PHARMACOGENOMIC BIOMARKERS

8:30-8:35 Chairperson’s Opening Remarks

8:35-9:00 Practical Application of Pharmacogenetics: From Marker Discovery to Clinical Utility
Eric Lai, Ph.D., Vice President, Pharmacogenetics Experimental Project Coordination and Analysis, GlaxoSmithKline
The completion of the Human Genome Project, the tremendous success of The SNP Consortium and the International HapMap Project have provided critical knowledge for understanding human diversity and have promised to greatly improve Healthcare. The application of genetics and genomics in the Pharmaceutical industry over the past decade has been focused on drug target discovery. In reality, the bottlenecks in the discovery and approval of new drugs are in the attrition rate in drug development (drugs with no positive efficacy) and adverse drug re-actions. This presentation will review the current status and barriers on the application of Pharmacogenetics to drug development and post-market management. The examples of Abacavir will be used to demonstrate the progress from biomarker discovery, replication/confirmation, to clinical utility and clinical practices.

9:00-9:25 Implementation of Pharmacogenomic Biomarkers into Clinical Practice 
Alan H.B. Wu, Ph.D., Professor, Department of Laboratory Medicine, Director, Clinical Chemistry, Toxicology and Pharmacogenomics Laboratories, University of California, San Francisco
Many scientific discoveries made through basic research studies have the potential to impact medical practices but never reach the approval stage. The implementation of pharmacogenomic biomarkers into clinical practice requires the confluence of many factors. These include availability of FDA-cleared testing platforms and reagents, a clinical need for testing, an adequate test reimbursement, and a mechanism to report and interpret results. It is important to show that pharmacogenomic testing leads to “actionable” medical decisions that can either improve drug efficacy or avoid adverse events, while demonstrating cost effectiveness (e.g., reduced hospital length-of-stay, unnecessary outpatient visits or procedures, etc). A successful pharmacogenomic program is a multidisciplinary effort of basic pharmaceutical sciences, clinical pharmacy, medical genetics, and laboratory medicine.

9:25-9:50 Biomarkers that Predict Risk for Cardiovascular Disease and Response to Statin Therapy
Thomas J. White, Ph.D., Chief Scientific Officer, Celera 
A variant of the gene encoding kinesin-like protein 6 (KIF6) is associated with up to a 55% increased risk of pri-mary and recurrent coronary heart disease (CHD) events. The increased risk of clinical events observed in KIF6 carriers was independent of other well-known CHD risk factors, including smoking, hypertension, cholesterol level, age and sex, supporting the conclusion that a KIF6 gene variant is a new, independent predictor of risk for CHD. This increased genetic risk was virtually eliminated by statin therapy, and high-dose atorvastatin therapy reduced risk in carriers of the KIF6 risk variant more effectively than did moderate-dose pravastatin therapy in acute coronary syndrome patients. Only 10 carriers of the KIF6 719Arg variant needed to be treated with intensive statin therapy to prevent one CHD event; in contrast, the number needed to treat for noncarriers was 125. 

9:50-10:50 Networking Coffee Break with Poster and Exhibit Viewing 

PHARMACODYNAMIC BIOMARKERS

10:50-11:15 Identification of Tumor Candidate Protein Biomarkers Using Multidimensional HPLC-MS Proteomics Platforms
Uma Prabhakar, Ph.D., Senior Director, Biomarkers, Centocor Inc.
A pilot study was conducted in two parts to evaluate the use of Caprion’s contract proteomics technology plat-form to: i) identify differentially expressed proteins in small groups of breast and ovarian cancer plasma samples compared to normal and, ii) identify candidate biomarkers that can discriminate normal plasma samples from prostate cancer plasma samples. Results of the first part of the pilot study indicated that several peptides were reproducibly and significantly differentially modulated between the Normal, Ovarian and Breast cancer groups and allowed for delineation between these groups. Approximately 181 candidate biomarkers were identified using MS/MS and VMS sequencing strategies, which included several known proteins associated with tissue dam-age/stress, immune/inflammation responses and cancer. The second part of the study with Prostate cancer samples suggested that >3500 peptides were differentially modulated between the cancer and normal samples. These resulted in the identification of approximately 271 proteins, which were then used to generate panels of candidate biomarkers that can segregate prostate cancer patients from normal individuals. The utility of this proteomics platform, study design, biomarker selection process, and results of these analyses will be presented.

