10:30-11:00     Predictive Safety Biomarkers in Non-Clinical Development

Phil Hewitt, Ph.D., Head, Molecular Toxicology, Institute of Toxicology, Merck KGaA

This presentation will examine the benefits of safety biomarkers as decision making tools, current predictive safety biomarkers, and assessing the impact of toxicogenomics.  It will consider the question: Can we predict hepatotoxicity using gene expression changes in primary hepatocytes?  And, finally, will discuss combining ‘omics technologies with traditional toxicology endpoints: a unique strategy for toxicity prediction and mechanistic elucidation.

11:00-11:30     Identification of Proteasome Gene Regulation in a Rat Model for Hyperlipidemia using Microarray Analysis

Jeffrey Waring, Ph.D., Associate Research Fellow & Group Leader, Cellular & Molecular Toxicology, Abbott Labs

Elevations in serum triglycerides and cholesterol can be an adverse effect associated with some classes of new drug candidates.  Identifying candidates in these drug classes that are not associated with dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. The present study evaluated the potential use of gene expression changes in rat liver in the development of an exploratory hyperlipidemia model.

11:30-12:00     Tissue-Specific, Non-Invasive Biomarkers for Pre-Clinical Safety Assessment

Patrick Y. Mueller, Ph.D., Project Leader, Safety Assessment, Novartis Pharma AG

Sensitivity and target tissue specificity are the major limitations of traditional, non-invasive clinical chemistry parameters used for monitoring of organ integrity during pre-clinical and clinical safety assessment. Several novel, tissue-specific biomarkers emerged as highly sensitive tools for non-invasive detection, monitoring, quantification and prediction of organ toxicity. However, transition of these biomarkers from pre-clinical drug development to first dosing in man is a major challenge despite recent regulatory endorsement of several kidney markers by FDA and EMEA. Currently emerging, highly tissue-specific, non-invasive biomarkers for hepatotoxicity, nephrotoxicity, cardiotoxicity and gonadotoxicity are presented and illustrated with data from selected case studies. A regulatory overview and a thorough species-specific compilation on available immuno-assays for these biomarkers will be provided.

12:00-12:30     Finding Biomarkers that Predict Rare Adverse Events: Assessing the Risk for Acute Idiosyncratic Hepatocellular Injury (AIHI)

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

Finding biomarkers that predict rare idiosyncratic adverse events has been problematic for many reasons. This has been particularly true for hepatotoxicity, or Acute Idiosyncratic Hepatocellular Injury (AIHI), which is the adverse event that most frequently leads to regulatory action on drugs, including failure to approve, post-marketing warnings added to the label and withdrawal from the market. Additional biomarkers are needed to enable more effective risk assessment and management of AIHI, including markers for identifying candidate drugs with this toxic potential and patients at risk or predisposed to AIHI, and for early detection and management of patients affected in clinical trials and practice. Approaches to the discovery and validation of such markers were reviewed in a recent meeting jointly sponsored by the Food and Drug Administration, the Pharmaceutical Research and Manufacturers of America, and the American Association for the Study of Liver Diseases; and in a recent Institute of Medicine Forum on Assessing and Accelerating the Development of Biomarkers for Drug Safety. This presentation will review the options that were identified for finding clinical biomarkers that predict AIHI, based on our current understanding of the mechanisms of this toxicity and the clinical populations at risk, and the research proposals that emerged from these discussions.

Sponsored by  

12:30-2:00 Luncheon Presentation
Biomarker Discovery, Validation and Implementation for Drug Development and Commercialization

Daniel Chelsky, Ph.D., Chief Scientific Officer, Caprion Proteomics

Caprion Proteomics and Covance have teamed up to provide a full biomarker service, including pre-clinical and clinical studies, biomarker discovery and validation, as well as assay development and implementation.

10:30-11:00     The Next Challenge for Biomarker Assay Development to Monitor Drug Effects

Francois Legay, Ph.D., Global Head, Marker Localization & Assays, Novartis Pharma AG

The understanding of drug effects requires following the pathway from the interaction to the drug target until the clinical/therapeutic effect in order to identify and select relevant biomarkers. To monitor drug effects, the development of specific, sensitive and validated assays for soluble, cellular or tissue biomarkers are necessary. This presentation will review the different areas where these technologies can play a key role and what future challenges will be.

