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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. 5/23/2017 2 PROPRIETARY Revolution in Personalized Medicine Then 3 Now The Perfect Storm •Biotech Funding and VC investment diminishing •Facing a global financial crises •Declining productivity and sales •Commoditization and downward price pressure 4 Perfect Storm or Perfect Wave 5 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 • • • 6 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 • • • • • 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):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. 7 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 8 US at an 'Inflection Point' for Targeted Therapies 5/23/2017 9 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 • • 10 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 • 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 Molecular Imaging, PGx and MDx Effective For: • Disease risk prediction • Disease diagnosis • Disease prognosis • Patient stratification • Therapeutic stratification • Monitoring therapeutic response 11 Stratified/Personalized Medicine will Profoundly Alter R&D and Business Strategies • • • • • • • • 12 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 • • • • • • • • • • • • • • • • 13 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: 14 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. 15 Phase III FDA Technology Transfer, Regulatory & Promotion Support Diagnostic Companies Manufacturing, Commercial Development & Distribution Uses of Morphological Biomarkers in Drug Development • Analyze effect on target/downstream pathways in pre-clinical studies e.g. • Transition assays to clinical specimens, can be used for e.g. • 16 Selecting/Guiding dose in Phase I/II Identifying potential biomarkers of response and/or resistance Refine Response/Resistance Biomarkers in Phase II • 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 Radiochemistry laboratory Translational research Imaging services PET CT 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 CH3 CH3 N N S HN S HN CH3 CH3 H N NH NH S S CH3 CH3 H NH NH CH3 CH3 2+ Cu 64 Cu2+ -2H+ + -2H N N 64 N N N 64 S HN S HN CH3 CH3 Pyruvaldehyde bis(thiosemicarbazone) Pyruvaldehyde bis(thiosemicarbazone) Cu 64 Cu S NN S N 64 Cu PTSM 64 CuPTSM NH NH CH3 CH3 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 - OOC N N 64 2+ N N Cu HOOC O COO- SO3- NH--mAb HOOC 64 CuCl2 pH6.5 HOOC N N N N O COOH 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 111InAvastin as a probe – A larger market in clinical practice. 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 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 TumorPixelmean 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 37 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 38 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 5/23/2017 39 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 5/23/2017 40 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. 5/23/2017 41 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 .. 5/23/2017 43 PROPRIETARY