11:15-11:40 Value of Pharmacodynamic Biomarker Analysis for the Early Development of Biopharmaceutical Drugs 
Mark Wing, Ph.D. Director, Clinical and Translational Sciences
The early development of large molecular weight biopharmaceutical drugs present some unique challenges com-pared to small chemical drugs. Amongst these the selection of the correct species to undertake the safety assessment is critical since toxicity is most likely to arise from exaggerated pharmacology and there is a possibility of a host immune response to the drug. These challenges can be met with the use of appropriate PD biomarkers to compare drug potency with man, which will in addition provide useful information when considering the starting dose in man. The inclusion of these assays on the toxicology studies and early clinical trials will not only demonstrate drug activity but may provide evidence for a neutralizing immune response to the drug. Real case studies w ill be used to illustrate the value of PD biomarkers for early biopharmaceutical development.

BIOMARKERS FOR MONITORING RESPONSE TO THERAPY

11:40-12:05 Biomarkers in Heart Failure and Osteoporosis 
Michael Samoszuk, M.D., Chief Medical Officer, Roche Diagnostics Corp.
This session will focus on emerging biomarkers that are potentially useful for patient selection and monitoring re-sponse to therapy in patients with heart failure or osteoporosis. The basic clinical features and current manage-ment of these two important diseases will first be presented. This will be followed by a high-level description of the two biomarkers that will be the subject of the remainder of the presentation: NT-pro-BNP and P1NP. Recent clinical and laboratory data describing the potential clinical utility of these two markers will be presented. The session will conclude with a discussion of the challenges that remain to be overcome before these two promising biomarkers can be implemented into routine clinical practice. 

12:05-12:30 Identification of Bcl-2 Family Members as Biomarkers of Response to ABT-263 Treatment 
Stephen Tahir, Ph.D., Research Investigator, Cancer, Abbott Laboratories
ABT-263, a potent, orally bioavailable Bcl-2 family protein inhibitor that we have shown to be effective against small cell lung cancer (SCLC) and leukemia/lymphoma cell lines is currently in multiple Phase 1/2a clinical trails for B-cell lymphoma, CLL and SCLC. The talk will cover how we have identified key Bcl-2 family proteins that influence the cellular response of SCLC and leukemia/lymphoma cell lines to ABT-263 and how we have incorporated the use of Bcl-2 family members as clinical biomarkers, more specifically, their application as patient stratification biomarkers.

LUNCHEON TECHNOLOGY SHOWCASE I: BIOMARKERS IN EARLY DRUG DEVELOPMENT

12:45-1:00 Acute Renal Injury Test™ Panel: Applications from Drug Discovery to Clinical Trials
Martin Shaw, Senior Scientific Officer, Biotrin International
Nephrotoxicity is a common cause of drug failure, a problem worsened by the shortage of appropriate biomarkers. The Biotrin Acute Kidney Injury biomarker panel enables renal effects to be detected earlier and at lower doses of compound. Data will be presented on their use from in-vitro to human studies.

1:00-1:15 An Integrated Biomarkers Collection: Bridging the Gap in Translational Medicine
Miriam Bayes, Ph.D., Head Scientific & Content Development, Thomson Scientific
In translational research and personalized medicine biomarkers are pivotal assets bringing together basic and clinical research. In this new scenario, a biomarkers pipeline database covering a wide range of biomarkers in different disciplines with standardized terminology and classification offers a unique possibility to connect experimental research, drug discovery & development and clinical practice.

1:15-1:30 UNIarray®: Systematic Discovery of Novel Biomarkers: The Multiple Sclerosis Success Story
Jens Beator, Ph.D., Director, Protein Biochips, Protagen AG
Novel indication-specific biomarkers based on antibody profiles can be systematically developed using the proprietary UNIarray® program. The Multiple Sclerosis (MS) case study uncovered multiple new biomarkers indicating new pathways involved in MS. A protein biochip prototype based on these biomarkers shows > 80 % diagnostic sensitivity and specificity.

1:30-1:45 Biomarker Discovery with the BIOBASE Knowledge Library™ and ExPlain™
Philip Stegmaier, Research Scientist, Research & Development, BIOBASE GmbH
Discovery and prioritization of potential biomarkers can be enhanced by inference of regulatory processes that are important for a biological condition, since components of such molecular mechanisms can be expected to be consistent diagnostic targets. Application of the BIOBASE systems biology approach to causal biomarker discovery will be presented.

