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

2. 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

3. Revolution in Personalized Medicine
Then
Now

4. The Perfect Storm Biotech Funding and VC investment diminishing
Facing a global financial crises
Declining productivity and sales
Commoditization and downward price pressure
The left side fades in first. Bullets are quoted directly from the case. The right side, “MPI” exactly mirrors the left.

5. Perfect Storm or Perfect Wave

6. The Future of Medicine: Molecular Diagnostics and DxRx Concepts
Overall Strategic Health Trends
Healthcare Paradigm Shift
More Molecular Testing in the Future
Genetic Testing-Personalized Medicine
Genetic Testing as a Prelim to Cancer Therapy
DxRx role in disruptive technology
Animal Models Bridging to Clinical and beyond to market

7. The Case for Personalized Medicine
There are approximately 350 biologics in phase III
>2,000 other treatments are in early development
Blue Cross Blue Shield plans reported:
Spending on specialty Pharma products ↑ 35%
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): : Mullins CD et al. Health Aff 2006;25(5):1332-9; Stern D, Reissman D. .J Manag Care Pharm. 2006;12(9):
Fish L. Amer J Manag Care 2006;12(6):

8. Current Role of Biomarkers in Drug Selection & Use
A recent Medco study of FDA-approved drug labels found that:
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

9. US at an 'Inflection Point' for Targeted Therapies
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.
Woodcock: US at an 'Inflection Point' for Targeted Therapies
December 15, 2010
In a plenary session at the Partnering for Cures conference being held in New York City this week, the Food and Drug Administration's Margaret Hamburg and Janet Woodcock announced the agency's latest draft guidance for industry, which aims, among other things, to enhance collaboration among pharmaceutical firms throughout the drug-development process. The draft form of FDA's "Guidance for industry: Co-development of two or more unmarketed investigational drugs for use in combination" was distributed to conference attendees yesterday. Hamburg, the FDA Commissioner, said that in order "to truly advance medical progress and see the return on our nation's investment in the sciences, we need to seamlessly pass the baton of innovation from one sector to the next."
Woodcock said the agency was committed to evaluating progressive drug-development paradigms to enable the approval of targeted therapies. She used FDA-approved targeted cancer therapies as examples of past success. Cancer therapies that target activated tumor pathways "have potential to significantly improve outcomes — and reduce toxicity," she said. "In order to bring these to market efficiently, we recognize … [that] we're going to have to develop new pathways, new drug development paradigms." 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. "And, in fact, this isn't just true of cancer," she added. "It's going to be true of many severe diseases, but I think cancer is a good paradigm because we have some early examples of targeted therapy on the market. We have more coming. We're seeing that inflection point."
Comments and suggestions related to the FDA's draft guidance addressed to the agency's Division of Dockets Management will be accepted up to 60 days after the announcement of its release appears in the Federal Register.
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PROPRIETARY

10. Definitions: Theranostics and Personalized Medicine
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
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
Right patient, Right drug/device, Right time, Right cost, Right reasons to do it again
is a tsunami that is coming …… here today

11. Molecular Imaging, PGx and MDx
Effective For:
Disease risk prediction
Disease diagnosis
Disease prognosis
Patient stratification
Therapeutic stratification
Monitoring therapeutic response

12. Stratified/Personalized Medicine will Profoundly Alter R&D and Business Strategies
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

13. Personalized Medicine
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)

14. Targeted prescription of medicines
Today
“One-size fits all” Prescription
Future
Rational “targeted” prescription
Personalized Medicine
Prescription Roulette
Diagnostic Test
Drug A
Drug A
Drug B
Drug C X
Drug B
Drug D
Drug C
Drug D
Savings: Time
Money
Illness
Cost: Time
Money
Well-Being

15. Pre-Clinical Biomarker Development Through Phase III and Beyond
Pharma & Biotech
Research
Pre-Clinical
Phase I
Phase II
Phase III
FDA
Launch
Master Research Agreement
Master Laboratory Services Agreement
Pathway
Elucidation
Efficacy & Mechanism
Biomarkers,
Resistance Pathways
Dose Selection (PD Biomarkers)
Drug Mechanism (Surrogate Efficacy Biomarkers)
Patient Selection (Predictive Biomarkers)
Companion Dx
Development
Development
Testing Support
Technology Transfer, Regulatory & Promotion Support
Targeted Molecular Diagnostics
Diagnostic Companies
Diagnostic companies need to manufacture and sell the final test, but frequently have a hard time understanding therapy companies.
Manufacturing, Commercial Development & Distribution

16. Uses of Morphological Biomarkers in Drug Development
Analyze effect on target/downstream pathways in pre-clinical studies e.g.
Phosphorylation (TKIs: Iressa, Tykerb, Gleevec)
Acetylation (HDACi: SAHA, MS-275)
Methylation (Vidaza)
Transition assays to clinical specimens, can be used for e.g.
Selecting/Guiding dose in Phase I/II
Identifying potential biomarkers of response and/or resistance
Refine Response/Resistance Biomarkers in Phase II
Correlating biomarkers with patient response
Selecting one (or a few) biomarkers for Phase III
Select Patients and Standardize in Phase III

