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DETERMINING THE IMPACT OF NEW THERAPEUTICDETERMINING THE IMPACT OF NEW THERAPEUTICPLEASE STAND BY… The webinar
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DETERMINING THE IMPACT OF NEW THERAPEUTICAPPROACHES: ADVANCING IMAGING IN ANIMALS
DETERMINING THE IMPACT OF NEW THERAPEUTICAPPROACHES: ADVANCING IMAGING IN ANIMALS
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Webinar SeriesWebinar SeriesWebinar SeriesWebinar SeriesScienceScienceScienceScienceDETERMINING THE IMPACT OF NEWDETERMINING THE IMPACT OF NEW
Brought to you by the Science/AAAS Custom Publishing Office
THERAPEUTIC APPROACHES:THERAPEUTIC APPROACHES:Advancing Imaging in Animals Advancing Imaging in Animals
7 December, 20117 December, 2011
Participating Experts:
Brought to you by the Science/AAAS Custom Publishing Office
Patrick McConville, Ph.D.Molecular Imaging, Inc.Ann Arbor, MI
Matthias Nahrendorf, M.D., Ph.D.Harvard Medical SchoolBoston, MABoston, MA
Sponsored by:
IN VIVO IMAGING OF DRUG RESPONSE AND FMT: RESPONSE AND FMT: A CRO PERSPECTIVE
Patrick McConville, Ph.D. CSO/COO - Molecular Imaging, Inc.
Presentation Outline
Background: imaging in drug research Brief history/evolution
f Rationale for use
Image based disease end points Anatomical, functional and molecular imaging end points
Image based biomarker: definition Image based biomarker: definition
Surrogate marker
Probe facilitated imaging of efficacy
RA model/optical probe example
Imaging probe based biomarkers and FMT Rationale for FMT in drug discovery and development
Example 1: protease and bone imaging in RA
Example 2: acute inflammation in sponge granuloma
Example 3: tumor burden
Future applications
Presentation Outline
Background: imaging in drug research Brief history/evolution
f Rationale for use
Image based disease end points Anatomical, functional and molecular imaging end points
Image based biomarker: definition Image based biomarker: definition
Surrogate marker
Probe facilitated imaging of efficacy
RA model/optical probe example
Imaging probe based biomarkers and FMT Rationale for FMT in drug discovery and development
Example 1: protease and bone imaging in RA
Example 2: acute inflammation in sponge granuloma
Example 3: tumor burden
Future applications
Preclinical imaging: a brief history
70s: Major clinical imaging developments
80s: Widespread use of clinical imaging for diagnosis
90s: Translation of imaging technology for rodent work
Last decade: introduction of dedicated rodent imaging systems
substantial development of new imaging probes MR, CT, PET, optical, SPECT, ultrasound, MR, CT, PET, optical, SPECT, ultrasound,
pharmaceutical industry invests and relies on imaging technology
Last 5-10 years: anatomical functional/molecular
d ffdiagnostic efficacy
academia industry
Next 5-10 years: efficacy safety/toxicologyy y y/ gy
Preclinical imaging: evolution
WAS IS
Modality centric Modality agnostic
Decentralized Centralized
A complex technology for physicists and engineers
A black box technology for multi-disciplinary scientists
A fA tool for disease progression and therapeutic
A tool for disease diagnosisA tool for disease progression and therapeutic
response
Expensive Expensive
Not a standard in drug development A standard in drug development
In academic institutions In industry
in vivo Imaging in Drug Research
IND NDA
Single Compound
Discovery Development Introduction/Registration
High throughput screeningscreening
Lead CandidateSelection
PreclinicalEarly-PhaseClinical
Phase II-III Phase IV
in vivo Imaging in Drug Research
Imaging in Drug Discovery and DevelopmentDiscovery and Development
in vivo Imaging in Drug Research
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Imaging in Drug Discovery and DevelopmentDiscovery and Development
in vivo Imaging in Drug Research
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Imaging in Drug Discovery and DevelopmentPharmacology, Toxicology
and PathologyDiscovery and Developmentand Pathology
in vivo Imaging in Drug Research: Why ?
Faster ? Early prediction
Eg imaging inflammatory cell recruitment Eg. imaging inflammatory cell recruitment
Better resolved ? Tissue, sub-tissue, cellularPET , ,
Eg. imaging of tissue heterogeneity
More relevant ?
PETMRI
Access to unique, mechanistic endpoints Eg. imaging of cathepsin activity
Translational ? Translational ? Discovery/development continuum
Eg. MRI and PET image based biomarkers
CT Optical/FMT Cost effective ?
