Transcript Slide 1

Medical Imaging in Clinical Trials
and Surrogate End Point
Discussions
R. Stephen Porter, Pharm.D.
Chairman, and CEO; VDDI Pharmaceuticals
International Multi-Center Clinical Trials
Shanghai China 9-10th December 2010
Biomarkers and Molecular
Imaging
Many hundreds of imaging biomarkers are already used in
drug discovery and development as well as in the clinic. At
Pfizer, for example, imaging-based endpoints are widely used
in translational oncology research. GlaxoSmithKline (GSK) has
established a clinical imaging center in London which, for
example, uses imaging biomarkers to help determine
dosing for central nervous system (CNS) drugs.
Merck also has a pre-clinical imaging center.
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PROPRIETARY
Revolution in Personalized
Medicine
Then
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Now
The Perfect Storm
•Biotech Funding and VC
investment diminishing
•Facing a global financial
crises
•Declining productivity and
sales
•Commoditization and
downward price pressure
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Perfect Storm or Perfect Wave
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The Future of Medicine:
Molecular Diagnostics and DxRx Concepts
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Overall Strategic Health Trends
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Healthcare Paradigm Shift
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More Molecular Testing in the Future
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Genetic Testing-Personalized Medicine
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Genetic Testing as a Prelim to Cancer
Therapy
DxRx role in disruptive technology
Animal Models Bridging to Clinical and
beyond to market
The Case for Personalized Medicine
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There are approximately 350 biologics in phase III
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>2,000 other treatments are in early development
Blue Cross Blue Shield plans reported:
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Spending on specialty Pharma products ↑ 35%
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Specialty Pharma = ~25% of all outpatient pharmacy
spending in 2008
As cost of some treatments exceed $10-20,000 per month,
affordability and access are key considerations
Need solutions to ↑ quality & outcomes
some products offer
only marginal benefits or no benefits to certain patients
Personalized medicine is one such solution
Watkins JB et al. Health Affairs 2007;25(5):1347-52: Mullins CD et al. Health Aff 2006;25(5):1332-9; Stern D, Reissman D. .J
Manag Care Pharm. 2006;12(9):736-44.
Fish L. Amer J Manag Care 2006;12(6):159-161.
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Current Role of Biomarkers in Drug
Selection & Use
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A recent Medco study of FDA-approved drug labels found that:
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121 drug labels contained pharmacogenomic information
• 69 contained human genomic biomarkers
• 52 contained microbial biomarkers relevant to human
treatment
24.3% of 36.1 million patients processed by Medco took one or more
drugs with pharmacogenomic information in the label
The importance of biomarkers in treatment selection and patient
management is only anticipated to increase in the coming years
Source: Frueh F. et al Pharmacotherapy 28(8): 2008
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US at an 'Inflection Point' for
Targeted Therapies
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Woodcock said that FDA expects that the
increased use of drug and diagnostic
combinations as well as "adaptive trial
designs to evaluate the multiple drug
and diagnostic pairings and to ensure
ethical treatment [of] enrolled subjects,
and increasing attention to the use of
novel biomarkers" will move R&D
forward.
