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About Biomarker Summit 2013 GTC’s Biomarker Summit will discuss a wide range of issues such as biomarker identification and validation strategies, patient stratification, enabling omics technologies, bioinformatics and systems biology techniques, regulatory and reimbursement trends and the development of companion diagnostics. These areas will be addressed in an intimate and highly interactive environment with perspectives from industry, academia and the public sector. Networking: With approximately 150 anticipated attendees, the Biomarker Summit is the perfect venue to network with the leaders in the biomarker field. The Summit provides a unique opportunity to gain the latest biomarker developments in three major therapeutic areas, formally organized in the following tracks: 6th Oncology Biomarkers 2nd Neurological Biomarkers 2nd Inflammatory & Immunological Biomarkers

2012 Demographics

To customize your package or to receive further information contact: Maribel Cortes, Senior Conference Producer [email protected]

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Biomarker Summit 2013 – Plenary Keynote Session – March 20-22, 2013 – San Francisco, CA

Agenda is subject to change. Please visit www.gtcbio.com for the most updated agenda. Updated 2/12/13

Day 1 - Wednesday, March 20, 2013

Plenary Keynote Session Chairperson: Christoph Borchers, Facility Director, University of Victoria Genome British Columbia Proteomics Centre

1:00 Chairperson's Opening Remarks

1:15 Translation of Biomarkers into Clinical Practice: the Future is Now

Daniel Chan Professor & Director of Clinical Chemistry Division Johns Hopkins University

During the last decade of biomarker research, significant progress has been made in the discovery of potential biomarkers. However, limited successes have been shown in the translation of these biomarkers into clinical practice. I believe that the time has come for us to focus on the translation of those promising biomarkers. Most human diseases, such as cancer, are often diagnosed either in their late stages when the chance of cure is relatively low or in the form of diseases that might not have to be treated. What we need is to be able to detect lethal diseases in their early stages. Molecular biomarkers offer the best opportunity for making significant impacts in the flights against lethal diseases. In my presentation, I will discuss our strategies from biomarker discovery, validation to translation. Case studies will be presented. To be successful, we need to develop a roadmap and identify several key steps that are critical in this process. I will discuss the 4Bs (bridge) and the 4Gs (gate) for biomarker translation. (1) To define clearly a specific “intended use” for unmet clinical needs, (2) to generate sufficient evidence in preliminary studies to support the investment for a large-scale validation study, (3) to select and develop assays with analytical performance suitable for clinical laboratory and (4) to conduct clinical trial to demonstrate clinical utilities in order to obtain regulatory approval and gain acceptance by the clinical community. The successful translation of biomarkers into clinical practice will require 4Ps (partnership) with close collaboration between researcher, industry, regulator and clinician/clinical laboratory.

2:00 Noninvasive Personalized Genomics

Charles Cantor Chief Scientific Officer Sequenom, Inc.

In a variety of clinical settings nucleic acids from apoptotic or broken cells appear in the peripheral circulation. These are potential sources of diagnostic markers. While various RNAs are present these are not always of sufficient stability to serve well in clinical assays. Hence this talk will focus on DNA biomarkers. Here clinically useful information can be derived from the sequences present, from specific mutations and epigenetic modifications not present in the normal plasma DNA of a healthy host. One case of interest is non-invasive prenatal diagnostics. Here fetally-derived DNAs can be used to detect fetal abnormalities including aneuplodies and Mendelian disorders. Commercial tests using highly parallel DNA sequencing have been available for more than a year to detect aneuploidies and the performance of these tests is nearly perfect. Indeed it is possible, but not yet commercially practical, to determine the entire genomic sequence of an unborn fetus by analysis of sufficient numbers of apoptotic DNA fragments in maternal plasma. Cancer presents a parallel situation since tumors have DNA sequences and epigenetic patterns not found in the normal host. The discovery of markers to use to detect the presence of cancer and assess tumor burden is still in early stages. Mass spectrometry has ideal characteristics to detect these markers at low abundance and to quantify their occurrence. It is clear that



clinically useful markers can be detected in plasma and that these associate well with markers found in specific samples of the tumor obtained invasively. We know that plasma DNA from the fetus is rather uniform in properties and also represents the entire fetal genome rather uniformly. Less is understood about the nature and possible diversity of plasma DNA derived from tumors. Benefits: state of the art technology, cutting edge diagnostic products, studying the root cause of clinical phenotypes

2:45 Afternoon Break

3:15 Why so Few Companion Diagnostics? The Difficulty of Translating Biological Data into Predictive Biomarkers

Nicholas Dracopoli Vice President, Head of Oncology Biomarkers Janssen Research & Development

Translating complex genomic data into widely used clinical tests has been much slower than anticipated. FDA-approved diagnostic tests have only been approved to predict response to therapy for nine oncology drugs a decade after the completion of the human genome sequence. All of these are simple tests that measure the status (mutation, translocation, over expression etc.) of the drug target or pathway. Three complex tests (in vitro diagnostic multiplex index assays - IVDMIA) have been approved as prognostic tests, but there has still not been a single approval of an IVDMIA to predict response to therapy. Retrospective analyses of the development of predictive biomarkers for first-in-class oncology drugs over the last ten years shows that (1) insufficient patients have been exposed to an efficacious dose to support complex statistical analyses to correlate high-content data against clinical endpoints, and (2) biomarkers that correlate to response in Phase II studies are not always good predictors of overall survival in Phase III trials. Consequently, we will need to modify the clinical development paradigm for fist-in-class agents to support the efficient co-development of predictive markers. • Overview of FDA approved companion diagnostics for oncology • Application of biomarkers in drug development • Translating complex genomic data into informative clinical tests • Role of companion diagnostics in development of new drugs in oncology • Novel strategies for the co-development of drugs and diagnostics

4:00

Kenneth Rhodes Vice President, Neurology Research Biogen Idec., Inc.

4:45 Translational Research on Cancer Biomarkers: It Takes a Village

Sudhir Srivastava Chief, Cancer Biomarkers Research Group National Cancer Institute, NIH



Thousands of research articles published in the last decade have fueled expectations that effective biomarker-based diagnostics would rapidly take form. However, much of the literature includes studies which were conducted without appropriate study designs and population statistics. In reality, only a handful of biomarkers have been approved by the Food and Drug Administration (FDA). Many of the previous studies have alluded to the fact that the discovery of biomarkers are not aligned with the intended clinical use and therefore these biomarkers are haphazardly being tested and continue to fail. In addition, most of the biomarkers continue to be derived from non-human sources, e.g., cell lines and animal models and they fail when tested in humans. Serendipity continues to play a major role in biomarker discovery. Use of convenience samples in discovery continues to complicate the generalizability of biomarkers for a specific use since these biomarkers suffer from being discovered by chance and are plagued by bias. The process of biomarker discovery is no different than drug discovery. It requires sustained, long-term efforts starting from basic research all the way to FDA filing. It is estimated that it costs more than one billion dollars to find one effective cancer drug. Biomarkers for early detection may be even harder because they entail finding the disease among asymptomatic populations. The cost of developing robust diagnostic FDA-approved biomarkers is speculative because there is a lack of published historical data. In light of these challenges and difficulties, NCI established a program called Early Detection Research Network (EDRN) with the goal of developing and evaluating biomarkers for cancer risk, early detection, diagnosis and prognosis. The translation of biomarkers into clinical use is a long and difficult process and the vast majority of biomarkers will never make it beyond verification as they lack sufficient sensitivity and specificity to be clinically useful. Successful translation requires not only close collaboration between investigators involved in discovery research, clinicians, assay developers and statisticians, but the investigators have to willing to have their assays and biomarkers verified by an independent laboratory. Some investigators have expressed reluctance to “hand-over” their biomarkers or to have them independently verified, asking “what’s in it for me.” The EDRN is designed to foster collaboration amongst investigators with different expertise and to allow for the biomarker discoverer to actively participate in the validation process. The Speaker will discuss these challenges with examples of collaborative processes leading to approval of five biomarkers by FDA.

5:30 End of Day 1

Biomarker Summit 2013 – Oncology Biomarkers – March 20-22, 2013 – San Francisco, CA


Day 2 - Thursday, March 21, 2013 Chairperson: Thomas Li, Senior Director, Technology Management, Chief Technology Office, F. Hoffmann-La Roche Ltd

7:00 Continental Breakfast & Registration


Circulating / Body-Fluid Biomarkers

8:15 Identifying Circulating Oncology Markers by Interrogating the Tissue Secretome Using Mass Spec-based Proteomics

Daniel Chelsky, Chief Scientific Officer, Caprion Proteome, Inc.

Discovering circulating biomarkers directly in blood has proven difficult due to the presence of very high abundance proteins as well as the challenge of linking candidate markers to the known biology of the disease. These problems can be circumvented by looking directly in the disease tissue for candidate markers and then verifying their presence and utility in plasma. We have used high resolution mass spectrometry to probe the contents of the Golgi and secretory vesicles from tumors and normal tissue, identifying proteins destined for secretion that are up-regulated in the tumors. These candidate markers are then quantified in plasma, using highly multiplexed MRM mass spectrometry to verify their utility as markers of disease. Other examples of this approach will also be provided.

8:40 Multiscale Approaches to Biomarker Discovery

Parag Mallick, Assistant Professor, Canary Center for Cancer Early Detection, Stanford University

Low cost, minimally invasive assays measuring Circulating Protein Biomarkers (CPMs) are of significant clinical interest for their potential to provide information about the molecular characteristics of a cancer thereby improving long-term survival rates by improving detection and by enabling personalization of treatment strategy. Proteomic marker discovery approaches attempt to broadly quantify up to thousands of proteins to find proteins that are 1) relatively unique to the tumor; 2) indicative of its presence and likely behavior; and 3) easily quantifiable in the circulation. Early technical challenges using direct serum discovery approaches have led the popularization of a multi-stage tumor-centric marker discovery approach, which is predicated on the belief that proteins are 'shed' from the tumor, traversing to and then persisting within the circulation. Despite early excitement, the multi-stage, tumor-centric approach has not been widely successful; bottlenecks include technologic challenges of platform reproducibility/sensitivity and affinity reagent availability. In addition, counter-intuitive observations have found that in many instances proteins that are both highly abundant in the tumor and strongly indicative of tumor state can fail to be viable candidates when interrogated in the circulation. In our studies we investigate the scale of proteomic changes associated with oncogene escape (the mechanism by which tumors become resistant to targeted therapies) as well as how a protein’s stability, cellular localization, and abundance affect its observability in blood by mass-spectrometry-based proteomics techniques. Together, these studies form the basis for rigorous mathematical models that might be used for marker discovery.

