & Data
management
Exploit/integrate
imaging techniques
• Gene Expression
• Biochemical Reactions
• Signal Transduction
• Regulatory Pathways
• DIRECT and INDRECT DRUG
ACTION
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Why do PET Imaging?
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Advantages of PET (Positron Emission Tomography)
• Spatial Resolution; center FOV (~4 mm / clinical; ~1.0 mm
preclinical)
• Highly sensitive readout (pM to nM)
• Pharmacologically inactive dose (< 50 ng/kg)
• Quantitative
• Dynamic, 3-D imaging technique
– Good temporal resolution (15 sec - 5 min)
– Molecules labeled with short t1/2 positron emitters
• Non-terminal studies, minimally invasive
– Important with higher species preclinically
– Unique bridge from lab to clinic: ONLY way to measure
receptor (pM to nM) pharmacology quantitatively in
vivo in animals and humans.
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Comparative Occupancy Studies: Choosing
the Best Compound
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• Compare occupancy of target in vivo
• Prioritize candidates for advancement to clinic
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Why do PET Occupancy Studies?
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PET
PET Imaging
Imaging in
in Phase
Phase 11 to
to guide
guide dose
dose
selection
selection and
and assure
assure adequate
adequate test
test of
of
concept/mechanism
concept/mechanism (ideally
(ideally 11 compound).
compound).
15
Introduction
Registration
PET
PET imaging
imaging in
in monkeys
monkeys to
to guide
guide
selection
selection of
of clinical
clinical candidates
candidates
(~
(~ 5
5 -- 10
10 compounds).
compounds).
Years
Development
Product Surveillance
Phase IV
1
Phase III
2
2-5
Clinical Tests
(Human)
5
5000
Substances
Basic
Research
0
Thousands of
Substances
Phase II
Phase I
Preclinical Tests
(Animal)
Synthesis
Examination &
Screening
Source: PhRMA
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CNS PET Tracer Discovery:
Typical Initial (Preclinical) Steps
z
z
z
z
z
Screen library for ligands with acceptable logP, Pgp, and
affinity which can be radiolabelled with C-11 or F-18.
Check for metabolic profile using liver microsome assays.
Synthesize a radioligand with good affinity (<5nM) moderate
lipophilicity and moderate (>60Ci/mmol = ~2 tritium atoms)
specific activity.
Characterize distribution of receptor/enzyme
(autoradiography in tissue slices)
Determine concentration (Bmax) of receptor/enzyme (tissue
homogenate)
z
Med Chem synthesize precursor and standard
z
Work out radiosynthesis of PET tracer
z
Evaluate in vivo (rhesus monkey) and/or rodent model
z
Radiation dosimetry, toxicity, metabolism across species MRL Imaging
11
L-mdr1a/L-MDR1: P-glycoprotein
A Key to Successful CNS PET Tracer Discovery
Potential Tracers Screened in
Monkey PET Study
Pgp Index
in vitro
Range 1 - 29
Compound
IC50 (nM)
Log P
Mouse
Human
(L-mdr1a) (L-MDR1)
[11C] Tracer A
0.73
2.8
4.43
1.11
[11C] Tracer B
0.85
2.1
12.32
2.44
[18F] Tracer C
0.75
2.7
9.51
1.52
Assumption: Human Pgp = Rhesus monkey Pgp
A
12.
Imaging for Initial Tracer Selection
[11C] Tracer A
h-IC50 0.73 nM
Log P
2.8
h-Pgp
1.11
-
0
+
[11C] Tracer B
h-IC50 0.85 nM
Log P
h-Pgp
2.1
[18F] Tracer C
Metabolism
2.44
Assumption: Human Pgp = Rhesus monkey Pgp
A
13.