PROPRIETARY
Definitions: Theranostics and Personalized
Medicine
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Theranostic
A diagnostic test that can increase the clinical utility of a given
therapeutic drug while reducing the risks and costs associated with
developing and marketing it clearly creates synergy
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CEO of PharmaNetics, John Funkhouser. He defined it as, "The
ability to affect therapy or treatment of a diseased state
This concept of combining a therapeutic entity with a corresponding
diagnostic test is termed Theranostics I prefer calling Dx/Rx
Personalized Medicine
Do the right thing
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Right patient, Right drug/device, Right time, Right cost, Right
reasons to do it again
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is a tsunami that is coming …… here today
Molecular Imaging, PGx and MDx
Effective For:
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Disease risk prediction
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Disease diagnosis
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Disease prognosis
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Patient stratification
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Therapeutic stratification
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Monitoring therapeutic response
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Stratified/Personalized Medicine will Profoundly
Alter R&D and Business Strategies
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Increased reliance on biomarkers
Greater reliance on Phase IV studies to verify clinical
effectiveness and safety
Emergence of new clinical development paradigm
(Phase 1‐3 distinctions will become obsolete)
New project management, business, and
manufacturing models
Increasing partnerships with diagnostics companies
New regulatory framework theranostics
Legal and ethical issues- who gets expensive
treatments procedures
Challenge to healthcare financing systems
Personalized Medicine
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Gleevec(Novartis) ‐pH+ CML kinase inhibitor
Iressa(AstraZeneca) –EGFR tyrosine kinase inhibitor
Tarceva(Genentech/OSI) –HER1/EGFR inhibitor
Erbitux(ImClone/BMS) –HER1/EGFR inhibitor
Avastin(Genentech) –VEGF/VEGFR inhibitor
Herceptin(Genentech) –HER2 inhibitor
BilDil(NitroMed) ‐heart failure in African American patients
Other “Semi Targeted” Treatments (approved or late stage trials)
Nexavar(Bayer/Onyx) –multi-kinase inhibitor
Tykerb(GSK) ‐ErbB‐2/EGFR inhibitor
Enzastaurin(Lilly) ‐PKC‐Beta, AKT/P13 inhibitor
Favrille–FavIdfor non‐Hodgkin’s lymphoma
Genitope–MyVaxfor non‐Hodgkin’s lymphoma
PGx Predict: warfarin
Strattera (ADHD Metabolism P450 2D6)
6-MP (leukemia , metabolism TPMT)
Targeted prescription of medicines
Today
Future
“One-size fits all” Prescription
Rational “targeted” prescription
Personalized Medicine
Prescription Roulette
Diagnostic
Test
Drug A
X
Drug B
X
Drug A
Drug D
X
Drug B
Drug C
Cost:
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Time
Drug C
Savings:
Time
Money
Money
Well-Being
Illness
Drug D
Pre-Clinical Biomarker Development
Through Phase III and Beyond
Pharma & Biotech
Research
Pre-Clinical
Master Research Agreement
Efficacy & Mechanism
Pathway
Biomarkers,
Elucidation
Resistance Pathways
Development
Phase I
Phase II
Launch
Master Laboratory Services Agreement
Dose Selection (PD Biomarkers)
Companion Dx
Drug Mechanism (Surrogate Efficacy Biomarkers) Development
Patient Selection (Predictive Biomarkers)
Testing Support
Targeted Molecular Diagnostics
Diagnostic companies need to manufacture and sell the
final test, but frequently have a hard time understanding
therapy companies.
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Phase III FDA
Technology Transfer,
Regulatory & Promotion
Support
Diagnostic Companies
Manufacturing, Commercial
Development & Distribution
Uses of Morphological Biomarkers in Drug
Development
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Analyze effect on target/downstream pathways in pre-clinical studies
e.g.
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Transition assays to clinical specimens, can be used for e.g.