9:05 Circulating Tumor Cells as a Guide to Personalized Medicine

David Nelson, President and Chief Executive Officer, Epic Sciences, Inc.

Circulating tumor cells (“CTCs”) are of great interest because they hold the promise to radically improve the treatment of cancer and accelerate the development of personalized medicines. Specifically, CTCs provide a real-time tumor biopsy that is both easily accessible and something that can be monitored routinely throughout the course of the disease. CTC counts have been validated as a prognostic tool in breast and prostate cancer. New technologies, including the Epic technology, are seeking to go beyond enumeration to molecularly characterize the CTCs. CTC characterization is receiving significant attention because it may provide a real-time assessment of each individual patient’s tumor. That information could be used both to guide treatment decisions for individual patients and to guide inclusion/exclusion decisions for clinical trials. The key is will be the availability of a CTC technology that finds enough CTCs in enough patients and in a format that will facilitate downstream CTC characterization. The Epic CTC platform has been designed for that purpose. Epic has established partnerships with 8 Pharmaceutical companies to develop Companion Diagnostic products. These Pharma partnerships include over a dozen clinical trials including multiple Phase I and Phase II studies involving over 1500 patients and 3000 samples across many cancer indications.



9:30 Disease States from Circulating Proteins

Heinrich Roder, Chief Technology Officer, Biodesix

Circulating proteins present viable candidates for the characterization of the phenotypical state of an organism. Such characterization may provide a powerful tool to define novel disease states on a molecular basis and assist in the detection, monitoring, and treatment of disease. I will present how we can use the high throughput mass spectrometry technology developed by Biodesix to generate signatures for specific questions in oncology. This technology allows for the simultaneous semi-quantitative measurement of thousands of proteins from serum and plasma. I will review the analytical validation of this technology, and the challenges arising from the large amount of data generated. As a concrete example the disease state defined by Biodesix’ VeriStrat test will be discussed using data from clinical studies.

9:55 Morning Networking Break

10:25 Urine Protein and Nucleic Acid Cancer Biomarkers

Anna Lokshin, Professor of Medicine, Pathology, Ob/Gyn; Director, Luminex Core Facility, University of Pittsburgh Cancer Institute

The measurement of biomarkers present in the bodily fluids of cancer patients represents an important avenue for the development of minimally invasive tests to predict tumorigenesis, disease recurrence, or treatment response. Since urine is available in greater quantities, it represents an attractive bodily fluid for biomarker development. Using Luminex® xMAP® multiplexing approach, we performed screening of a large array of >150 candidate proteins in serum and in urine of patients with ovarian, pancreatic, lung, and breast cancers vs. appropriate matched non-cancer controls to identify a number of biomarkers with high disease association. We have determined that multibiomarker algorithms perform independently of urine hydration status. Our multivariate analysis identified several urine multimarker panels capable of discriminating the cancer from the control groups with high sensitivity and specificity. We will discuss the possibilities of combining protein biomarkers with nucleic acid urine biomarkers for cancer screening. Urine could potentially become bodily fluid of choice for first line cancer screening.

10:50 The Utility of Transrenal Nucleic Acids for the Monitoring of Molecular Disease

Charlie Rodi, Vice President & Chief Technology Officer, Trovagene, Inc.

Cell-free nucleic acids have been found in a variety of human bodily fluids with the nucleic acids isolated from urine having been extensively characterized. Transrenal nucleic acids (TrNAs) originate from the death of both normal and diseased cells, enter the circulation, and then pass through the kidneys into the urine. They have been proven to contain oncogene mutations, including KRAS and p53; mutated viral DNA; and other markers of disease, including microRNA (miRNA). In contrast to other specimens, urine allows for truly non-invasive collection, provides a larger sample size, and allows for frequent collection. These factors, combined with recently commercialized technologies to digitally count and track nucleic acids, make the development of these truly non-invasive diagnostics both practical and scalable. To unlock the full potential of TrNA, Trovagene has developed a proprietary method for the isolation of the short, fragmented nucleic acids that pass through the kidneys; developed proprietary “ultra-short” amplicon assays necessary for the efficient detection of TrNA; and created genetic and mutation panels to be offered through its San Diego-based CLIA laboratory. Benefits: • Understand the science behind transrenal nucleic acids • Learn how NGS and digital PCR have enabled transrenal molecular diagnostics to move from the research setting into the commercial setting • Understand the inherent benefits and limitations of tissue, blood, and urine as diagnostic specimens • Learn why isolation of short DNAs and small footprint assays are critical for cell-free nucleic acid -based diagnostics • Understand the advantages of transrenal-based diagnostics for monitoring disease - and about implications for future diagnostic testing



Implementation of Next-Generation Sequencing

11:15 Clinical Application of Comprehensive Cancer Genomic Analysis Utilizing Next Generation Sequencing (NGS) in Clinical Oncology

Matthew Hawryluk, Director of Business Development, Foundation Medicine, Inc.

Advances in our understanding of cancer biology and the explosion of discoveries emerging as academic and public efforts worldwide apply NGS to cancer genomes are being translated into real clinical benefits for cancer patients. The elucidation of genomic changes to inform rationally targeted therapies is becoming a reality, and the pace of this translation from bedside to bench and back is accelerating. Dramatic responses to EGFR inhibitors in EGFR mutated lung adenocarcinomas, to crizotinib in lung cancers with ALK fusions, and, most recently, to a BRAF inhibitor in BRAF-V600E mutant melanomas, are driving a paradigm shift in cancer treatment. With over 500 compounds targeting over 150 genomic alterations in clinical trials, we anticipate the need to comprehensively characterize the genomic alterations across all cancer-related genes in solid tumors in the near future. To meet these demands on oncologists and pathologists coupled with limited tissue resources, Foundation Medicine has developed a CLIA-certified pan-cancer diagnostic assay based on NGS technology to comprehensively interrogate all cancer-related genes using minimal DNA from FFPE tumor specimens to identify all classes of genomic alterations (base substitutions, insertions and deletions, copy number alterations and rearrangements) at high sensitivity and specificity. This assay, FoundationOne, which is currently being utilized on routine clinical FFPE specimens, typically identifies three times the number of actionable alterations in a patient’s tumor compared to traditional HOT SPOT type approaches. Summary data of hundreds of clinical cases plus a series of vignettes highlighting the power of this approach will be presented. • Understand how comprehensive genomic sequencing is being applied in the clinic • Understand the benefits of comprehensive genomic sequencing vs. traditional hot-spot sequencing based on real clinical cases • Describe specific cases where targeted therapeutic options based on targeted therapies have resulted in improved patient outcomes

11:40 Scripps Genome ADVISER

Ali Torkamani, Director of Genome Informatics and Drug Discovery, The Scripps Translational Science Institute, Scripps Genomic Medicine

SG-ADVISER is an automated computational system for the interpretation of genome sequence data. SG-ADVISER produces known and predicted information about genetic variants – otherwise known as variant annotations. SG-ADVISER produces four major classes of variant annotations including: 1) residence within known or inferred genomic elements (e.g., exons, promoters, conserved elements, transcription factor binding sites, protein domains etc.); 2) annotation and prediction of the functional impact of a variant on genomic elements (prediction of impact on protein function, changes in transcription factor binding strength, splicing efficiency, microRNA binding, etc.); 3) annotation of molecular and biological processes which link variants across genes and/or genomic elements with one another, and 4) annotation of known or predicted population-based, clinical, and/or molecular characteristics of the gene or variant (e.g. population frequency, pharmacogenetic variants, disease associations, eQTLs etc.). Annotation execution proceeds in highly parallel fashion and includes classes of variant annotations that are entirely independent of one another, serially dependent annotations whose execution are dependent upon the completion and status of prior annotations, and synthetic annotations that generate new information through the combination of multiple annotation outputs. In this talk, I will present details of the SG-ADVISER system and its use in genome interpretation.

12:05 Lunch on Your Own

1:35 Paul Billings, Chief Medical Officer, LIFE Technologies



Diagnostic & Therapeutic Development for Cancer

2:00 FEATURED PRESENTATION

Molecular Diagnostics to Guide Drug Development and Patient Tailoring in Oncology

Andrew Schade Senior Director, Diagnostic and Experimental Pathology, Tailored Therapeutics, Lilly Research Labs Eli Lilly and Company

Scientific advances elucidating the molecular pathophysiology of certain cancer types have created an opportunity for using molecular diagnostic tools to identify patients most likely to benefit from a given therapeutic agent. While generally met with excitement and an understandable desire to improve outcomes for individual patients, there are many challenges that must be addressed by multiple stakeholders – including the biopharmaceutical industry, diagnostics companies, clinical laboratories, and regulators – to effectively move the field forward. This presentation will highlight some challenges around co-development of drugs and companion diagnostics as the practice of medicine is rapidly evolving. There are market forces and regulatory directives that impact how we develop new therapeutics targeting patient sub-populations, and the role of the clinical laboratory is becoming more prominent as patient selection for oncology clinical trials is increasingly biomarker-driven. With regard to biomarkers, the choice of analyte to pursue (e.g. protein vs. nucleic acid), how to analyze (e.g. PCR vs. sequencing), and platform selections are just a few of the key considerations in developing companion diagnostics that demonstrate robust technical performance, ability to pass regulatory scrutiny, fit clinical workflow, and are commercially viable. The one certainty in all of this is the requirement for more extensive collaboration across the multiple stakeholders to enable efficient, cost-effective drug development and patient access to new medicines with the potential to reshape the oncology therapeutic landscape.