Yes, if one or more of the above is true
Presentation Outline
Background: imaging in drug research Brief history/evolution
f Rationale for use
Image based disease end points Anatomical, functional and molecular imaging end points
Image based biomarker: definition Image based biomarker: definition
Surrogate marker
Probe facilitated imaging of efficacy
RA model/optical probe example
Imaging probe based biomarkers and FMT Rationale for FMT in drug discovery and development
Example 1: protease and bone imaging in RA
Example 2: acute inflammation in sponge granuloma
Example 3: tumor burden
Future applications
In Vivo Imaging in Drug Research
ANATOMICAL FUNCTIONAL MOLECULAR
Microscopy
Morphology
Structure
Hypoxia
Proliferation
Inflammation
Necrosis
Apoptosis
Receptor occupancyStructure
Bone resorption/loss
Implanted devices
Inflammation
Blood flow
Perfusion
Receptor occupancy
Metabolite levels
Biodistribution
Imaging of plaques
Vascular mapping
Metabolism
Ejection fraction
H d i
Protease activity
Immune cell tracking
C ll i tiMyocardial infarction
Medical devices
Hydration Cell migration
Target modulation
In vivo imaging in safety and toxicology
In Vivo Imaging in Drug ResearchCorrelation with Disease Progression
Image-based Quantifiable Image-based
BiomarkerProgression (validation I)Parameter Biomarker
Correlation with Clinical End Point Clinical End Point
(validation II)
Surrogate Surrogate Marker
Imaging: the Core Facility Challenge
OpticalU/S
IntegratedMultiple Modality
Imaging
Imaging: the Core Facility ChallengeM l i l i i d li i• Multiple imaging modalities
IntegratedMultiple Modality
• Multiple protocols per modality• Multiple therapeutic areas (TAs)
Imaging
• M lti l d l TA• Multiple models per TA• Safety• Medical devices
Presentation Outline
Background: imaging in drug research Brief history/evolution
f Rationale for use
Image based disease end points Anatomical, functional and molecular imaging end points
Image based biomarker: definition Image based biomarker: definition
Surrogate marker
Probe facilitated imaging of efficacy
RA model/optical probe example
Imaging probe based biomarkers and FMT Rationale for FMT in drug discovery and development
Example 1: protease and bone imaging in RA
Example 2: acute inflammation in sponge granuloma
Example 3: tumor burden
Future applications
Biomarker access through imaging probes
Imaging probe Molecule or nanoparticle designed to modulate imaging contrast
Degree of signal or contrast modulation is generally dependent on: probe concentration (voxel based)
Tissue access
PK/PD Degree of uptake (for captured probes)
Degree of activation (for conditional probes)
Probe Type Examples
Targeted Receptors (eg. integrins, estrogen R, VEGF R)Bone (eg. hydroxyapetite)Proteins (eg. VEGF)
Conditionally ‘captured’
Metabolic cycle (eg. FDG)Cell cycle (eg. FLT)Hypoxic cells (eg. MISO)
d llConditionally activated probes
pHProteases (eg. caspases, cathepsins, MMPs)
Imaging probes: drug research concept
Drug Target or Bi l f i t tBiology of interest
PROBE FACILITATED IMAGING OF MECHANISM
Model choice
Imaging probe choice
Why FMT ? - the CRO perspective
Quantitative, three-dimensional imaging High throughput, efficient imagingg g p , g g
probe multiplexing
10-20min per subject for image runs of up to 50+ animals possible
Available biomarkers bounded only by probe developers rapidly increasing commercial availability
access to prior large probe patent estates access to prior large probe patent estates
technology is now emerging from major probe discovery labs
True molecular imaging disease mechanism
drug response mechanism
Applications readily cross disease states and into safety Applications readily cross disease states and into safety Clinical translation potential
Validation: the CRO perspective
‘Pharma-ready’ validation Biomarker readout correlates with:
disease progression response to therapy
Correlation t diti l li i l t
Understood for:• EACH probe or
traditional clinical measurements traditional biomarkers histopath
Study design and limitations understood
biomarkerin• EACH model Study design and limitations understood
image timing probe clearance uncoupling or interference
EACH modelwith • EACH
study powering Advantage/value vs traditional
uniqueness; more predictive time saving
treatment
time saving clinically translatable
V lid i ‘Ph d ’
Example: Mouse RAValidation: ‘Pharma-ready’
Histopath CorrelationTraditional in vivo vs image based end pointsTraditional in vivo vs image based end points