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Selecting/Guiding dose in Phase I/II
Identifying potential biomarkers of response and/or resistance
Refine Response/Resistance Biomarkers in Phase II
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Phosphorylation (TKIs: Iressa, Tykerb, Gleevec)
Acetylation (HDACi: SAHA, MS-275)
Methylation (Vidaza)
Correlating biomarkers with patient response
Selecting one (or a few) biomarkers for Phase III
Select Patients and Standardize in Phase III
The evolution of diagnostic imaging
PAST
PRESENT
Anatomic
Functional
Hybrid
plain films, CT,
MRI, US
angiography,
doppler US, NM,
MRI, PET
PET/CT,
SPECT/CT, PET/MR
“FUTURE”
Molecular
NM, PET, SPECT,
MRS, optical,
PET/MRI
contrast-enhanced
MRI/US/CT
Molecular imaging modalities
Sensitivity
Modality
Agents
H
R
Primary uses
Examples
FMT
fluorescent
proteins
x
X
gene expression, tagging
superficial structures
GFP, RFP, NIRF
probes
BLI
luciferin
X
gene expression, therapeutic
monitoring
fLuc rLuc
X
site-selectivity, protein labeling
99mTc-annex
Optical
pM
Nuclear
SPECT
nM
99mTc, 123/5I, 111In
X
in V, 123I-
A85380
PET
11C, 18F, 124I,
X
X
64/62/60Cu
site-selectivity, gene
expression, drug development
11C-RAC, 124I-FIAU,
64Cu-ATSM
MRI
M
spectroscopy
endogenous
metabolites
X
X
CNS, prostate , heart , breast
NAA, Cr, Cho, Glx, mI,
31P
contrast
agents
Gd, Mn, FeO
x
X
cell trafficking, enzymatic
activation
poly-L-lysine,
dendrimers, MION
X
drug-delivery, gene
transfection
human albumin
(Optison)
Ultrasound
one
bubble
contrast
agents
perfluorinated
microbubbles
H=human, R=rodent
Molecular imaging modalities
MR Spectroscopy
PET/CT
Optical
Imaging
SPECT/CT
Targeted
ultrasound
Positron emission tomography:
PET
18FDG
511 kev+
- 511 kev
180o
Radiotracer
PET-CT image
How is molecular imaging relevant to
cancer patient care?
Imaging cellular
and molecular
phenomena
metastasis
in vivo
Patient selection
by genotype
Diagnostic and
therapeutic agents
combine as
“theranostics”
malignant
M. Harisinghani
D. Artemov
S. Gambhir
Molecular imaging and cancer
Optical: Activatable
MR: Amide proton
fluorescence
for intestinal adenoma
transfer imaging to
assess brain tumor
characteristics
U. Mahmood
Nuclear:
Nuclear:
[18F]FHBG for
PSMA imaging
for prostate
cancer
tracking T cells
J. Babich
S. Gambhir
P. Van Zijl
Molecular Imaging:
Preclinical
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Radiochemistry laboratory
Translational research
Imaging services
PET
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CT
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Drug distribution (in vivo ADME)
Biologics labeling of cells including,
bacteria, yeast, t-cells, and stem cells
Radiolabeling of antibodies, peptides,
siRNA and nanoparticles
Radiotracers: 18FDG, 18FLT, 64Cu, 124I
Tumor models: Xenograft, Orthotopic,
Metastasis
CNS and autoimmune disease models
Fetal skeletal analysis
Bone healing
Arthritis
Osteoporosis
Imaging Cell Trafficking
H
H
HN
HN
N
CH 3
CH 3
N
N
S
HN
S
HN
CH 3
CH 3
H
N NH
NH
S
S
CH 3
CH 3
H
NH
NH
CH 3
CH 3
64
2+
Cu
64
Cu2+
-2H+ +
-2H
N
N
N
NN
64
N 64CuPTSM
N
Cu
64
64
Cu
CuPTSM
S
S
NH
HN
S
S
NH
HN
CH 3
CH 3
CH 3
CH
Pyruvaldehyde bis(thiosemicarbazone)
Pyruvaldehyde bis(thiosemicarbazone)
N
3
HBSS
HBSS
64
Cu
64
Cu
Radiolabel any type of cells, including T-cell,
stem cell, bacteria, and yeast.
Imaging Antibody Targeting
Normal
Radiolabeling:
Peptide,
Antibody,
siRNA,
Small molecules,
Nanoparticles,
FcRKO
O O
HOOC
N
N
N
N
HOOC
HOOC
COOH
EDC
sulfo-NHS
pH5.5
COOH
N
N
O N
N
N
O
COOH
HOOC
pH7.5
mAb--NH2
NH--mAb
NH--mAb
-
OOC
N
N
64
2+
N
N
Cu
HOOC
O
COO-
SO3-
64
HOOC
CuCl2
N
N
pH6.5
N
N
HOOC
O
COOH
New Diagnostic Imaging Biomarker &
Clinical Application
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We discovered a new mechanism for diagnostic imaging of tumor
detection other than receptor-binding mechanism (e.g. Herceptin).