2:25 Reticulocycte Hemoglobin (Ret-He/CHr) as a Biomarker of Erythropoiesis and Anemia Assessment

Denise Uettwiller-Geiger, Director of Laboratory Services and Clinical Trials, John T Mather Hospital

Iron deficiency is the most common nutritional deficiency and the leading cause of anemia in the world. Currently used laboratory assessment for iron deficiency may not always be accurate in different clinical settings. A cellular biomarker, Reticulocycte Hemoglobin (Ret-He/CHr) has been shown to provide new insights into erythropoiesis and more targeted assessment of the iron available for hemoglobin synthesis in reticulocytes that have been recently released from the bone marrow. The measurement of reticulocyte hemoglobin content (Ret-He) is a direct assessment of the incorporation of iron into erythrocyte hemoglobin that provides useful information for the diagnosis and treatment of iron-deficient states. This session will describe how Ret-He/Chr has been shown to be more sensitive and predictive than the traditional anemia-defining guidelines in screening for iron deficiency and monitoring response to iron. Benefits: • Describe a biomarker which can estimate the functional availability of iron into RBC precusors and quality of reticulocyctes • Discuss the Ret-He threshold for defining iron insufficiency • Understand how Ret-He helps monitor Iron deficiency, Iron Deficiency Anemia, and Erythropoietin Stimulating Agent therapy

2:50 Rajesh Chopra, Vice President, Translational Research, Celgene

3:15 Afternoon Networking Break

3:45 Predictive and Prognostic Gene Signatures in Breast Cancer

Brian Leyland-Jones, Director, Edith Sanford Breast Cancer Institute, Sanford Research

Molecular profiling of archival patient tumours with well-documented survival outcome data is an excellent approach for discovery of prognostic drivers. Patient samples from cooperative group clinical trials with randomized therapies, long-term follow up, excellent response, progression free survival and overall survival data adds the ability to discern



predictive drivers. We have utilized genomic profiling data from E2100, BIG1-98, E2197, TransHERA, Stanford, TCGA, GSE25055, GSE25065, METABRIC, SuperCohort, and DOD Center of Excellence trial sets for gene signature analysis. We used Gene Set Enrichment Analysis (GSEA) to analyze molecular function, canonical pathways, transcription factor families (TFFs), promoter regulatory elements and chromosomal position as drivers of subtype and outcome. Promoter analysis of enriched genes can provide insight into the role transcription factors play as drivers of phenotype and outcome. Additionally, we have developed Gene Set Outcome Analysis (GSOA) to determine gene signature combinations sharing common attributes that are predictive or prognostic of outcome. TFFs of interest that may differentiate TN from ER+PR+ subtype are ETSF, RXRF, KLFs, FKHD with specific interest in ELF5, SPDEF, KLF5 and FOXA1. GSEA of the TransHERA event group found GO molecular terms Actin Filament Binding, Extracellular Matrix Structural Constituent, and Calmodulin Binding are enriched. GSOA of predicted TFFs in Actin Filament Binding finds prognostic gene signatures from the nuclear receptor families RXRF (THRB, PXR), NR2F (TR2, TR4) and ETSF (SPI1, ETV4, ELK4, ETV5, SPIB). In ER+ cohorts, we have identified gene signatures representing 34 canonical pathways and 47 chromosomal regions that are prognostic of outcome. In the E2100 cohort, we have verified the Perou Hypoxia signature and determined a VEGF signature as predictive of overall survival for bevacizumab. In BIG1-98, we identified a canonical pathway gene signature [CYP8B1,CYP2D6/CYP2A6,CYP2S1,ADH1B,ALDH2] that is predictive of response to treatment where tamoxifen is activated by CYP2D6 and letrozole targets CYP2A6.. Based upon our extensive exploratory analyses, we have discovered a large collection of prognostic and predictive gene signatures that are constrained to molecular function, chromosomal location, canonical pathways and transcription factor families. Analyzing gene signatures in the context of higher-level domain knowledge allows us to gain insight into the key drivers of breast cancer. An integrated analysis of these various signatures will be presented at the meeting.

4:10 Improving the Diagnostic Yield of Bronchoscopy for Lung Cancer Using Bronchial Airway Gene-expression Testing

Duncan Whitney, Senior Vice President, Research & Development and and Technical Operations, Allegro Diagnostics, Inc

Lung cancer remains a major medical problem in the U.S. and lung cancer remains as the leading cause of cancer-related deaths primarily due to diagnosis at late stage. Recently reported improvements in detection sensitivity for early-stage disease using low-dose CT are tempered by the associated low specificity. However the combination of molecular testing with existing diagnosict paradigms can be an important way to improve diagnostic yield. Bronchoscopy is used as an integral part of the lung cancer diagnosis routine today, whereby suspect lung cancer patients with suspicious lesions are examined. Unfortunately of the >300,000 bronchoscopy procedures performed in U.S. per year, approximately 40-60% are indeterminate. We have investigated the use of gene-expression profiling of normal bronchial epithelial cells obtained during bronchoscopy, from suspect lung cancer patients who are either current or former smokers. Approximately 90% of all newly diagnosed cases are in either current or former smokers. We identify both up and down regulated genes associated with smoking damage, and more importantly with the presence of cancer remotely in the lung. Trials designed to train and validate cancer signatures will be described, as well as the clinical utility of such tests. The primary endpoint of such tests is to demonstrate a high negative predictive value to minimize the number of benign cases that are currently referred on to more invasive procedures such as transthoracic needle biopsy and thoracic surgery. Benefits: • Develop an understanding of the limitations in pulmonology practice today and discussion of the need for improved lung cancer diagnostics. • Show how gene-expression profiling of non-malignant cells can aid in the clinical management of suspect lung cancer patients • Demonstrate the importance of developing tests with high negative-predictive value in the clinical diagnostic setting • Describe the importance of prospective, multi-center trials in the validation of new molecular tests

4:35 Glycan “Node” Analysis for Detecting and Monitoring Cancer

Chad Borges, Associate Research Professor, Arizona State University



Dysregulated glycotransferase enzymes in cancer cells produce aberrant glycans—some of which can help facilitate metastases. Within a cell, individual glycotransferases promiscuously help construct dozens of unique glycan structures, making it difficult to comprehensively track their activity in biospecimens—especially where they are absent or inactive. An approach will be described to deconstruct glycans in whole biospecimens then analytically pool together resulting monosaccharide-and-linkage-specific degradation products (glycan “nodes”) that directly represent the activities of specific glycotransferases. To implement this concept a reproducible, relative quantitation-based glycan methylation analysis methodology was developed that simultaneously captures information from N-, O-, and lipid linked glycans and is compatible with whole biofluids and homogenized tissues; in total over 30 different glycan nodes are detectable per GC-MS run. Numerous non-liver organ cancers are known to induce production of abnormally glycosylated serum proteins. Thus following analytical validation in blood plasma the technique was applied to a cohort of 59 lung cancer patient plasma samples and age/gender/smoking-status-matched non-neoplastic controls from the Lung Cancer in Central and Eastern Europe Study to gauge the clinical utility of the approach towards detection of lung cancer. Ten smoking-independent glycan node ratios were found that detect lung cancer with individual ROC c-statistics ranging from 0.76-0.88. Two glycan nodes provided novel evidence for altered ST6Gal-I and GnT-IV glycotransferase activities in lung cancer patients. In summary, a conceptually novel approach to the analysis of glycans in unfractionated human biospecimens has been developed that, upon clinical validation for specific applications, may provide diagnostic and/or predictive information in glycan-altering diseases. Benefits: • A new, patent-pending GC-MS based technology for the analysis of N-, O-, and sphingolipid-linked glycans in small volumes of whole biofluids and tissues without the need for biological reagents (e.g., antibodies or enzymes) will be described. • The new technology will be compared and contrasted with existing approaches to using glycans as cancer markers.

5:00 Overcoming the Challenges of Biomarker Development for Cancer Immunotherapy

Heinz Zwierzina, Chairman Biotherapy Development Association, Innsbruck Medical University

Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers as a tool for the prediction of prognosis and response to therapy. In colorectal cancer, for example, the presence of T cells in the tumour has been shown to predict clinical outcome even after adjusting for stage, lymph node count, and well-established prognostic tumor molecular biomarkers including microsatellite instability (MSI) or BRAF mutation. A wealth of knowledge is available that suggests that immunotherapy can be successfully applied for the treatment of cancer, where it has been demonstrated to induce both clinical and robust immunological responses. Restoring the immune system in cancer patients respresents one of the rare potentially curative approaches even in metastatic disease. Numerous biological barriers are encountered in generating effective immune responses to tumours and a major issue in this context is the improvement of immunological monitoring. To define biomarkers to identify patients who will have clinical benefit, and to ultimately identify appropriate patient groups to enroll, clinical trials testing immune-based interventions should conduct more thorough and standardized immunologic assays. The goal is to comprehensively study clinical responders and nonresponders, and report data and their analysis methodology in greater detail. An increased focus on immune assessments in patients will allow us to learn more about the mechanisms of action of the tested interventions and the positive and negative immune responses in treated patients. Biomarker development for immunotherapy of cancer is even more complex than for other targeted therapies: not only subgroups of tumours may express the target amenable for immunotherapy but also the patients´ immune system is known to be very heterogenous. Therefore both the tumour and the immune system must fulfill certain criteria to enable an immune response. To meet the challenges of utterly complex biomarker development for immunotherapy, strategies including preoperative trials and proteomic approaches will be discussed.

5:25 Oral Presentations from Exemplary Submitted Abstracts

To be considered for an oral presentation, please submit an abstract here by February 20, 2013. Selected presentations will be based on quality of abstract and availability. Presentation slots fill up fast so please submit your abstract ASAP.

