Biomarkers in Early Drug Development

Sponsored by  

10:30-10:45 Title to be Announced

Ilya A. Mazo, Ph.D., President, Ariadne, Inc.

Sponsored by  

10:45-11:00 Identification of Master-Regulators of Adverse Toxic Reactions of the Antibiotic Drug Trovafloxacin (TVX) through Promoter Analysis and Network Modeling

Alexander Kel, Ph.D., Senior Vice President Research & Development, BIOBASE GmBH

In this talk, we will present a case study of applying the BIOBASE Knowledge Library™ and the ExPlain™ Analysis Platform for discovery of drug toxicity biomarkers. We analyzed data on the antibiotic drug trovafloxacin (TVX), which was recently removed from the market because of severe idiosyncratic hepatotoxic side effects. The aim of this study was to find molecular mechanisms of adverse drug reactions and identification of potential causal biomarkers for patient stratification. Expression profiles of primary human hepatocytes treated with trovafloxacin were analysed through ExPlain™ performing promoter analysis of differentially expressed genes followed by topological modeling of signal transduction networks. We predicted the following transcription factors, which are involved in coordinated deregulation of genes upon treatment with TVX: HNF1α, HNF4, AhR/ARNT, ELK1 and others. Topological modeling of respective transcription regulatory and signal transduction networks allowed us to identify master-regulators of the toxic reactions in liver cells and propose perspective causal biomarkers of liver toxicity of trovafloxacin.

Sponsored by  

11:00-11:30 Prioritization of Biomarker Candidates Based on Pathway and Phenotype Associations

Megan Laurance, Ph.D., Senior Scientist, Ingenuity Systems   

As technologies that detect transcripts, microRNA levels, and epigenetic events mature to become common components of biomarker discovery programs, the challenge has shifted to translating large scale datasets into biomarkers that can be used to diagnose disease and predict patient response to treatment.  Prioritization of biomarker candidates requires – at a very practical level – an understanding of candidates’ expression patterns in bodily fluids and target tissues and – at the mechanistic level – identification of molecular paths between candidate markers and physiological responses, cellular phenotypes, or disease processes of interest.  In this session we will present a case study in which the biomarker discovery tool IPA was used to prioritize biomarker candidates and elucidate the molecular mechanisms connecting those markers to disease phenotypes and pathways.

11:30-12:00 Sponsored Presentations

(Opportunities Available. Contact Ilana Schwartz at 781-972-5457  or ischwartz@healthtech.com.)

Sponsored by  

10:30-10:45Sponsored Presentation

Speaker to be Announced

Sponsored by  

10:45-11:00 Current Information Trends in Biomarker Research

Colin Williams, Product Manager, Biology & Bioinformatics,   Thomson Reuters

Biomarkers are becoming a key tool in enhancing the productivity of pharmaceutical research & development, both in discovery and the clinic and an essential element for regulatory purposes. It will become increasingly difficult to manage the rapidly increasing information about a biomarker. A new fully indexed biomarker database, BIOMARKERcenter, will help to address this problem. Using BIOMARKERcenter we will show how biomarkers mimic the lifecycle of a drug, from discovery to approval, and show the diversity of roles and techniques currently being employed in biomarker research.

11:00-11:30                           
In Situ Multiparametric Analysis of Biomarkers In Heterogeneous FFPE Tissue Using the Definiens XD™ Image Analysis Platform  

Peter Duncan, Director, Marketing and Business Development Life Sciences, Definiens Inc.
Although we are now beginning to benefit from the genetic, genomic, and proteomic discoveries over the last decade, the implementation of biomarkers for patient stratification to improve diagnostics, prognostics, and companion assays for oncology targeted therapies is still an extremely challenging endeavor with limited success. This is due to many factors including the lack of implementation of true systems-based approaches to achieve in situ multiplexed, multiparametric, phenotypic profiling of protein biomarkers. This talk will illustrate how this challenge is currently being met utilizing the Definiens XD image analysis platform, citing specific examples including: The automation of the Dako Herceptest, and the development of a multivariate model for overall survival of non-small cell lung cancer patients treated with Iressa®. Applications of the Definiens XD image analysis platform to xenograft detection and 3D in vivo imaging will also be presented.