Clinical Score2.5
Traditional250
Control
Image Based
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Paw Swelling
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Histopath Score
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RA: Inflammation imaging with ProSense
Naïve Quantification of ProSense 680 Uptake in Right (blue) & Left
DAY 7
29.624.9
25 0
30.0
p g ( )(red) Paws
∆ = 5-6 x DAY 7
20.621.1
15 0
20.0
25.0
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DAY 11 5.8
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DAY 21
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L ft ( d) & Ri ht (bl ) P
Response correlates with known onset of
paw inflammation
Confidential© 2008 VisEn Medical, Inc.25
Left (red) & Right (blue) Paws
RA: Bone imaging with OsteoSense
NaïveQuantification of OsteoSense
750 Uptake in Right (blue) & Left (red) Paws
DAY 720.8
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L ft ( d) & Ri ht (bl ) P
© 2008 VisEn Medical, Inc.26
Left (red) & Right (blue) Paws
M l d l
Example: Acute inflammationMouse sponge granuloma model
19F MRI: Imaging of Macrophages
PBS Sponge CFA SPBS Sponge CFA Sponge
Low 19F signal High 19F signal
V-Sense in Sponge Granuloma Model of Acute Inflammation
Cathepsin Imaging: Acute Inflammation
CFA SpongePBS Sponge ImplantImplant
Fluorescence SignalFluorescence Signal
CFA
PBS
Pre-injection6.5 Hours Post-injection24 Hours Post-injection
Pre-Injection 6.5 Hours 24 HoursPre-Injection 6.5 Hours 24 Hours
Sponge Granuloma Model of Acute Inflammation
Activated probes in acute inflammation
MC MCSponge Granuloma Model of Acute Inflammation
pre
C: Cathepsinactivation (Prosense)
urs
M: MMP activation (MMP Sense)
Greater cathepsin and
6 ho
u Greater cathepsin and MMP activity was detected in CFA sponges (diseased animals), compared with PBS sponges (controls) 6h
4 ho
urs
PBS sponges (controls) 6h and 24h after probe injection.
24
PBS (control) CFA (diseased)
Feasibility of tumor burden measurement across
Example: Tumor imaging• Feasibility of tumor burden measurement across
a broad panel of models• Testing imaging throughput and workflow (104 g g g g p (
scans in a 24h period)
FMT imaging in tumor models
Study # Study Name Description Mouse
Strain# of
Mice
# FMT In-vivo Scans
Agent 1 Required
Agent 1: Doses
Required
Agent 2 Required
Agent 2: Doses
Required1 CAIA In-vivo imaging & Quantification of Collagen Antibody-Induced Arthritis (CAIA) Model in mice
OsteoSense Control Mouse #1 Nu/Nu 2 2 ProSense 680 1 OsteoSense 800 1
Experimental Mice #2-#8 Nu/Nu 6 14 ProSense 680 7 OsteoSense 800 7
2 Bone Metastasis In-vivo imaging & Quantification of Bone metastasis from Prostate Adenocarcinoma (PC-3M-luc) in murine models
Exp Mice #1-#3 Nu/Nu 1 2 ProSense 680 1 OsteoSense 1Exp. Mice #1-#3 Nu/Nu 1 2 ProSense 680 1 800 1
4 Breast Adenocarcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Breast Adenocarcinoma (MX-1) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
5 Breast Adenocarcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Breast Adenocarcinoma (A-375) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
6 Large Cell Lung Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Lung Carcinoma (H-460) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
7 Colorectal Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Colorectal Carcinoma (HT-29) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense 680 1 ProSense 750 1
8 Colorectal Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Colorectal Carcinoma (HCT-116) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense 680 1 ProSense 750 1
Colorectal
© 2008 VisEn Medical, Inc.32
9 Colorectal Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Colorectal Carcinoma (Colo-205) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense 680 1 ProSense 750 1
FMT imaging in tumor models
Study # Study Name Description Mouse
Strain# of
Mice
# FMT In-vivo Scans
Agent 1 Required
Agent 1: Doses
Required
Agent 2 Required
Agent 2: Doses
Required10 Gastric Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Gastric Carcinoma (N-87) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
11 Colorectal Adenocarcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Colorrectal Adenocarcinoma (DLD-1) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
12 Pancreatic Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Pancreatic Carcinoma (Panc-1) in murine modelsCarcinoma
Exp. Mice #1-#3 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