5:55 Networking Reception and Poster Session

http://www.gtcbio.com/index.php?option=com_conference&file=poster&cn=6th%20Oncology%20Biomarkers&cid=64

Biomarker Summit 2013 – Neurological Biomarkers – March 20-22, 2013 – San Francisco, CA


Day 2 - Thursday, March 21, 2013 Chairperson: Andreas Jeromin, Chief Scientific Officer, Nextgensciences



Updates on Biomarkers in Alzheimer's Disease

KEYNOTE PRESENTATION

8:15 Using Imaging and CSF biomarkers in Clinical AD Trials: The Alzhiemer's Disease Neuroimaging Initiative (ADNI)

Michael Weiner Professor of Medicine, Radiology and Psychiatry University of California San Francisco; Director, MRS Unit, DVA Medical Center San Francisco

The goal of ADNI (from 2004-2010 see ADNI-info.org) has been to determine the value of MRI and PET imaging together with blood and CSF biomarkers for disease modifying Alzheimer’s treatment trials. In our initial project (ADNI1), we longitudinally studied: MCI (n= 400); AD (n= 200); Controls (n= 220) with clinical visits, neuropsychological assessments, MRI (1.5 T), FDG PET, blood and urine, and CSF. About 300 subjects from ADNI 1 continue to be followed. We found that the rate of hippocampal atrophy had high statistical power for measuring change over time. Data from the normal controls suggests that normal healthy elders with APOƐ4 and/or low CSF Aβ amyloid have worse memory scores and higher rates of hippocampal atrophy, consistent with the hypothesis that some controls have preclinical AD pathology. Similar ADNI-like projects, with similar methods, are underway in Australia, Japan, Europe, China, Taiwan, and Korea leading to the “World Wide ADNI network.” The Parkinson’s Progressive Markers Initiative (PPMI) has been modeled after ADNI. ADNI 2 with 3Tesla MRI and F18 amyloid PET imaging with Florbetapir on an additional 150 controls, 300 subjects with early MCI, 150 subjects with late MCI and 150 subjects with dementia due to AD. A new cohort of normal subjects with cognitive complaints is being added. All ADNI data is available on UCLA/LONI/ADNI, without embargo. ADNI methods are now widely used in clinical treatment trials, and have led to the development of the “new” research criteria for AD developed by the Alzheimer’s Association and NIH.

9:00 Lack of Correlation between Clinical and Biomarker Effects in Therapeutic Trials of Anti-Amyloid Antibodies

Ronald Black, Assistant Vice President, Alzheimer Immunotherapy, Primary Care Business Unit, (retired) Pfizer

The results of the recently-completed phase 3 trials of anti-amyloid antibodies have forced a reexamination of the role of biomarkers in the development of disease modifying treatments for AD. While these negative clinical results have had little effect on the overall enthusiasm for the amyloid hypothesis, the effects of these therapeutic agents on several well-accepted biomarkers for the diagnosis and progression of AD failed to predict the clinical efficacy of these agents. This disconnect between the clinical and biomarker effects of these agents has important implications for the utility of these biomarkers in early proof-of-concept studies, and as evidence of disease modification in registration studies. This talk will examine the relationship between biomarker and clinical effects in therapeutic trials for the major fluid and imaging biomarkers in common use in AD. The implications of this data on the therapeutic potential of these agents in AD, as well as the potential selection of patients for clinical trials will be discussed. A reconsideration of the use of biomarkers in the development of AD therapeutics will be discussed, as will some new strategies for targeting the amyloid cascade.

9:25 Effect of Bapineuzumab on Brain Fibrillar Amyloid Burden in Mild-Moderate Alzheimer’s Disease: Results from the PET Substudies of 2 Phase 3 Trials

Eric Yuen, Vice President, Head of Clinical Development, Janssen Alzheimer Immunotherapy R&D

Bapineuzumab, an anti-amyloid-beta monoclonal antibody, was evaluated in separate phase 3 trials for APOE Ɛ4 allele carriers (Study 302) and non-carriers (Study 301) with mild-moderate Alzheimer’s disease (AD). This study examined the effect of bapineuzumab treatment on brain fibrillar amyloid deposition, as measured by 11C-PiB PET in a subset of



enrolled subjects. 11C-PiB PET scans were obtained at baseline and at 45 and 71 weeks after treatment initiation. Subjects were studied at 14 US PET centers using acquisition protocols and image QC criteria developed in ADNI. For each PET scan a standardized uptake value ratio (SUVr) was calculated for multiple ROIs with a global cortical average (GCA) SUVr calculated using 5 cortical ROIs known to accumulate substantial fibrillar amyloid in AD. Changes from baseline SUVrs were determined, and differences between treatment groups were compared using a mixed model for repeated measures (MMRM). In APOE Ɛ4 carriers, a statistically significant treatment difference in fibrillar brain amyloid burden (GCA SUVr) at Week 71 was observed for bapineuzumab as compared to placebo. In non-carriers, no difference was seen for the pooled dose levels. Pooling all bapineuzumab doses across studies revealed a difference between bapineuzumab and placebo treatment. These studies confirmed the bapineuzumab-associated reduction of amyloid accumulation observed in phase 2.


10:25 Amyloid, Metabolic and MR Imaging Biomarkers in Preclinical AD: Update from the DIAN Study

Tammie Benzinger, Assistant Professor of Radiology and Neurological Surgery, Washington University School of Medicine in St. Louis

The Dominantly Inherited Alzheimer Network (DIAN) study is an NIH-funded study of familial Alzheimer Disease (fAD). More than 10 universities around the world are collaborating to fully characterize the clinical, biological, and imaging profile of fAD. To date, over 300 participants have enrolled in this longitudinal study. Imaging components include amyloid PET (Pittsburgh Compound B [PiB] and florbetapir [AV45]), metabolic PET (FDG), and structural and functional MRI, included grey and white matter volumetrics, diffusion tensor imaging (DTI), and arterial spin labeling (ASL) for cerebral blood flow. Using this unique cohort we are able to tease apart the imaging timeline for biomarker positivity prior to symptom onset in fAD, with amyloid deposition detected 15-20 years prior to dementia. Comparison to proposed timelines for sporadic AD will also be discussed. • The Imaging Biomarker Timeline in familial AD • What are the earliest changes identified in imaging asymptomatic participants? • What differences are identified between brain regions? • Which brain regions develop PiB positivity (amyloid deposition) first? • In which brain regions does amyloid burden increase the most over time? • What are the earliest detected regions of grey matter atrophy? • When are findings of white matter disease, including atrophy and microhemorrhages, detectable?

10:50 Synergy of Imaging and Genomics for Neurological Biomarkers

Belinda Seto, Deputy Director, National Institute of Biomedical Imaging and Bioengineering (NIBIB)

While there is a strong genetic risk for late or early-onset Alzheimer’s disease (AD), only a few genes that contribute to this risk have been identified because objective clinical symptoms do not provide quantitative markers for gene involvement. Additionally, the large number of genes that could be involved in AD complicates the statistical methods. However, with the advent of new technological discoveries, there is now an opportunity to precisely integrate highly resolved 3D MR images of the entire human brain, inclusive of fiber level functional detail, with extensive Single Nucleotide Polymorphism (SNP) data sets. The application of this approach to specific neurodegenerative or mental diseases does not require a priori hypotheses about the brain regions that are altered by the disease, or about the SNPs that have a role in the disease. Rather, the integration of these two large datasets can identify changes in the whole brain that are related to the disease and identify the genetic factors that are linked to these changes.

CSF / Blood-Based Biomarker Approaches

11:15 Cerebrospinal Fluid (CSF)-Based Biomarkers in Alzheimer’s Disease

Judy Suiciak, Scientific Program Manager, Neuroscience, Foundation for the National Institutes of Health, Inc.

The Foundation for the National Institutes of Health (FNIH), a 501(c)(3) non-profit organization, is the sole entity authorized by the U.S. Congress to raise private funds in support of the NIH mission of improving health through scientific discovery and translational research. Since 1996, the FNIH has raised over $500 million towards more than 100 projects. This presentation highlights one of the efforts of the FNIH Biomarkers Consortium, a precompetitive



public-private partnership, in facilitating the development of Alzheimer’s Disease biomarkers. The progress of the Biomarkers Consortium project ““Use of Targeted Multiplex Proteomic Strategies to Identify Novel Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease,” a project submitted to the Biomarkers Consortium by a subgroup of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Industry Private Partner Scientific Board (PPSB), will be reviewed. This collaborative initiative, including participation from academia, government, foundations and the pharmaceutical industry, represents the second part of a multi-phased effort seeking to utilize samples collected by ADNI from healthy controls, and subjects with mild cognitive impairment and Alzheimer’s Disease. The goal of this effort is to qualify multiplex panels in both plasma and cerebrospinal fluid (CSF) in order to diagnose patients with Alzheimer’s Disease and monitor disease progression.

11:40 Intercepting Cellular Communications from the CNS Using Exosomes

Reyna Favis, Scientific Director, Neuroscience Biomarkers, Johnson & Johnson

Neurological and neuropsychiatric disease research has been hampered by the inability to perform molecular assessments of the CNS in living patients. While analyses of post mortem brain tissue and lymphocytes from living donors have been exploited in an attempt to obtain insight, both tissue types suffer from numerous caveats. Exosomes are a recognized mechanism for intercellular communication. By tapping into this cellular communication modality, we reason that it will be possible to gain insight into the activities of inaccessible tissue of the central nervous system. • What are the caveats of using post mortem brain tissue or lymphocytes to assess CNS function? • Can we tap into cellular communication modalities to understand the CNS? • What can we learn about temporal changes and inter-individual differences in CNS state? • What are the caveats of eavesdropping on cellular communications?