(Opportunities Available. Contact Ilana Schwartz at 781-972-5457  or ischwartz@healthtech.com.)

12:00-1:00 Lunch on your own

Implementing Personalized Medicine

Robert E. Epstein, M.D., M.S., Senior Vice President, Medical & Analytical Affairs; Chief Medical Officer, Medco Health Solutions, Inc.

This session will cover experience to date of a pharmacy benefit manager ‘rolling out’ programs that promulgate the use of pharmacogenomic tests.  From data gleaned from actual experience with programs that address both Tamoxifen and Warfarin pharmacogenomics, payer concerns, results of actual physician and member adoption, ability of test values to change treatment decisions, and other practical issues will be shared.  Opportunities for improvement to the healthcare system to facilitate greater adoption will be suggested.

Brian B. Spear, Ph.D., Director, Scientific Affairs, Global Pharmaceutical Research and Development, Abbott Labs

Targeting new medicines to specific patients is an attractive concept commercially as well as medically.  However, not all new drugs will be suited to this approach.  Whether a personalized medicine strategy is appropriate for any specific drug will depend on, among other things, the nature of the disease, variability in patient response, the competitive environment, and the availability of biomarkers for patient categorization.  The presentation will describe criteria useful in assessing the likelihood of success in the development and commercialization of a targeted or personalized medicine.   

Kwan Lee, Ph.D., Senior Director, Department of Biostatistics and Data Management, GlaxoSmithKline           

Personalized medicine is the delivery of the right drug, at the right dose, for the right patient, at the right time.  In theory, personalized medicine is the management of a patient’s disease or disease predisposition, by using molecular analysis to achieve the optimal medical outcomes for that individual — thereby improving the quality of life and health, and potentially reducing overall healthcare costs.  In practice, personalized medicine is a comprehensive approach utilizing molecular analysis of both patients and healthy individuals to guide decisions throughout all stages of the discovery and development of pharmaceuticals and diagnostics.  It involves application of this knowledge in clinical practice for a more efficient delivery of accurate and quality healthcare through improved prevention, diagnosis, treatment, and monitoring methods. Pharmacogenomics is the science that allows us to predict a response to drugs based on an individual’s genetic makeup (genome and expression of genes) and it is the major contributor to the theory and practice of personalized medicine.  In this talk we will briefly review the important biostatistics component of Pharmacogenomics.  Topics will include design and analysis of ‘omics data and reliable diagnostic algorithm development.  We will also discuss biomarker based targeted clinical trials, and early biomarker development in oncology drug discovery and how pharmacogenomics allows us to project the information to clinical development.

Scott D. Patterson, Ph.D., Executive Director, Medical Sciences, Amgen, Inc.

Patient stratification biomarkers would ideally be implemented prior to randomization of pivotal trials, but this may not always occur due to a sufficient understanding of the mechanisms of resistance to therapy being elucidated later in the clinical trial process rather than early. The various factors one needs to consider will be presented through example in this presentation.

Linda C. Surh, M.D., Ph.D., FRCPC, Director, CEDD Global Regulatory Affairs, Neurosciences and Pharmacogenetics, GlaxoSmithKline, UK

The context in which emerging biomarkers are used is critical, so that appropriate decision-making can be made in the face of limited resources whether in industry, government or medicine.  This presentation will attempt to take an emerging biomarker beyond the ‘what is the technology and why do it’ to ‘what is the clinical relevance and where to do it.’ Using pharmacogenomics (PGx) as an example of an emerging biomarker, it is evident that with assay capabilities more widely understood, it is now important to address the challenges of clinical interpretations in different situations.  Thus, depending on the pipeline phase, how do innovative biomarkers integrate so as to aid in the progression of new medicines which are timely, effective, and safe.

Yaping Shou, M.D., Ph.D., Director, Oncology Biomarkers and Imaging, Novartis Pharmaceuticals   

The presentation will discuss the definition and qualification criteria of surrogate endpoints and as a case study, describe the development of blood BCR-ABL transcripts as a surrogate endpoint in CML.  The technical challenges and regulatory considerations will be discussed in the implementation of this surrogate endpoint in clinical drug development and routine clinical practice.