Comparison of mGluR5 Tracers [11C]M-MTEB,
[18F]F-MTEB & [18F]F-PEB in Rhesus
*
[11C]M-MTEB
Baseline
After 1mg/kg MTEP
[18F]F-MTEB
Baseline
After 1mg/kg MTEP
[18F]F-PEB
Baseline
After 3mg/kg MTEP
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[18F]MK-9470: A Tracer for In Vivo PET Brain
Imaging of the Cannabinoid-1 Receptor
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Introduction – Cannabinoid CB1 Receptors
• Two receptor subtypes: CB1 (brain) and CB2 (immune
system cells).
• Applications to treatment of pain, nausea, glaucoma,
eating disorders, Parkinson’s tremors, stroke.
• CB1 receptor PET tracer needed for preclinical and
clinical occupancy studies with therapeutic CB1R
inverse agonists.
Synthesis of Ether-Containing CB1R PET Tracers
[11C]MeI
or
18
[ F]FCH2Br
or
18
[ F]FCH2CH2Br
CN
O
X
N
H
O
N
O
X
Y
HO
CN
DMF
Cs2CO3
100oC
5 min
X=H, F
Y=CF3, CH3
N
H
O
N
Y
RO
X=H, F
Y=CF3, CH3
R=11CH3, 18FCH2, 18FCH2CH2
Tracer
Radiochemical
Yield (%)
Specific Activity
(Ci/mmol)
[11C]CB-119
34±1.1
5454±1286
[18F]MK-9470
4.6±0.32
1736±296
[3H]CB-119 Binding: Blockade in Rhesus Monkey
Brain by CB-119 or Rimonabant
Total
Ctx
CPu
Ctx
GP
Th
GP
Hy
CPu
Hp
pTh
Hp SN
Cb
BS
10µM CB-119
10µM Rimonabant
Ctx=cortex; CPu=caudate/putamen; GP=globus pallidus; Th=thalamus; Hy=hypothalamus; Hp=hippocampus; pTh=posterior thalamus; SN=
substantia nigra; Cb=cerebellum; BS=brain stem
Comparison of CB1 Receptor Binding in Rhesus
Monkey Brain with [3H]CB-119 or [18F]MK-9470
[18F]MK-9470
Ctx
CPu
Ctx
Th
GP
pTh
Hp
Cb
BS
[3H]CB-119
CPu=caudate/putamen; Ctx=cortex; Th=thalamus; GP=globus pallidus; Hp=hippocampus; pTh=posterior thalamus; Cb=cerebellum;
BS=brain stem
[18F]MK-9470 Baseline/Blockade In Rhesus
c Putamen
… Occipital cortex
‘ Cerebellum
U Thalamus
x White matter
CPu
Th
Occ Ctx
Cb
ƒ Images of baseline (panel A) and taranabant blockade (panel B).
ƒ Taranabant chase carried out at 120 min via bolus/infusion.
ƒ Tracer reinjected at 190 minutes.
ƒ Good uptake/specific signal.
ƒ [18F]MK-9470 exhibits reversible binding.
ƒ Tracer exhibits slow kinetics.
ƒ Distribution agrees with autoradiographic results.
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Relationship between CB1R occupancy measured
without
without permission
permission of
of author.
author.
with [18F]MK-9740 and plasma drug concentrations
in Rhesus monkeys
CB1 Receptor Occupancy (%)
100
80
60
40
Occ50 = 34 nM
20
0
0.0001
0.001
0.01
0.1
1
MK-0364 Plasma Concentration (µM)
10
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Uptake of [18F]MK-9740 in Human Brain
Symbols:
Symbols: ○
○ putamen,
putamen,
occipital
occipital cortex,
cortex, ◊◊ cerebellum,
cerebellum, ∇
∇ thalamus
thalamus
and
and ×× white-matter
white-matter
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[18F]MK-9740 Time Activity Curves Before and
After Placebo or 7.5 mg MK-0364
Placebo
7.5 mg
MK-0364
Symbols:
Symbols: ○○ putamen,
putamen,
occipital
occipital cortex,
cortex, ◊◊ cerebellum
cerebellum and
and D
D thalamus.
thalamus. Open
Open
symbols
symbols == baseline
baseline scan
scan values;
values; closed
closed symbols
symbols == scan
scan after
after treatment.
treatment.