1:35 Application of Kinetic Biomarkers to Diagnose and Treat Alzheimer’s Disease and other Neurological Disorders

Patrizia Fanara, Vice President, Neuroscience, KineMed

Understanding the complex metabolic networks that control functions in living organisms is widely seen as the next great challenge in biological research. In the field of therapeutics, particularly for chronic neurodegenerative conditions, the inability to predict the functional consequences of manipulating molecular targets in living organisms is the central problem presently limiting the development of effective and safe drugs. KineMed’s unique kinetic biomarker platform creates companion diagnostic tests for personalized medicine and reduction in disease heterogeneity in clinical trials. The platform utilizes stable isotope labeling combined with specialized mass spectrometric analysis to reveal the dynamics of molecules through critical processes that drive neuronal dysfunction, disease progression and reparative processes in individual patients. The presentation will address: • Systems biology-based markers: Insight into intact living systems, rather than simplified models, to ensure that drug effects are understood in their intended biological context. Information gained on neurodegenerative processes in humans can be back-translated into preclinical models. • Focusing on causes rather than symptoms: Generating real-time disease signals for the development of novel therapeutics that target underlying biochemical causes relevant to neurodegeneration. • Unique assays of disease state: Custom-developed assays to create companion diagnostic tests for personalized medicine. • Reduce late-stage attrition: Early, decision-relevant metrics of drug activity to reduce later failures and improve the net present value of R&D spending.

Biomarkers in Other Neurological Disorders

Parkinson's Disease

2:00 Diagnostic Biomarkers in Parkinson’s Disease – From Rodents to Man

Marcelle Bergeron, Director, Pharmacological Sciences; Head of Neuropharmacology, Elan Pharmaceuticals, Inc.

Huntington's Disease

2:25 Cristina Sampaio, Chief Clinical Officer, CHDI Foundation



Schizophrenia

2:50 Neurophysiological Biomarkers of Risk for Psychosis Onset in Clinical High Risk Youth

Daniel Mathalon, Professor in Residence, Departments of Psychiatry and Biomedical Sciences, University of California, San Francisco and the San Francisco VA Medical Center

Schizophrenia is associated with event-related potential abnormalities during automatic processing of auditory deviance (mismatch negativity; MMN), as well as higher order processing of stimulus deviance leading to orienting (novelty P3a) or target detection (target P3b). Auditory steady state response (ASSR) paradigms also reveal deficient entrainment of electroencephalographic (EEG) gamma oscillations to 40 Hz click trains in schizophrenia, although baseline EEG gamma power is increased. We asked whether these neurophysiological abnormalities are present in youth at clinical high risk (CHR) for psychosis. As part of the ongoing multi-site NAPLS study, 259 CHR youth meeting criteria for a psychosis prodrome syndrome (SIPS interview) and 146 healthy controls (HC) underwent EEG recording during 1) a 3-deviant (pitch, duration, pitch+duration) MMN paradigm, 2) 3-stimulus (target, novel, standard) auditory and visual oddball paradigms, and 3) a 40 Hz ASSR paradigm. In addition, 30 CHR individuals who subsequently converted to psychosis were compared with 40 CHR individuals who had not converted by the 24-month follow-up assessment. Relative to HC, CHR individuals showed significant amplitude reductions of MMN (across deviant types) and P300 (auditory, but not visual, P3a and P3b). In addition, although CHR individuals showed normal 40 Hz ASSR, baseline EEG gamma power was increased. Relative to non-converters, converters had significantly smaller amplitudes of MMN and auditory P300 (P3a and P3b). CHR individuals have schizophrenia-like neurophysiological abnormalities associated with processing deviant auditory stimuli, as well as elevated baseline EEG gamma power. Neurophysiological deficits during auditory deviance processing shows promise as a predictive biomarker of psychosis risk. Benefits of talk: • Provides an overview of efforts to identify individuals at risk for psychosis prior to illness onset. • Provides a description of neurophysiological measures of auditory processing that are abnormal in schizophrenia. • Presents data showing that auditory EEG and event-related potential (ERP) measures are predictive of psychosis onset in youth at clinical high risk for psychosis. • Describes data from the largest prospective study of psychosis risk in the world (the North American Prodromal Longitudinal Study)


3:45 The Role of Experimental Medicine in Early Drug Discovery

Gerard Dawson, Chief Scientific Officer, Department of Psychiatry, University of Oxford, P1vital LTD

In the pharmaceutical industry deciding whether to progress a compound to the next stage of development or choosing between compounds in a development portfolio is laden with risk. This is particularly true of compounds developed to treat CNS disorders. The use of pre-clinical models in CNS drug development is well established but these models often lack predictive validity and many compounds fail when they reach the target patient group. Bridging the gap between pre-clinical CNS models and patient studies is one of the objectives of experimental medicine. Recently we have been developing human volunteer models that will enable rapid, accurate and reliable decision making about which compounds to progress into patient trials. Here we will describe our recent research using healthy volunteer models combined with novel behavioural, fMRI, phMRI biomarkers to elucidate the mechanisms of action of novel compounds developed to treat depression and schizophrenia. Finally we will illustrate how social networks can be used to recruit particular behavioural phenotypes which can enhance the signal to ratio in clinical trials. Benefits: • experimental medicine can accelerate drug development. • the latest fMRI and phMRI techniques can be used to elucidate the mechanism of action of novel compounds • how healthy volunteers can be used to detect drug efficacy. • how social networks can be used to recruit particular behavioural phenotypes



Autism Diagnostic

4:10 The Role of RNA Expression from Blood in the Diagnosis of Autism

Stanley Lapidus, President, SynapDx

Autism Spectrum Disorders (ASD) are developmental disorders, affecting children early in their childhood, characterized by symptoms of impaired social interaction with impaired communication, and repetitive behaviors and restrictive interests. On average, it takes more than two years from the time parents first suspect a problem until their child receives a clinical diagnosis of ASD. Intensive early behavioral intervention such as Applied Behavioral Analysis (ABA) can be initiated earlier if a diagnosis is made, yet children cannot typically access intensive therapies without being diagnosed. Experts agree that earlier diagnosis leads to optimal outcomes. SynapDx is developing a blood-based RNA expression signature to help physicians identify children at greater risk for autism from those suspected of developmental delay. With an objective test that stratifies risk, appropriate referrals for higher risk children could take place at an earlier age. SynapDx will report preliminary findings from a 270 patient study of children ages 24 to 60 months that support the ability of gene expression signatures to differentiate between children with ASD and other developmental delays.

Frontotemporal Dementia

4:35 Clinical Therapeutic Development in Frontotemporal Lobar Degeneration

Adam Boxer, Director, Neuroscience Clinical Research Unit; Director, AD and FTD Clinical Trials Program; Associate Professor of Neurology, University of California, San Francisco

Frontotemporal Lobar Degeneration (FTLD) is the neuropathological description for a group of neurodegenerative disorders encompassing the clinical diseases frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and a number of other less common syndromes. In patients less than age 65, FTLD is as common or more common than Alzheimer’s disease (AD). Approximately half of all FTLD cases are associated with deposition of abnormal tau protein in neurons and glia (FTLD-tau), with the other half associated with accumulation of TAR DNA binding protein 43 kDA (TDP-43; FTLD-TDP). FTLD-TDP often overlaps clinically and pathologically with amyotrophic lateral sclerosis (ALS). There are currently no effective or FDA-approved therapies for FTLD, however a variety of disease modifying therapies for different types of FTLD are entering human clinical trials. Rapid disease progression, relatively pure molecular neuropathology and strong genetic linkages in up to 40% of cases suggests that there may be advantages to developing disease-modifying therapies for FTLD as compared to AD and other forms of dementia. There is a growing consensus that an effective therapy for FTLD-tau may predict successful applications to other tauopathies such as AD or chronic traumatic encephalopathy, and an efficacious therapy for FTLD-TDP may predict efficacy in ALS or certain autoimmune diseases. I will describe the leading therapeutic indications for clinical trials in FTLD, the status of imaging and fluid biomarkers for FTLD and how an efficacious therapy for FTLD-tau or FTLD-TDP might predict efficacy in other diseases.



Panel Discussion: CNS Biomarkers in Clinical Applications -- Strategies to Regulatory Approval and Commercialization

5:30 Panelist: Eric Yuen, Vice President, Head of Clinical Development, Janssen Alzheimer Immunotherapy R&D

Panelist: Cristina Sampaio, Chief Clinical Officer, CHDI Foundation

Panelist: Ronald Black, Assistant Vice President, Alzheimer Immunotherapy, Primary Care Business Unit, (retired) Pfizer

Panelist: Judy Suiciak, Scientific Program Manager, Neuroscience, Foundation for the National Institutes of Health, Inc.

http://www.gtcbio.com/index.php?option=com_submitanabstract&cn=2nd%20Neurological%20Biomarkers&cid=99



Topics to be Discussed:

Utilities/Uses of biomarkers in CNS drug discovery o Introduction/Overview of consortia efforts for biomarker qualification

Current technological approaches to CNS biomarker assessment

Use of biomarkers for patient enrichment in clinical trials : do results from the current immunotherapy trials justify the investment?

How do you recruit patients and retain them?

Clinical trial design : Time for change to adaptive designs and patient-reported outcome

Strategies for biomarker qualification and validation: what are the challenges?

How to engage with the biomarker qualification efforts by the Coalition Against Major Diseases (CAMD)

The Alzheimer Disease Neuroimaging Initiative (ADNI): How applicable is this model to other CNS disorders? What should and should not be used?

Reimbursement and post-approval marketing : how much clinical evidence is enough?