1:45-2:15 Technology Short Talks

BIOMARKERS IN CLINICAL TRIALS

2:30-2:40 Chairperson’s Opening Remarks

2:40-3:05 Translating Biomarkers for Clinical Trials
J. Suso Platero, Ph.D., Associate Director, Clinical Biomarkers, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Co.
With the increase number of drug compounds arriving in the clinic and the added level of scrutiny by the regulatory agencies, there is an added urgency to select the best patient population in which to carry out clinical trials. A strategy to increase the selection of patients for clinical trials is to look for biomarkers that may select your patients. These biomarkers may give you information regarding the mechanism of action of your compound or they may lead to increase the efficacy of the drug. Several examples will be shown that take biomarkers all the way from discovery to their application in clinical trials.

3:05-3:30 Predictive Biomarker Strategies in Clinical Drug Development
Michael E. Burczynski, Ph.D., Associate Director, Biomarker Laboratory, Clinical Translational Medicine, Wyeth Research
Various categories and types of biomarkers can provide predictive insights into the eventual success or failure of a therapeutic intervention within a given disease indication. Genetic variants in key ADME genes can profoundly influence pharmacokinetic exposure with subsequent implications for both safety and efficacy, while polymorphisms in target genes involved in the drug’s mechanism of action can impact the ability of a compound to exert a beneficial therapeutic effect. Gene expression profiles in target tissues can likewise illuminate activated molecular pathways within the target tissue and predict the likelihood of success for therapeutic strategies employing targeted signal transduction inhibitors. Cytokine patterns in the circulation can be used to identify patients with active forms of inflammatory diseases who are more likely to respond to administered therapies, and disease-related products can be measured in circulating fluids to identify patients with advanced forms of diseases. All of these types of biomarkers can be identified either prior to or during clinical drug development, and the pros and cons associated with each of these approaches will be discussed.

DEVELOPMENT OF MOLECULAR DIAGNOSTICS

10:50-11:15 Progress in Translating Biomarkers for Clinical Use: FDA's Perspective 
Elizabeth Mansfield, Ph.D., Senior Policy Analyst, Office of Diagnostic Device Evaluation and Safety (OIVD), Center for Devices and Radiologic Health, US Food and Drug Administration
The talk will provide a brief history of biomarker review at FDA's Office of Diagnostic Device Evaluation and Safety (OIVD), followed by a description of translation problems identified by stakeholders in the biomarker field, and some proposed solutions, with emphasis on the role of biospecimens, and problems in analytical and clinical validation. 

11:15-11:40 Novel Clinical Diagnostics for Breast Cancer
Yixin Wang, Ph.D., Executive Director, Research & Development, Veridex, LLC., a Johnson & Johnson Company
Cancer patient care requires diagnostic decisions at multiple integration points including screening, disease characterization, effective surgery, drug therapy selection and treatment response monitoring. Because of the highly heterogeneous nature of cancer disease multiple markers performed on various technology platforms may be needed to produce clinically useful assays. Several technologies that have been used in research laboratories be-gan to be adopted in clinical practice for breast cancer. This presentation will review some of the opportunities and challenges facing these assays and three examples from Veridex, Johnson & Johnson that aimed to develop and commercialize such technologies in clinic.

11:40-12:05 Strategies for Regulatory Submissions of Early Detection Biomarkers
Thomas F. Soriano, President and Chief Executive Officer, DOCRO, Inc. 
This presentation will review the issues that are important to a successful regulatory submission for an early detection biomarker. The determination of the likely classification of the IVD product using FDA's risk-based system (i.e., the criteria FDA uses to determine if the submission is a PMA or a 510(k)) and the scope of the resultant trial will be reviewed in detail. This session will provide the listener with a review of past and present successful submissions of early detection markers and will describe the evolution of thought and practice at FDA regarding such submissions, including the hot topics of Diagnostic Multivariate Index Assays (IVDMIA), Laboratory Developed Tests (LDT, aka, “home brews”), and molecular diagnostics.

12:05-12:30 Incorporating Patient Preferences into Product Design 
Patrick Terry, Co-founder, Director of Industry Relations, Genomic Health, Inc.
This talk will share some important lessons learned from a successful commercial venture about the difficulties associated with quantification and incorporation of the elusive elements of “patient preference” in product profiles and development protocols for commercially viable biomarkers.

LUNCHEON TECHNOLOGY SHOWCASE II: BIOMARKERS IN CLINICAL DEVELOPMENT AND DIAGNOSTICS

12:45-1:00 Comparative Evaluation of Gyrolab®, UPLC-MS/MS and Immunoassay for Biomarker Analysis
Clare Kingsley, Ph.D., Client Manager, Biomarkers, HFL Ltd.