11:00-11:30 The Critical Role of Characterizing Emerging Technologies Prior to Biomarker Development

Michael E. Burczynski, Ph.D., Associate Director, Biomarker Lab, Clinical
Translational Medicine, Wyeth Pharmaceuticals

Novel technologies enabling more specific and highly sensitive assays for detection and/or quantitation of biomarkers are constantly emerging.  While the benefits of such instrumentation advances are clearly evident, a thorough understanding of the molecular principles (and limitations) by which these biomarker detection technologies work is required.  Careful characterization and analytical validation of these platforms is a critical first step prior to generating data that will assist in biomarker-driven decision making in clinical development. 

11:30-12:00

Fit-for-Purpose Assay Validation in the  Protein Biomarker Pipeline   
Richard C. Jones, Ph.D., Head, Mass Spectrometry, NextGen Sciences, Inc.

The ability to generate putative protein biomarkers increases every year with improved discovery platforms in multiple disciplines. However, a major bottleneck has been the ability to develop assays in an acceptable timeframe in order to begin to validate putative biomarkers and move the viable biomarker candidates forward. Multiplexed mass spectrometry based assays are of considerable interest as they offer a potential solution to the biomarker validation problem.  Using a multiplexed mass spectrometry platform it is possible to significantly shorten assay development time relative to other more conventional platforms such as immuno-affinity based methods.  This allows resources to be focused on the utility of the putative biomarker and not on the development of the assay.  Depending on the application, the level of bioanalytical assay validation may be tailored such that it is fit for a given purpose.  In early biomarker discovery stages, minimal validation is required but as the usefulness of a single biomarker or a panel of multiple biomarkers is more clearly defined, the level of assay validation increases.  Here, we will discuss several example assays and outline the level of validation deemed fit-for-purpose in their application.

Sponsored by  

12:00-12:30 Meso Scale Discovery’s Multiplexed Assays for Safety and Toxicology Assays

Pankaj Oberoi, Ph.D., Director, Qualified Kit Development, Meso Scale Discovery

Traditional clinical markers for organ toxicity are not always sensitive enough to detect subtle damage and histopathology is not amenable to high enough throughput for preclinical studies. Meso Scale Discovery (MSD) has an electrochemiluminescence platform that is fast (1-3 minutes per plate independent of plate density), robust (non-fluidics instrument), radioactive free, sensitive (detection limits near 10 attomoles) and has a wide dynamic range (5 logs) with multiplexing capabilities. MSD has developed several multiplex panels for traditional and emerging safety biomarkers for kidney, cardiac, muscle, vascular, and liver damage.  This talk will discuss assay development challenges (critical reagent characterization, specificity, abundance of biomarkers, and matrix interaction) encountered during development of Qualified kits used in preclinical and clinical studies. 

Sponsored by  

12:30-2:00 Luncheon Presentation
Use of Mass Spectrometry-Based Protein Assays for Sensitive and Selective Analysis of Biomarkers in Preclinical and Clinical Efficacy and Physiology Models

Mu Wang, Ph.D., Vice President, Research and Development, Monarch LifeSciences

Biomarkers for use in preclinical animal models and clinical applications can be instrumental in studying disease physiology and drug efficacy. Often sensitive and selective antibodies and subsequent immune or radioimmunoassays, are unavailable. Additionally, in cases where isoforms of a protein or modifications of a protein require discrimination, a reagent based assay might be impractical or subject to poor selectivity. In these instances a mass-spectrometry (MS) based assay may be a viable and sensitive alternative. We will discuss the development of several highly sensitive, high-throughput mass spectrometry-based assays for use in preclinical and clinical analysis or biomarkers. One assay for P1NP from rat plasma or serum that does not rely on antibody reagents and a second assay for human Alcohol Dehydrogenase (ADH) which distinguishes the various isoforms in liver tissue will be discussed in detail. Sample preparation considerations, development of sensitive and selective MS-based assays, and absolute quantification methodology will be discussed.  P1NP immunoassay data will be compared to MS-based P1NP data to access reproducibility.  In addition to absolute selectivity, the MS-based assays provide throughput parallel to that of most antibody-based assays so they can handle a large number of samples that are generated from preclinical animal studies.