Biomarker Summit 2013 – Inflammatory & Immunological Biomarkers – Mar 20-22, 2013 – San Francisco, CA


Day 2 - Thursday, March 21, 2013 Chairperson: Bruce McManus, Professor, Department of Pathology and Laboratory Medicine, UBC; Director, NCE CECR

Centre of Excellence for Prevention of Organ Failure (PROOF Centre); Co-Director, Institute for Heart + Lung Health



8:15 Biomarker Signatures along the Life Cycle of Failing Hearts and Lungs

Bruce McManus, Professor, Department of Pathology and Laboratory Medicine, UBC; Director, NCE CECR Centre of Excellence for Prevention of Organ Failure (PROOF Centre); Co-Director, Institute for Heart + Lung Health

Caregivers, scientists and policy makers are committed to providing more patient-specific care. The NCE CECR Centre of Excellence for the Prevention of Organ Failure (PROOF Centre) was established by competitive federal funding, and fortified by matching funds from many public and private organizations to implement biomarker solutions that define risk, predict disease occurrence, diagnose, prognose, or refine our understanding of responses to therapies and other care interventions along the life cycle of heart, lung and kidney failure. The Centre’s experience and directions with regards to the biomarker identification and clinical evaluation as “fit for purpose” has been based on work related to immune rejection of transplanted hearts and kidneys, and more recently arising from questions related to “acute COPD attacks”, various forms of heart failure, and progression of kidney failure. This presentation will highlight lessons learned from the PROOF Centre journey: • Seamless science, building on clinically-driven needs, well-phenotyped clinical cohorts, establishment of quality-assured, state-of-the-art platforms for biological interrogation, and rigorous data mining • Translation of technology platforms that can be cost-effective and workable in real-world clinical laboratory settings • Shared commitment of a diversity of clinicians, life and computational scientists, policy makers, health economists, technologists, and patients. • Pursuing health system implementation by evaluating biosignatures for intellectual property value, interfacing with regulatory agencies, and entraining experts in health system implementation processes for new diagnostic tests • Pushing to better understand the biology of injury and repair of hearts, lungs and kidneys, and enabling pharma in drug discovery

Vascular and Metabolic Biomarkers

8:40 Application of MRM and MSIA Proteomics to the HDL Structure and Function

Hussein Yassine, Assistant Professor, Medicine, University of Southern California

In this talk, I will explore the application of Multiple Reaction Monitoring (MRM) and Mass Spectrometric Immunoassay (MSIA) on cardiovascular disease, specifically understanding high density lipoprotein structure (HDL) structure and function. We will discuss the relevance of molecular variants of apolipoprotein A1 together with inflammatory HDL protein composition to the efflux functions of HDL particles in cardiovascular disease.

9:05 Christoph Borchers, Professor, Department of Biochemistry & Microbiology, University of Victoria; Director, University of Victoria - Genome BC Proteomics Centre

9:30 Mass Spectrometric Immunoassay Analysis of Inflammatory Protein Biomarkers

Urban Kiernan, Senior Scientist, Thermo Fisher Scientific Inc

Inflammation has long been identified as a key pathogenic process in numerous different indications. Largely dependent upon molecular biomarkers for assessment, a variety of proteins have become routinely screened in both the study and assessment of various disease states. As the study of these biomarkers progresses, the introduction of improved technology has already demonstrated influence in the field. A key enabling technology development of such inflammatory protein biomarkers is Mass Spectrometry (MS), a high sensitivity detection technique that capitalizes on molecular mass for precise analyte measurement. In recent years, MS detection of proteins has been even further enhanced by coupling with upfront immuno-affinity protein/peptide purification. This approach, called the Mass Spectrometric ImmunoAssay (MSIA), has already been utilized to identify aspects of these inflammatory biomarkers that are missed using traditional protein analytical methods. Presented will be data from the application of this platform and workflow on an array of protein biomarkers. This data will demonstrate clear enhancements from using MS detection using samplings of biomarkers from indications such as Type 2 Diabetes, Cardio Vascular Disease, and Cancer.



Benefits of the Talk: • Explain the advantages of such high data of inflammation biomarker using MS detection. • Demonstrate the need Immuno-affinity enrichment to provide such data. • Understand the platform needs to produce a standardized approach for global adoption. • Describe protein variation as related to both biological and analytical performance. • Describe the enhancement of biomarker utility by using select protein variants of already known and established biomarkers.


10:25 Tissue Biomarkers for Inflammatory Atherosclerosis

Yonghua Zhu, Molecular Biomarkers, Merck

During the past decade, compelling experimental and clinical evidence has demonstrated that atherosclerosis is an inflammatory disease associated with low-density lipoprotein accumulation in the intima of blood vessels, activation of the endothelium, and recruitment of monocytes and T cells. Further understanding of the underlying disease pathophysiology and the inflammatory components of the atherosclerotic plaque could facilitate the discovery of new therapies. The key challenges are attributable not only to the disease itself, but also to the tools we use to evaluate the plaque tissues. This presentation will provide an overview of the state of the art of plaque characterization. Key considerations in developing a successful tissue biomarker strategy for illustrating histological characteristics of atherosclerotic plaque tissue in preclinical animal models will also be discussed.

10:50 Biomarker Development for Brain and Myocardial Injury: A Road to Individualizing Medicine

Jennifer Van Eyk, Professor, Medicine, Johns Hopkins University

The application of discovery and validation proteomic pipeline to identify circulating biomarkers with clinical utility has been questioned. Our group has applied a discovery mass spectrometry based methods to identify plasma proteins from selected patent cohorts combined with proteins secreted from target primary cells that under ischemia focusing on brain and cardiac subclincal injury. Validation in other clinically-well defined cohorts using mass spectrometry or antibody quantification has honed which are the relevant clinical domains for each set of biomarkers. Differentiating between i) cell specific necrotic markers and those which represent ii) ischemic injury or iiii) broad systemic changes that may have functional importance has given insight into potential treatment routes. This may provide a basis for individualize medicine. Bullet points: • proteomic discovery and validation is a valid approach to uncover novel protein biomarkers • circulating brain – specific proteins can be used to detect subclinical brain injury in children during surgery, on ECMO and with a number of diseases. • unique proteins are detected in the blood prior to myocardial injury differ from those released due to cellular necrosis and observed with myocardial infarction. • proteins specifically secreted from myocytes or cardiac fibroblasts with hypoxia are detected in blood of individuals with myocardial ischemia.

11:15 Molecular Biomarkers of Stroke

Frank Sharp, Professor of Neurology, Neuroscience and Genetics, Department of Neurology and the MIND Institute, University of California at Davis

Whole genome expression microarrays can be used to study gene expression in blood, which comes in part from leukocytes, immature platelets, and red blood cells. Since these cells are important in the pathogenesis of stroke, RNA provides an index of these cellular responses to stroke. Our studies in rats have shown specific gene expression changes 24 hours after ischemic stroke, hemorrhage, status epilepticus, hypoxia, hypoglycemia, global ischemia, and following brief focal ischemia that simulated transient ischemic attacks in humans. Human studies show gene expression changes following ischemic stroke and Transient Ischemic Attacks (TIAs). These gene profiles predict a second cohort with >90% sensitivity and specificity. Gene profiles for ischemic stroke caused by large-vessel atherosclerosis and cardioembolism have been described that predict a second cohort with >85% sensitivity and specificity. Atherosclerotic genes were associated with clotting, platelets, and monocytes, and cardioembolic genes were associated with inflammation, infection, and neutrophils. These profiles predicted the cause of stroke in 58% of cryptogenic patients. These studies will provide diagnostic, prognostic, and therapeutic markers, and will advance understanding of stroke in humans. New techniques to measure all coding and noncoding RNAs along with alternatively spliced transcripts will markedly advance molecular studies of human brain disease. Extracellular RNA may also provide novel diagnostic approaches to for diagnostic and prognostic biomarkers.



Outcomes/benefits related to this talk for Biomarkers: • Using inflammatory response of leukocytes in blood as biomarkers for brain injury • Intracellular RNA/proteins versus Extracellular (Plasma) RNA/proteins – rationale for both • Potential other Biomarkers in Blood – miRNA, other non-coding RNAs, alternatively spliced RNAs • Network approach to developing biomarker panels

11:40 Intravenous Administration of Human Bone Marrow-perived Multistem® Cells After Ischemic Stroke: Preclinical Studies and Translation to Clinical Biomarker Assay Development

Jason Hamilton, Senior Scientist, Regenerative Medicine, Athersys

Numerous cellular therapies are currently being evaluated as potential treatments following ischemic insult to the central nervous system. Published studies have reported varying levels of functional improvement in animal models of ischemia after infusion of adult stem/progenitor cells. However, early suggestions that transplanted stem cells might provide true neuronal replacement within injured brain tissue have not been supported by the emerging body of literature investigating cellular therapies, and little is known regarding the mechanisms by which they do provide benefit. This presentation will describe the preclinical mechanism of action studies we have undertaken to examine the effects of MultiStem® treatment after ischemic stroke, and how our preclinical data contributed to clinical biomarker assay development. MultiStem is an allogeneic adult bone marrow-derived cellular product based on the Multipotent Adult Progenitor Cell (MAPCTM) technology, that is manufactured under strict specifications and release criteria and has received allowance from the FDA for testing in humans in the treatment of acute myocardial infarction, prophylaxis of graft-versus-host disease in leukemia patients, inflammatory bowel disease, and ischemic stroke. It is currently the only cellular therapeutic undergoing clinical evaluation in acute ischemic stroke patients in the U.S..


Biomarkers in Allergy and Autoimmune Diseases

1:35 Protein Arrays for Guiding Personalized Therapy

Paul Utz, Professor of Medicine, Stanford University School of Medicine

DNA microarrays have been instrumental at identifying pathways and targets in cancer and many other diseases. Protein arrays are now rising to the fore for studying many disease states, particularly autoimmunity and other inflammatory diseases. Many protein analytes can be measured such as autoantibodies, cytokines, chemokines, and signaling molecules. Perhaps the most impactful use of protein and peptide arrays is in identifying self targets of the immune response, which can then be used to develop antigen-specific therapies. This represents a ‘holy grail’ of immune-mediated diseases - autoimmunity, allergy, transplantation, and tumor immunology. • Protein arrays What platforms are currently available? What key things are missing from the field? What disease(s) represent the best targets? • Personalized medicine Can autoantibody profiling really be predictive? Is antigen-specific therapy feasible?

2:00 Molecular Phenotyping of Asthma: from Concept to Biomarkers

Prescott G Woodruff, Associate Professor of Medicine and Vice Chief for Research, Pulmonary Division, University of California San Francisco

A large body of experimental evidence supports the hypothesis that T-helper 2 (Th2) cytokines orchestrate allergic airway inflammation in asthma. However, human asthma is heterogeneous with respect to clinical features, cellular sources of inflammation, and response to common therapies. Differences in cytokine-driven inflammation may underlie this heterogeneity, and studies in human subjects with asthma have begun to elucidate these molecular differences. This molecular heterogeneity may be assessed by existing biomarkers (induced sputum evaluation or exhaled nitric oxide testing) or with novel biomarkers (serum periostin) developed from translational human studies. Effective testing and application of emerging therapies that target Th2 cytokines will depend on accurate and easily obtained biomarkers of this molecular heterogeneity in asthma. Furthermore, whether other non-Th2 cytokine pathways underlie airway inflammation in specific subsets of patients with asthma is an unresolved question and an important goal of future research using both mouse models and human studies.