13 Pancreatic Carcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Pancreatic Carcinoma (MiaPaca-2) in murine models
Exp. Mouse #1-#2 Nu/Nu 1 2 MMPSense 680 1 ProSense 750 1
14 Pancreatic C i In-vivo Imaging & Quantification of Sub-Q tumours of Pancreatic Carcinoma (MiaPaCa-2) in murine models14 Carcinoma In vivo Imaging & Quantification of Sub Q tumours of Pancreatic Carcinoma (MiaPaCa 2) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense680 1 AngioSense
750 1
15 Bone Metastasis In-vivo Imaging & Quantification of Bone Metastasis from Prostate Adenocarcinoma (PC-3M-luc) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense 680 1 AngioSense
750 1680 750
16 Pancreatic Carcinoma
In-vivo Imaging & Quantification of Sub-Q tumours of Pancreatic Epithelioid Carcinoma (Panc-1) in murine models
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense 680 1 AngioSense
750 1
17 Ovarian Adenocarcinoma In-vivo Imaging & Quantification of Sub-Q tumours of Ovarian Adenocarcinoma (A2780) in murine models
33
Exp. Mice #1-#3 Nu/Nu 1 2 IntegriSense 680 1 ProSense 750 1
Totals 52 104 N/A 52 N/A 52
se68
04000
6000
MX-1
A-375
DLD 1
FMT technology in d l
MM
PSen
s
0
2000
DLD-1
Panc-1
MiaPaca-2
N-87
tumor models
CONCLUSIONS• Can be used to locate tumors
se75
0
150
200
250MX-1
A-375
HT-29
Colo-205
0
mol
)
• Can be used to track tumor growth
• Best probe for each model should be determined
ProS
en
0
50
100HCT-116
DLD-1
Panc-1
MiaPaca-2
N-87resc
ence
(p • Imaging throughput not limiting in running large, powered industry drug response studies
nse
680
0 A-2780
4500
6000
7500
HT-29
Colo-205
HCT-116
Flou
r
ADVANTAGES• Does not require transfected
line (eg. luciferase)
• Facilitates rapid use of new
Inte
griS
en
0
1500
3000
HCT 116
Panc-1
MiaPaCa-2
A-2780
ppatient derived models
• Deep tissue models not limiting
34
0
Tumor Size
Future expanded applications ?
To come … Biodistribution
Huge current emphasis on targeted biologics
Cell tracking
Obesity and metabolic disease Lack of mechanistic end points
New biomarkers
N d d Increasing focus on cell based therapies
Pulmonary disease COPD, Pulmonary fibrosis
Lack of non-invasive biomarkers for preclinical study
Neuro-degenerative diseases MS: eg. EAE model
Alzheimer’s
Parkinson’s
Inflammatory Bowel Disease Lack of robust preclinical end points
Atherosclerosis Lack of non invasive end points
Systemic tumor models Leukemia
Lymphoma
Metastasis Lack of non-invasive end points
Preclinical imaging remains deficient in athero models
Hybrid athero/metabolic models
Imaging burden AND mechanism in tumors
primary, patient derived models
genetically well characterized models
target modulation
Imaging outlook including FMT• Proof of principle has been established for most of these examples
• Further widespread adoption and application needed• Further widespread adoption and application needed
• More comprehensive validation – qualified biomarkers
Expanded use and benefit in pharmaceutical research
Webinar SeriesWebinar SeriesWebinar SeriesWebinar SeriesScienceScienceScienceScienceDETERMINING THE IMPACT OF NEWDETERMINING THE IMPACT OF NEW
Brought to you by the Science/AAAS Custom Publishing Office
THERAPEUTIC APPROACHES:THERAPEUTIC APPROACHES:Advancing Imaging in Animals Advancing Imaging in Animals
7 December, 20117 December, 2011
Participating Experts:
Brought to you by the Science/AAAS Custom Publishing Office
Patrick McConville, Ph.D.Molecular Imaging, Inc.Ann Arbor, MI
Matthias Nahrendorf, M.D., Ph.D.Harvard Medical SchoolBoston, MABoston, MA
Sponsored by:
Webinar SeriesWebinar SeriesWebinar SeriesWebinar SeriesScienceScienceScienceScienceDETERMINING THE IMPACT OF NEWDETERMINING THE IMPACT OF NEW
Brought to you by the Science/AAAS Custom Publishing Office
THERAPEUTIC APPROACHES:THERAPEUTIC APPROACHES:Advancing Imaging in Animals Advancing Imaging in Animals
7 December, 20117 December, 2011
Participating Experts:
Brought to you by the Science/AAAS Custom Publishing Office
Patrick McConville, Ph.D.Molecular Imaging, Inc.Ann Arbor, MI
Matthias Nahrendorf, M.D., Ph.D.Harvard Medical SchoolBoston, MABoston, MA
Sponsored by:
Webinar SeriesWebinar SeriesWebinar SeriesWebinar SeriesScienceScienceScienceScienceDETERMINING THE IMPACT OF NEWDETERMINING THE IMPACT OF NEW
Brought to you by the Science/AAAS Custom Publishing Office
THERAPEUTIC APPROACHES:THERAPEUTIC APPROACHES:Advancing Imaging in Animals Advancing Imaging in Animals
7 December, 20117 December, 2011
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