64Cu-Avastin (or other anti-VEGF Ab) can detect tumor earlier and better
than 18FDG (see Cancer Focus news release).
64Cu-Avastin may could apply to more tumor types (any solid tumor) than
18FDG due to its unique anti-angiogenesis mechanism.
64Cu-Avastin can detect tumor metastasis of bone, brain, peritoneum.
The same mechanism can be applied to SPECT imaging by using 111InAvastin as a probe – A larger market in clinical practice.
New Diagnostic Imaging Biomarker &
Clinical Application
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Multi-modality imaging approach – PET/CT and
SPECT/CT using multifunctional probe (patent#
11/460,500 ).
64Cu-Avastin can be used to evaluate therapeutic
response of cancer treatment with any kind of anticancer drug or drug candidates.
Avastin-analogs (other anti-VEGF Ab) with higher
affinity with target (VEGF) and faster blood
cyclolation as better diagnostic imaging agent (see
Cancer Letter paper we published in 2009).
Avastin-analogs (other anti-VEGF Ab) have
potential applications on cancer therapeutic and
targeted drug delivery properties.
Experimental Therapeutics
and Molecular Imaging
Effects of Anticancer Agents on HCT-116 Xenograft
Tumor Growth
Tumor Volume (mm3)
2000
1500
Group 1 (Vehicle)
Group 2 (Irinotecan, 75mg/kg)
Group 3 (Irinotecan,150 mg/kg)
Group 4 (5-FU, 50 mg/kg)
Group 5 (5-FU, 100 mg/kg)
Group 6 (Irinotecan+5-FU )
1000
500
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Study Day
New Biomarker of Tumor Detection PET/CT Imaging of Tumor Angiogenesis
1 hour
5 hour
20 hour
44 hour
64Cu-Bevacizumab
on Pancreatic Cancer Model
%
100
%
100
50
52.
5
5
0
64Cu-Bevacizumab
44hr
64Cu-Bevacizumab
%
100
%
50
27.
5
5
50
0
18FDG
FDG
1Hr
1hr
64Cu-Bevacizumab
44hr
18FDG
1hr
18FDG
1hr
44hr
64Cu-Bevacizumab
%
100
%
100
50
52.
5
5
0
64Cu-Bevacizumab
44hr
%
100
50
0
64FDG
FDG
1Hr
on Breast Cancer Orthotopic Mouse
1hr
%
45
22.
5
0
64Cu-Bevacizumab
64Cu-Bevacizumab
on H460 Lung Cancer Model
%
100
%
100
50
0
52.
5
5
%
100
%
20
44hr
64
FDG FDG 1hr
1Hr
50
10
0
0
Contrast of Tumor over Tissue
Tum orPixelmean  TissuePixelmean
Contrast 
TissuePixelmean
Tumor-Tissue Contrast on MiaPaca2 Xenograft Model
8
7
6
Contrast
5
4
3
2
7.50
1
0.68
0
Avastin
FDG
64Cu-
Bevacizumab
18FDG
Imaging Orthotopic Cancer Model
%
100
52.
5
5
64Cu-Avastin
44hr
%
45
22.
5
0
FDG
1Hr
18FDG
1hr
Imaging Personalized Medicine
Tumor-Tissue
Contrast
on Different
Models
Tumor-Tissue Contrast
on Different
Tumor Models
8
7
7.50
MiaPaca2, Pancreatic Ca.
MDA-231, Breast Ca.
Contrast
6
5
4
5.27
H460, Lung
Ca.
3
2.99
2
1
0.68
0
-1
Avastin
-0.14
FDG
0.1
5
Theranostics: Companies
A&G Pharmaceutical
Abbott Laboratories
Affymetrix
Amorfix Life Sciences
AstraZeneca
Axis-Shield
Bayer
Biogen Idec
Bristol-Myers Squibb
Cambridge Theranostics
Chiron
Clinical Data
CyGene
DakoCytomation
Digene
DNAPrint Genomics
Epigenomics
EXACT Sciences
Fornix Theranostics
Gemini (Eurona)
Genaissance Pharmaceuticals
Genentech
Genetic Vectors
Gen-Probe
Glaxo Wellcome
HBV Theranostica
Hyseq
IGEN International
ImClone Systems
Innogenetics
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Investigen
Itsi-Biosciences
Kingo Diagnostika
Lpath Therapeutics
Merck & CO.