Benefits: • An understanding of molecular heterogeneity in common complex diseases • How translational studies can yield biomarkers of specific disease endotypes • How genomics can direct biomarker development efforts • An understanding of periostin, one such blood biomarker Th2 inflammation • How clinical trials of novel therapeutics in asthma may depend critically on biomarkers of disease heterogeneity for their success

2:25 Epigenetic Immune Cell Markers – Robust Immune Monitoring in Clinical Trials without Flow Cytometry

Ulrich Hoffmueller, Chief Business Officer and Founder, Epiontis GmbH

The responsiveness of the immune system is a prominent medical parameter with high relevance in oncology, autoimmunity and infectious diseases. This responsiveness often described by cell counts and ratios of different leukocyte subpopulations. Current standard methods – flow cytometry in peripheral blood, immunohistochemistry (IHC) in solid tissue - have a limited ability for exact cell quantification owing to arbitrary/subjective gating protocols for FACS and lacking precision for IHC. In addition, stability of blood samples is a big issue especially in samples from clinical trials. The discovery of cell type specific epigenetic markers allows precise and robust quantitation of immune cells in all human samples. The tests are based on quantitative PCR targeting genomic DNA. Therefore, readout is stable and samples can be frozen and easily shipped. This allows monitoring of patients in multicenter studies, retrospective studies, comparison of results between different studies, and routine monitoring. Application of epigenetic assays for Th17, Treg, overall T-cells, Granulocytes; Monocytes, NK, naïve CD8, CD4 and B cells will be presented in cancer and immune disease patients. The results reveal the same trends as measurements with alternative methods, while showing higher precision. Furthermore, the tests can be applied on both blood and tissue allowing measurements of circulating and tissue-infiltrating immune cells. In addition to technical benefits, higher specificity (for Tregs) or detection without stimulation (Th17) is achieved using epigenetic assays.

Compound Profiling in BioMAP® Systems Reveals Patterns of BioMarker Regulation that Enable Early Evaluation of Efficacy, Selectivity and Safety

2:50 Andrew Melton, Scientist and Project Leader, BioSeek, a division of DiscoveRx

Traditional target-based drug discovery often relies on a predefined, sometimes poorly validated, target biology that is typically assessed with simple biochemical or cell line-based assays. In contrast, profiling compounds in primary human cell-based BioMAP® systems, which are designed to recapitulate complex signals and phenotypic responses of diseased tissues, simultaneously addresses target selectivity, efficacy and safety in an unbiased manner. Here we present the analysis of BioMAP® profiles for a Jak kinase inhibitor (tofacitinib), a BTK inhibitor (ibrutinib) and inhibitors of the p38 MAPK pathway. Testing these compounds in a panel of 12 BioMAP® systems generated hypotheses relating to dose-dependent selectivity, efficacy and safety of these drugs in patients. We observed a correlation between dose-dependent selectivity, efficacy and adverse effects that include gastrointestinal perforations (Jak) and skin rash (p38 and MEK). At higher concentrations ibrutinib (BTK) was broadly active on endothelial, epithelial, smooth muscle cells and fibroblasts, in contrast to activities observed with another BTK inhibitor, GDC-0834. Earlier detection and better understanding of these effects can help guide future clinical development. Our results support the use of a systems biology approach for phenotypic screening compounds to help prioritize drug candidates prior to testing in


3:45 Gene Expression Profiling Coupled to Reverse Causal Reasoning Identify Response Signatures Associated with Differential Responses to Infliximab Treatment in Ulcerative Colitis

Frederic Baribaud, Associate Scientific Director, Immunology Biomarkers, Janssen Research and Development

Infliximab has been shown to induce clinical response and remission in ulcerative colitis (UC). To characterize the biological response of patients to infliximab in responders and nonresponders and the impact on the alterations in intestinal permeability in UC, we analyzed the mRNA expression patterns of mucosal colonic biopsies taken from UC patients enrolled in the Active Ulcerative Colitis Trial 1 (ACT1) study. Biopsies were obtained from 48 UC patients before treatment with 5 or 10 mg/kg infliximab, and at 8 and 30 weeks after treatment ( n = 113 biopsies). Global gene expression profiling was performed using Affimetrix GeneChip Human Genome U133 Plus 2.0 arrays. Computational reverse causal reasoning was applied to build causal network models of UC and response and nonresponse of UC to treatment.



Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Unlike responders, non-responders do not effectively modulate TH1, TH2, and TH17 pathways. Reverse causal reasoning provided a mechanistic disease model of the biology of gene expression observed in UC. The biology of nonresponders to infliximab, including evidence for increased intestinal permeability compared with normal and responder samples was highlighted. Analysis of mRNA expression in mucosal biopsies using causal network modeling following infliximab treatment provided insight into the response to therapy and molecular mechanisms of non-response.

Development of Immunotherapy for Cancer

4:10 The Two Sides of Cancer Biomarkers: Cancer Indicators but also Microenvironment Modifiers

Nathalie Scholler, Assistant Professor, University of Pennsylvania

The ovarian cancer fatality-to-case ratio remains exceedingly high. More than 60% of the patients experience disease recurrence with discouraging response rates of 20%. While current research for early detection of ovarian cancer largely focuses on biomarker discovery, biomarkers already approved by the FDA such as CA125, as well as other markers still under investigation (mesothelin) offer hope for women at risk for disease development especially those with predisposing genetic mutations. As part of this effort, we have generated site-specific biotinylated recombinant antibodies secreted by yeast (biobodies) to cost- and time-effectively generate antibodies for developing screening tools for large populations of women, as well as for targeting T cells against tumor antigens. However, discrepancies between antibody affinity in vitro and clinical responses currently prompt more questions than answers. The presentation will provide a comprehensive review of the structures of CA125 and mesothelin, and of their interactions with each other as well as with the tumor microenvironment. • Presentation of biobodies and use in immune assays; • Novel use of biobodies in combination with engineered T cells for cancer therapy; • Overview of the role of mesothelin GPI anchor as a modifier of tumor-associated macrophages • Analysis of the functional consequences of CA125 mucin overexpression by the tumor.

4:35 The Mechanism of Action of a Whole Yeast Based Immunotherapy Predicts Both the Efficacy Signal and the Associative Biomarkers Observed in the Clinic Trials

Donald Bellgrau, Professor of Immunology, Integrated Department of Immunology, University of Colorado School of Medicine and Founding Scientist GlobeImmune Inc.

A major goal of immunotherapy is to generate cellular immunity, in particular antigen specific CD8 “killer” T cells. A difficult barrier to be overcome is pathogen or tumor induced suppression. In this regard, we have discovered the potential of recombinant yeast Saccharomyces cerevisiae that are avidly taken up intact by professional APCs, such as neutrophils, macrophages and dendritic cells. Multiple antigens can be engineered for expression within a single yeast. The organism S. cerevisiae has a clean safety profile when administered as a subcutaneous suspension to humans with cancer or infectious disease (see www.GlobeImmune.com). While the CD8 T cells may provide much of the efficacy signal the CD4 T cells induced by the yeast are critical in shaping a durable immune response. The talk will focus on the expected mechanism of action of the yeast as it relates to the clinical trial efficacy signals.

The talk will provide the following benefits. • An overview of the essential problems confronting immunotherapy • A mechanism of action that predicts whom might respond best to the immunotherapy and why • A rationale for identifying the biomarkers associated with the efficacy signal • An explanation for why some subjects should respond less well and what treatments might improve their responsiveness.

5:00 Biomarkers for Immuno-oncology Therapies: Translating Tumor-host Networks

Jason Simon, Director, Immuno-Oncology Biomarkers, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Biomarkers are now routinely used in the clinical study of novel therapies to optimize the development of these agents and targeted oncology drugs are increasingly being co-developed with a biomarker/diagnostic to select the most appropriate patient population. Targeting the immune system for cancer therapies presents novel challenges in the application of biomarkers due to the complex interactions between the tumor and host. There is a large repertoire of



biomarkers and technologies that can be used to monitor either the immune system or the tumor. Analyses of such biomarkers in clinical trials of novel immuno-oncology therapies, including ipilimumab have produced a wealth of data regarding pharmacodynamic effects both in the periphery and in the tumor. These include changes in both number and function of lymphocytes as well as the expression of regulatory factors, including cytokines, chemokines and immune-cell receptors, that reveal mechanisms of action. The search for patient stratification biomarkers has begun to demonstrate a range of baseline and post-treatment immune status factors that are prognostic, including the presence and activation of tumor infiltrating lymphocytes. Some of these may also be predictive of efficacy to immunotherapy, but further study will be necessary to validate those hypotheses. Critical to these efforts is the integration of both tumor and immune biomarker data to characterize the interactions between the host and tumor that define optimal points of intervention.




http://www.gtcbio.com/index.php?option=com_submitanabstract&cn=2nd%20Inflammatory%20&cid=98

Biomarker Summit 2013 – General Session – Mar. 20-22, 2013 – San Francisco, CA


Day 3 - Friday, March 22, 2013 Chairperson: Avi Kulkarni, Vice President and Partner, Booz & Company

7:30 Continental Breakfast


Regulatory and Reimbursement Updates

8:40 Combination of Regulatory and Reimbursement Strategies for Diagnostics

Felix Frueh, Executive Partner, Opus Three LLC

Both regulatory and reimbursement are seen as hurdles in getting a diagnostic successfully to the market. To the most part, the diagnostic industry has not yet convincingly adapted to address those needs: in particular the demonstration of clinical utility, with a focus on outcomes derived in setting(s) resembling the environment in which payers are actually paying into has been only partially explored. New approaches, such as the engagement of pharmacy benefit management companies, integrated health plans, or larger hospital settings are providing a tremendous opportunity to create data that is useful for regulatory submissions as well as the generation for clinical evidence that helps payers to make coverage decisions. However, such strategies require a careful evaluation of the engagement and strategic approach to ensure that timeline, cost, and data are in line with expectations. What are some of the recent developments and trends in this space and how is industry adapting? Where do we see the engagement head in the future and can it become a new paradigm for diagnostic development?