2:30-3:30 Networking Refreshment Break with Poster and Exhibit Viewing

Darren Hodgson, Ph.D., Biomics Advisor,Oncology Therapy Area, AstraZeneca

When, how and why can one develop a new predictive biomarker in parallel to a candidate drug?  In this talk we will discuss the requirements of assays, human samples, data and trials needed in order to develop diagnostic pre-cursors and the decision making data required to justify investing in a co-development program.

John C. Bloom, V.M.D., Ph.D., Executive Director, Diagnostic & Experimental Medicine, Eli Lilly & Co.

The development and commercialization of novel diagnostics that enhance the value of drugs to patients, payers and prescribers is increasingly critical to “personalizing” medicines and differentiating new drugs in the marketplace. Strategies for building the capability to address such anticipated and unforeseen opportunities entail understanding the regulatory process and options for approval; and ensuring access to the appropriate specimens required for development, intellectual property rights and mutually profitable business partnerships. This presentation will review the challenges that building the required virtual technical and process diagnostic development expertise entail in today’s rapidly changing Research & Development environment.  

Alberto Gutierrez, Ph.D., Deputy Director, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), U.S. Food and Drug Administration

In Vitro Diagnostics are medical devices. FDA regulation is science-based and involves an overlapping series of well-defined but flexible pre-market and post-market controls. Personalized medicine has placed the diagnostic in center stage, since the safety and effectiveness of therapeutic decisions are dependent on a single diagnostic.  The regulatory challenges presented by this prominent role will be discussed.

Christoph Petry, Ph.D., Head, Molecular Research Germany, Siemens Healthcare Diagnostics Products GmbH 

Until very recently breast cancer therapy was selected based on consensus guidelines that made little use of the diagnostic power nucleic acid based diagnostics offers. New mRNA-based test systems may have a superior power than classical approaches to stratify the risk of cancer recurrence. They often focus on identifying low risk patients to scale back unnecessarily aggressive therapies. While this remains a key area for molecular breast cancer assays new predictive biomarkers will also help to select specific drug regimen for defined cancer subtypes.

Hans Winkler, Ph.D., Senior Director & Global Head, Oncology Biomarkers, Pharmaceutical Research & Development, Johnson & Johnson

Novel targeted therapeutics are expected to improve the treatment of cancer. However, they are expected to be effective in only a subpopulation of any tumor type.  It is therefore of prime importance to identify these tumors up front and select patients for treatment based on predictive markers.  Before major investments in such a strategy are warranted, the value of a compound needs to be assessed thoroughly. Demonstration in the clinic of adequate target modulation (Proof of Principle) is critical for progressing compounds to efficacy analyses. Examples of clinical pharmacodynamic results, opportunities and pitfalls will be discussed.

Paul J. Fielder, Ph.D., Senior Director & Senior Scientist, Early Development Pharmacokinetics, Pharmacodynamic and Bioanalytical Sciences,Genentech, Inc.

The development of novel biological therapies is a complex and dynamic process, which involves the interplay between the pharmacology and biology of both the disease target and the biology of the therapeutic.  These unique complexities can impact molecule selection, preclinical testing strategies, development of clinical plans, and help inform second generation molecules. Translational pharmacology is an approach which combines data from preclinical efficacy studies and knowledge about the clinical target and uses PD-biomarkers and PK/PD modeling to help inform the development path.  A major focus will be on how to use these novel approaches to inform key decision points during the development process and to inform second generation molecules.

Mark Fidock, Ph.D., Head, Biochemical and Molecular BioMarkers, Experimental Biological Sciences, Pfizer Limited

The presentation will describe the utilization of biomarkers in early clinical drug development. This will focus on developing techniques to successfully identify molecules or processes that have changed in response to therapeutic treatment to deliver accurate decision making data.  It will include a case study of assays for immune modulation in pre-clinical species and in man.

Chetan Lathia, Ph.D., Director, Global Clinical Pharmacology, Bayer Corp.

Abstract unavailable at the time of printing.

5:30 Close of Day