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Relationship Between Plasma Drug Concentrations
and CB1R Occupancy in the Human Brain Measured
with [18F]MK-9740
60%
CB1-R Occupancy
50%
Subjects received daily dose of MK-0364 or
placebo for 14 days. PET scans were
performed at baseline and 24 hr after last dose.
40%
30%
20%
10%
0%
Placebo (N=2)
1.0 mg (N=2)
4.0 mg (N=3)
7.5 mg (N=2)
-10%
MK-0364 dose
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Drug Candidate and PET Tracer Discovery Timeline
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& Preclinical Applications of PET Imaging
Ideal Time
for PET Studies
Drug Candidate Timeline
Target
Identification
& Validation
PET Tracer
Discovery
Timeline
Lead
Identification
Lead
Optimization
Tracer Lead
Identification
Tracer Lead
Optimization
Clinical Candidate
Preclinical
Development
Tracer
Preclinical
Development
PET Tracer
Preclinical Application
Existing & Novel Tracers
Phase 1
Clinical Studies
Tracer
Clinical
Validation
Latest Time
PET Tracer
Clinical Validation
Preclinical Receptor Occupancy Studies
Î
Confirm Brain Penetration by Clinical Candidates
Î
Aid in Selection of Clinical Candidates (Relative in vivo Potency)
Î
Guide Dose Selection for FIH Studies
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Summary
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ƒ
Increasing pressure to develop drugs more efficiently
ƒ
Clear strategies required to manage this process in terms of
trade-offs in cost, time, product value and possibility of success
(POS: early go/no-go, fail candidates sooner)
ƒ
PET (and SPECT) imaging is one key strategy being employed
ƒ Target Engagement: Proof of Concept (POC), increase POS
ƒ Dose selection & Compound / Back-up selection
ƒ Monitor disease progression and treatment effects
longitudinally
MRL Imaging
Acknowledgements for CB1R Tracer
Development
Imaging Research
¾ D. Burns
¾ R. Hargreaves
¾ T. Hamill
¾ S. Sanabria
¾ B. Francis
Drug Metabolism/Metabolic Disorders
¾J. Chen
¾X. Guan
¾J. Lao
¾ W. Li
¾N. Pudvah
¾ K. Riffel
¾K. Samel
¾ G. Terry
¾C. Shen
¾ A. Vanko
¾ C. Ryan
¾ S. Krause
¾
¾
¾
¾
B. Connolly
R. Gibson
S. Patel
W-S Eng
Labelled Synthesis Group
¾A. Chaudhary
Summed PET images of acquired after intranasal
administration of a carbon-11 labelled H3 PET Radioligand
MIP
2D OSEM, 20 cm region-ofsupport PET
reconstructions. PET image
display range SUV 0-3
Summed PET images of acquired after intranasal
administration of a carbon-11 labelled H3 PET Radioligand
PT_OAc_PETCT90min3DDYNAMIC_20070205_TAC_05Feb07
PT_03R323_H3_PETCT70min3DDYNAMIC_20070130_TAC_01Feb07 5:26:18 PM 2/1/
4
4
Striatum
Thalamus
Frontal Cx
Parietal Cx
Insula
Temporal Cx
Occipital Cx
Cerebellum (cx)
Cerebellum Trunk
Pons
White matter
3.5
3
3.5
3
2
2
1.5
1.5
1
1
0.5
0.5
0
0
0
20
40
Temporal Cx
Cerebellum (cx)
Cerebellum Trunk
Pons
White matter
2.5
SUV
SUV
2.5
Striatum
Thalamus
Frontal Cx
Parietal Cx
Insula
Occipital Cx
60
Start-frame-time(min)
80
100
0
20
40
60
Start-frame-time(min)
80
100