9:05 Understanding Rapid Evolution of Molecular Diagnostics Reimbursement Policy

Bruce Quinn, Senior Health Policy Specialist, Foley Hoag LLP

The speed of advances in genomic technology and the application to combination diagnostics and clinical next-generation sequence is unprecedented. Until recently, the coding and reimbursement system for US healthcare services had been unable to keep up. In 2013, abrupt changes are occurring in the policy environment, including coding standards. Some in the genomics industry view the changes as a “perfect storm” while others have forecast new opportunities. We will discuss how the third party payer and reimbursement system has profound impacts on both the de novo development and the market adoption of molecular tests. We will discuss early lessons learning in the first quarter of 2013 and implications for the industry. • How are combination diagnostics coverage and reimbursement dramatically different from drugs? • How were diagnostics reimbursed up until December, 2012? • How is the 2013 reimbursement system different? • What distinctive Medicare policies must be considered in the commercialization of novel diagnostics? • How do standards for health technology assessments adversely impact the market adoption of novel molecular diagnostics? • How soon will next generation sequencing significantly impact this clinical space?

Panel Discussion: Regulatory Landscape of Biomarkers & Diagnostic Development

9:30 Panelist: Andrew C. Fish, Executive Director, AdvaMedDx

Panelist: Christine Gathers, Senior Director of Regulatory Affairs – Diagnostics, Eli Lilly

Panelist: Felix Frueh, Executive Partner, Opus Three LLC

Panelist: Kathy Hibbs, Senior Vice President & General Counsel, Genomic Health


How is the balance of power between the FDA and CLIA going to shake out?

How harmonized are European regulations, especially with the publication of the 2012 “Regulation of the European Parliament and the Council on In Vitro Diagnostic Medical Devices” with US regulations governing diagnostics?

What additional considerations need to be included in a truly global diagnostics regulatory strategy?

What are the major regulatory risks faced by Dx-Rx companies and what are some of the risk mitigation strategies?

Looking out over a 5 and 10 year horizon, what do you predict will be the role of regulations in biomarker development and go-to-market strategies?




New Technologies & Novel Approaches to Biomarker Development

10:45 Of Biomarkers & Bits: Convergence of Diagnostics and Healthcare IT

Achim Plum, Principal Consultant, Corporate Technology, Siemens AG

With the advent of novel cost-effective and robust technologies the assessment of predispositions, the diagnosis of diseases and the decision on adequate preventive and therapeutic strategies may soon rely on the analysis and interpretation of comprehensive molecular signatures on DNA, RNA, protein, and metabolite level. The transition from well defined individual biomarkers assessed by singleplex or multiplex diagnostic assays to clinical decision support systems based on algorithms and mathematical models integrating multiscale data from molecular profiling and advanced imaging technologies with traditional clinical parameters will lead to a convergence of diagnostics and healthcare IT fundamentally changing the clinical routine of the future. The talk will elaborate on this vision and its implications on how the development, regulatory approval, and commercialization of diagnostic products is pursued. The interested audience will learn about • an integrated healthcare company’s perspective on future diagnostics and HIT • the importance of ICT in next generation diagnostics • the role of mathematical algorithms and modeling future medical decision making • opportunities and challenges through a shifting value proposition from instruments and reagents to content and knowledge

11:10 The Complete Picture: Tumor Heterogeneity Envisaged

Fiona Ginty, Molecular Pathology Project Leader, GE Global Research

Protein analysis in formalin-fixed, paraffin-embedded tissues is typically limited to 1-2 markers per tissue slide using chromogenic stains, or up to four markers using immunofluorescence. The increasing demands on tissue for predictive and prognostic biomarker testing presents significant challenges for pathologists and oncologists to ensure that the most important markers are selected for patient care. Coupled with this, tumor and cellular heterogeneity may confound genomic results. Pharma and clinical researchers are faced with the same challenges in their efforts to define mechanism of action, tumor phenotype etc. To address these challenges, GE has developed a multiplexed immunofluorescence technology that allows measurement of up to 60 markers at single cell level in a 5 um FFPE tissue section. DNA FISH analysis may also be conducted on the same sample, following multiplexed protein analysis. Algorithms for visualization and quantitation allow analysis of heterogeneous distribution in context of tumor histology and microenvironment. In addition to sparing precious sample, this technology allows visualization of tumor biology in ways not previously possible. Benefits: • Learn about a new imaging technology that combines multiplexed protein analysis with FISH in a single section of FFPE tissue • Gain new insights into tumor and cellular heterogeneity

11:35 Joint Presentation

Ligand-directed Therapy and Molecular Imaging Based on in Vivo Phage Display Technology

Renata Pasqualini, Buchanan & Seeger Professor of Medicine and Experimental Diagnostic Imaging, David H. Koch Center, The University of Texas MD Anderson Cancer Center

Wadih Arap, Stringer Professor of Medicine and Experimental Diagnostic Imaging, David H. Koch Center, The University of Texas MD Anderson Cancer Center

We have developed in vivo phage display, a functional peptide screening established in animal models and later in patients. Isolation of homing peptides enables subsequent identification of tissue-specific receptors. Systematic implementation of this strategy will lead to the construction of a comprehensive map of vascular markers in each organ, tissue, or disease, and may result in a new pharmacology.

12:00 Lunch Provided by GTC



1:00 Fine Needle Aspirate (FNA) Normalization Assay: Liver-specific mRNA Biomarkers for Determining Liver Mass and Drug PK

Andrea L. Webber, Director, Assay Development, Merck

The gold standard for liver biopsy is Core Needle Biopsy (CNB), but safety concerns restrict its use. Tools for predicting liver pharmacokinetics (PK) are thus limited. Fine Needle Aspiration (FNA) is a less invasive procedure and affords the opportunity for serial sampling of the liver. The objective of our study was to qualify FNA as an alternative platform for assessing hepatic PK. As FNA samples contain variable amounts of liver and blood, biomarker methodologies were developed to quantify liver mass versus blood contamination. Assay conditions were optimized to afford compatibility with both [mass spectrometry-based] drug quantification and liver mass determination. Leveraging liver- and blood-enriched gene expression biomarkers, we showed linearity of liver-enriched gene expression with regard to liver input, thus enabling FNA liver mass determination using TaqMan Ct values. FNA sample collection and processing were qualified in preclinical proof-of-concept studies. We also evaluated stability, specificity, reproducibility, and accuracy of the liver-enriched gene signature. Next, we applied the normalization assay to samples from preclinical studies in which we measured the PK of a Merck compound. Future efforts will focus on assessing FNA as an alternative platform to CNB for quantifying hepatic PK in the clinic. Fine needle aspiration coupled with qPCR will enable non-invasive serial sampling of multiple organ systems in preclinical and clinical studies The platform will: • enable PK modeling • inform compound selection • inform on tissue biomarkers related to disease processes or therapeutic interventions

1:25 Development of New Cancer Biomarkers and Mechanisms Using Global Metabolomics

Michael Milburn, Chief Scientific Officer, Metabolon, Inc.

After a hiatus of nearly 30 years, the interest in research towards understanding cancer cell growth and function from a metabolic standpoint has returned. Much of the research for the past 30 years has focused entirely on molecular biology andwhile some stunning discoveries have been made with regard to oncogenes, other aspects of cancer cells have largely gone unnoticed. This renewed interest in cancer cell metabolism coincides with the timely development of global metabolomics as a key technology that provides an unrivaled tool for understanding metabolism. Through this unique ability to monitor the concentration changes in these biochemicals, we are better able to identify and understand metabolic differences in cancer cells relative to normal cells. The focus of this talk will be to better educate the listener about the importance of understanding cancer metabolism and how global metabolomics is an ideal technology for gaining these new insights. A number of case studies across multiple cancer types will be presented.

Companion Diagnostics Development

1:50 Maximizing Patient Access to CDx Testing at Time of Drug Launch

Jay Foust, Senior International Business Leader, Companion Diagnostics, Ventana

Panel Discussion: The Future of Personalized Medicine -- Companion Diagnostics Development & Partnering Strategies

2:15 Panelist: Paul Billings, Chief Medical Officer, LIFE Technologies

Panelist: Trevor Page, Director, Corporate Business Development, Dako North America, Inc.

Panelist: Nicholas Dracopoli, Vice President, Head of Oncology Biomarkers, Janssen Research & Development

Panelist: Jay Foust, Senior International Business Leader, Companion Diagnostics, Ventana


Can you point to any company in the space that has executed a Fully Integrated Personalized Medicine Co (FIPMCO) strategy? Is this historical happenstance or is it a valid strategy for companies that are getting in Personalized Medicine today?

Would you agree with the statement that for a pharma company to succeed in personalize medicine today, having a partnership strategy for the development and/or commercialization of diagnostics is critical?



Why do the same few/selected companies make it to the top of every Rx company’s wish list of preferred Dx partners? What are the critical capabilities that these companies possess that make them valuable partners (e.g., global coverage; FDA approved platforms with DMFs); assay development and validation experience)

In the world of biomarkers which sorts of companies make better partners: platform companies or clinical labs?

What are the relative advantages and disadvantages of these companies as biomarker development partners?

What are key partnership considerations in biomarker assay development?

What are key partnership considerations in biomarker assay commercialization?

What are major partnership risks in Dx-Dx and Dx-Rx partnerships and what are some of the risk mitigation strategies that you would recommend?

What are the types of deals and deal terms that you are seeing?

If you put on your dreamer’s hat and look into the future which capabilities will continue to require partnering and why? How will the web of partnerships affect the future of personalized medicine?

3:00 Conference Concludes

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