17. The evolution of diagnostic imaging
PAST PRESENT “FUTURE”
Anatomic
plain films, CT,
MRI, US
Functional
angiography,
doppler US, NM,
MRI, PET
Hybrid
PET/CT,
SPECT/CT, PET/MR
Molecular
NM, PET, SPECT,
MRS, optical,
PET/MRI
contrast-enhanced
MRI/US/CT

18. REALLY QUICK on this one! OR POSSIBLY DELETE

19. Molecular imaging modalities
MR Spectroscopy
PET/CT
Optical Imaging
SPECT/CT
Targeted
ultrasound

20. Positron emission tomography: PET
PET-CT image
+ -
180o
511 kev
18FDG
Radiotracer

21. How is molecular imaging relevant to cancer patient care?
Imaging cellular and molecular phenomena
in vivo
Patient selection
by genotype
Diagnostic and therapeutic agents combine as “theranostics”
metastasis
malignant
M. Harisinghani
Scientists are beginning to use these nanoparticles to image cellular and molecular phenomena, such as in this patient with metastatic prostate cancer… at incredibly high resolution, to select patients for appropriate therapies, based on their genetic makeup, such as trying to detect a certain receptor such as her-2/neu to see if that patient will respond to her-2/neu-directed therapy. Through nanomolecular imaging, we are beginning to see agents that can be used concurrently as diagnostic and therapeutic agents, i.e., “theranostics”.
D. Artemov
S. Gambhir

22. Molecular imaging and cancer
Optical: Activatable fluorescence
for intestinal adenoma
MR: Amide proton transfer imaging to assess brain tumor characteristics
U. Mahmood
Nuclear: PSMA imaging
for prostate
cancer
Nuclear: [18F]FHBG for
tracking T cells
J. Babich
S. Gambhir
P. Van Zijl

23. Molecular Imaging: Preclinical
Radiochemistry laboratory
Translational research
Imaging services
PET
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 CT
Fetal skeletal analysis
Bone healing
Arthritis
Osteoporosis

24. Imaging Cell Trafficking
To study cell trafficking and molecular expression in immune response using microPET
Specific antiCD4 monoclonal antibody
Radiolabel any type of cells, including T-cell, stem cell, bacteria, and yeast.

25. Imaging Antibody Targeting
Normal
FcRKO
Radiolabeling:
Peptide,
Antibody,
siRNA,
Small molecules,
Nanoparticles,

26. New Diagnostic Imaging Biomarker & Clinical Application
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 111In-Avastin as a probe – A larger market in clinical practice.

27. New Diagnostic Imaging Biomarker & Clinical Application
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 anti-cancer 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.

28. Experimental Therapeutics and Molecular Imaging

29. New Biomarker of Tumor Detection - PET/CT Imaging of Tumor Angiogenesis
1 hour 5 hour 20 hour 44 hour

30. 64Cu-Bevacizumab on Pancreatic Cancer Model
100 50 %
100
52.5 5 %
64Cu-Bevacizumab 44hr
64Cu-Bevacizumab 44hr
64Cu-Bevacizumab 44hr
100 50 % 50
27.5 5 %
18FDG 1hr
18FDG 1hr
18FDG 1hr
FDG
1Hr

31. 64Cu-Bevacizumab on Breast Cancer Orthotopic Mouse
100 50 %
100
52.5 5 %
64Cu-Bevacizumab 44hr
100 50 % 45
22.5 %
64FDG 1hr
FDG
1Hr

32. 64Cu-Bevacizumab on H460 Lung Cancer Model
100 50 %
100
52.5 5 %
64Cu-Bevacizumab 44hr
100 50 % 20 10 %
64FDG 1hr
FDG
1Hr

33. Contrast of Tumor over Tissue
0.68
7.50
64Cu-Bevacizumab
18FDG

34. Imaging Orthotopic Cancer Model
100
52.5 5 %
64Cu-Avastin 44hr 45
22.5 %
18FDG 1hr
FDG
1Hr

35. Imaging Personalized Medicine

36. Tumor-Tissue Contrast on Different Models
7.50
MiaPaca2, Pancreatic Ca.
MDA-231, Breast Ca.
5.27
H460, Lung Ca.
2.99
0.68
-0.14
0.15

37. 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
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

38. Molecular Imaging Companies
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.
Carestream Molecular Imaging 
CoreLab Partners, Inc. 
VirtualScopics 
Affibody AB 

39. 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

40. 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

41. 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

42. R. Stephen Porter, Pharm. D
R. Stephen Porter, Pharm.D., FCP, MRCP VDDI Pharmaceuticals Chairman, President and CEO 115 Penn Warren Drive Suite Brentwood, TN (615) (cell) (Cell China)

43. Special Thanks to:
Zheng Jim Wang, PhD Director Molecular Imaging MPI Research North Main Street • Mattawan, MI Tel: x2286 • ..
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