1:00-1:15 Bringing Biomarkers to Life: Clinical Trials to Diagnostic Commercialization
Rajesh Krishnan, Ph.D., Director, Business Development and Strategic Alliances, Pathway Diagnostics
Biomarkers identified early during clinical trials can have profound consequences for successful late stage clinical trials and ultimately therapeutic impact of the drug. Pathway Diagnostics offers assay development, validation and testing services for biomarkers during the clinical trial process. Specific examples including novel biomarkers will be described.

1:15-1:30 Monitoring Protein Expression and Protein Phosphorylation in the Tumor Microenvironment for Preclinical Studies and Clinical Trials
Steven J. Potts, Ph.D., MBA, Scientific Director, Biotechnology and Pharmaceutical, Aperio Technologies
The ability to track protein expression and activity changes in the local tumor environment is important for effective preclinical studies and clinical trials. Using whole slide scanning and semiquantitative immunohistochemistry algorithms, the expression levels of nuclear, cytoplasm, and membrane protein markers can be measured. This talk will review the use of this technology in animal models and clinical trials, and discuss standardization approaches.

1:30-1:45 Reverse-Phase Protein Microarrays: Identification and Quantitation of Signaling Pathway Biomarkers in Cell Lines, Tumors and Patient Populations for Drug Discovery, Clinical Trials and Companion Diagnostics
Debra A. Hope, Ph.D., MBA, Director, Business Development, Theranostics Health
Theranostics Health (THX) reverse-phase protein microarray platform inverts the usual protein array format by spotting an entire proteome, as a lysate, onto nitrocellulose-coated slides. Lysates can be prepared from cell lines or from cells microdissected from patient biopsy samples. Each array of proteomes is incubated with one detection protein, e.g. an antibody, and a single analyte endpoint is measured and directly compared across multiple samples. As many as 100 drug targets or signaling proteins can be quantitatively measured from as few as 5,000 cells microdissected from a pa-tient biopsy. With detection levels approaching attogram amounts of an analyte protein, THX arrays are sensitive enough for low abundance, phosphorylated protein isoforms to be reliably measured from a spotted lysate representing less than 10 cell equivalents, with variances of less than 10%. The platform has been analytically validated on fine-needle aspirate and tissue biopsy material, making it possible to measure changes in signaling phenotypes in minute clinical samples for use in tissue biomarker discovery and development as well as theranostic applications. 

1:45-2:00 A 10-Plex Angiogenesis Biomarker Multiplex Immunoassay for the Avantra™ and Its Potential in Adaptive Clinical Trials
Peter Maimonis, Ph.D., Vice President, Biological Research, Decision Biomarkers Inc.
Decision Biomarkers has developed a 10-plex angiogenesis biomarker multiplex immunoassay for its Avantra™ platform. The ability of the platform to generate real-time data at the trial site enables immediate decision-making necessary in adaptive clinical trials. This angiogenesis panel will be a useful adjunct in drug trials evaluating angio-genesis inhibitors.

2:00-2:15 Title to Be Announced
Aushon Biosystems, Inc.

PREDICTIVE VALUE OF EXPRESSION SIGNATURES AS BIOMARKERS

2:30-2:40 Chairperson’s Opening Remarks

2:40-3:05 Biomarker Identification for Tumor Stratification and Prognosis by Multi-Scale Systems Biology Models
Andreas Schuppert, Ph.D., Director, Applied Sciences, Bayer Technology Services GmbH
The identification of reliable, predictive biomarkers for the individual progression of cancer diseases and the re-sponse on drug treatment is crucial in order to improve cancer therapy and drug development. However, despite huge investments in biomarker development, the accuracy required for the expected breakthrough could not be achieved. Whereas lots of effort is focussed on improvement of data quality and protocols, potential impacts on the performance of the biomarkers due to biological factors, like stress response, tumor development or ageing, are less understood. Because a strong interference of biological variance with the prognosis-related signals can be expected, we aimed to develop an approach allowing the deconvolution of the respective patterns in the data. We show that a multi-scale modeling approach allows such a deconvolution of gene expression data. The decomposition of the data into the genome-wide expression shifts due to mere biological variability and the prognosis – related signals allows a tumor stratification resulting in a significant increase of the performance of the biomarkers. 