Millennium Predictive Medicine
Myriad Genetics
Neighborhood Connections
NGI
Novartis
Oncogene Science
Organon Teknika
PeptiFarma
PGxHealth
PharmaNetics
Pronto Diagnostics
Provalis
Quidel
Roche
Seapro Theranostics International B.V
Sequenom
The Boston Consulting Group
TheraNostics GmbH
Tibotec-Virco
Ventana Medical Systems
Visible Genetics
Vysis
Wyeth
Molecular Imaging Companies
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Carestream Molecular
Imaging
http://www.carestreamhealth.c
om/molecular-imaging.html
CoreLab Partners, Inc.

http://www.corelabpartners.
com/
VirtualScopics

http://www.virtualscopics.c
om/
Affibody AB
 http://www.affibody.com/e
n/
•
•
1. VirtualScopics Services provides imaging
support to pharmaceutical and biotechnology companies
for every clinical trial stage, from initial design to
submission to the FDA. Its proprietary software algorithms
are able to take hundreds of medical images from MRI or
CT sessions and create a three-dimensional model to
enable the detection of minuscule changes in anatomical
structures or in metabolic activity. VirtualScopics reports
that its “Therapeutic area expertise includes: oncology,
rheumatoid arthritis, osteoarthritis, neurology, and
cardiovascular studies utilizing MRI, PET, CT, Ultrasound,
and X-Ray imaging modalities.” This publically-traded
company, located in Rochester NY, grew out of a research
initiative at the University of Rochester Medical Center
and School of Engineering in 1999.
2. Carestream Molecular Imaging, a division of
Carestream Health of Rochester NY, provides in vivo and
in vitro optical molecular imaging solutions for molecular
biology research. Carestream reports that it has a global
market for its digital capture systems, image analysis
software, imaging agent chemistry and traditional
scientific films. Carestream's Albira combines PET, SPECT
and CT imaging into an integrated preclinical research
platform. With Albira’s multi-modal modular design,
companies can only buy what they need at the moment
and then purchase additional units as their needs change
in the future.
Power of the Image
”Seeing a tumor shrinking with nuclear
magnetic resonance will take weeks;
whereas to see a change in its
metabolism with PET will probably
take a few days. That’s where the power
of imaging is.” Oliver Steinbach, Philips
Research Laboratories
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PROPRIETARY
Challenges
Technology is actually not the point anymore.
It’s more like how do you handle, store, retrieve,
and analyze the enormous amount
of data generated by these technologies, how do you tackle
the 4.2 trillion voxels (or 3-dimensional pixels) that
imaging a single mouse’s brain will produce
in just one week. SO the challenge for the future is
data collection, transmission, storage and review
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PROPRIETARY
Conclusions
Imaging biomarkers are the new kids on the block in drug
development but their advantages, from saving time, detecting
subtler drug effects and bolstering confidence in early results
mean they look set to stay. In the clinic imaging biomarkers
are providing earlier diagnosis and localization of disease, as
well as helping clinicians navigate treatment by determining
whether drugs are working — a strategy that will save money in
the long term, but challenges remain.
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PROPRIETARY
R. Stephen Porter, Pharm.D., FCP, MRCP
VDDI Pharmaceuticals
Chairman, President and CEO
115 Penn Warren Drive
Suite 300-389
Brentwood, TN 37027
(615)445-5761 (cell)
+86.15021242314 (Cell China)
http://www.virtualdrugdevelopment.com
Special Thanks to:
Zheng Jim Wang, PhD
Director Molecular Imaging
MPI Research
54943 North Main Street • Mattawan, MI 49071
Tel: +1.269.668.3336 x2286
[email protected] • www.mpiresearch.com
..
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PROPRIETARY