4:55-5:20 Need for Biomarkers: Too Much of a Burden for Clinical Trial Participation?
Geert Kolvenbag, M.D., Ph.D., Executive Director, Development, Emerging 
Oncology and Infection Brands, AstraZeneca 
Currently only 5% of cancer patients are participating in clinical trials. There are clear reasons why or why not patients participate in clinical trials. In general, the public perception on clinical research is not positive, despite the good experiences reported by clinical trial participants. Given that clinical trial participation is already a challenge, the addition of tissue collection and agreement to genetic and other testing may increase the hurdle for participation in clinical trials. Therefore, there is a general need for education and awareness of clinical research. 

5:20-5:45 Biomarkers for Clinical Development in Alzheimer Disease and Multiple Sclerosis 
Christine Betard, Ph.D., Senior Director, Global Strategic Drug Development Unit, Quntiles
Multiple Sclerosis (MS) and Alzheimer disease (AD) are two common devastating neurological diseases with pathophysiological processes leading to inflammation and neurodegeneration beginning long before early clinical symptoms emerge and thus can be detected. Existing therapeutic interventions are only moderately effective in improving clinical symptoms, and research efforts are focusing on the development of disease-modifying therapies to impede disease progression. Biomarkers are critical to identify the presymptomatic phase of the disease and to allow the development of new therapies, since limitations in animal models and inadequate understanding of the pathophysiology still persist. A panel of clinical biomarkers is been used in early drug development to determine whether the drug is reaching/affecting the appropriate molecular target in humans, allowing comparisons with preclinical data and providing measurable endpoints. Non invasive neuroimaging techniques, particularly MRI and PET, are applied to clinical trials to assess therapeutic mechanisms in MS and AD, in addition to molecular biomarkers emerging from genomics and proteomics research. Molecular and neuroimaging biomarkers will be discussed in parallel, focusing on inflammatory and neurodegenerative features, with their applications in clinical development.

5:45 Close of Day

4:30-4:55 Classification Biomarkers in Psychiatry by “Omic” Approaches 
Enrico Domenici, Ph.D., Director, Molecular Psychiatry, GSK Medicines Research Centre
The search of peripheral markers reflecting psychiatric disease state and trait has been under constant scrutiny for few decades and numerous candidates have been tested based on several disease pathogenetic hypotheses. The results however, have often been of poor outcome or not replicable. Recent developments in proteomic and genomic approaches are expanding the number of testable hypothesis by some orders of magnitude and allowing for the identification of patterns or signatures rather than single markers thus creating the premises for a paradigm shift in the search for biomarkers in psychiatry. A series of evidences documenting the potential offered by large-scale transcription analyses and proteomic profiling in a number of psychiatric disorders will be reported. Specific applications of microarrays to psychiatry disorders to generate blood-derived disease signatures will be discussed.

4:55-5:20 Pathways and Biomarkers: Moving Correlation to Cause
Michael N. Liebman, Ph.D., Senior Institute Fellow, Windber Research Institute
While many studies identify biomarkers for important physiological processes, there is a significant difference between biomarkers, diagnostics and causal diagnostics. To convert a biomarker into a molecular diagnostic requires both an understanding of the complex inter-molecular networks involved even more than simple path-ways, and the functional response that variations within these networks express in both normal and abnormal conditions. Frequently this requires qualitative reasoning about pathway function because only limited experimental data exists. This presentation will describe the use of such approached in clinically important systems in two systems: coagulation disorders and response to breast cancer treatment.

5:20-5:45 Informative Set of Genes: The Missing Link Between Diagnostic Biomarkers and Biological Processes Underlying Differentiation
Darius Dziuda, Ph.D., Assistant Professor, Mathematical Sciences, Central Connecticut State University
Biology and biomedical research are now information sciences. Discovering biomarkers for medical diagnosis, prognosis and therapy selection is based on large and huge data sets. Microarray and mass spectrometry technologies provide training data sets with tens or hundreds of thousands of variables but significantly fewer biological samples. Traditional analytical and data mining approaches, the same that work well for business data, should not be directly applied. Publications based on such approaches provide anecdotal rather than scientific results; some may just be fitting the noise. The talk will focus on combining the multivariate approach to biomarker discovery with a novel method of linking multivariate diagnostic biomarkers with the underlying biological processes. The method allows for identification of the Informative Set of Genes, which is defined as the set of variables (such as probe sets, genes, or proteins) containing all information significant for class differentiation. Analysis of the Informative Set of Genes allows for elucidation of biological processes associated with class differences and may result in new biomedical knowledge.

5:45 Close of Day