The Expanding Impact of New Animal Models in Drug Safety - The Expanding Impact of New Animal Models in Drug Safety

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MONDAY, JUNE 8

3:00 – 5:00pm Main Conference Pre-Registration - Click here for more information

MAIN CONFERENCE

TUESDAY, JUNE 9

7:30 am – 6:00 pm Registration Open

7:30 Morning Coffee

TEACHING AN OLD MODEL NEW TRICKS: IMPROVING CURRENT MODELS

8:30 Chairperson’s Remarks

8:40 Early Prediction of Clinical Adverse Drug Reactions: in vitro Safety Pharmacology
Laszlo Urban, Ph.D., Executive Director, Preclinical Safety Profiling, Novartis Institute for Biomedical Research
Broad-scale in vitro pharmacology profiling of new chemical entities during early phases of drug discovery has recently become an essential tool to predict clinical adverse effects. Modern, relatively inexpensive assay technologies and rapidly expanding knowledge about G-protein coupled receptors, nuclear receptors, ion channels and enzymes have made it possible to implement a large number of assays addressing possible clinical liabilities. Together with other in vitro assays and in silico tools focusing on toxicology and bioavailability, they provide a powerful tool to aid drug development. In this presentation, we will discuss the application of in vitro safety pharmacology for drug discovery, its appropriate use and predictive value.

9:10 Biomarkers of Functional Toxicities: Identification and Assessment of their Translation into Humans
Jean-Pierre Valentin, Ph.D., Senior Director, Head of Safety Pharmacology, Astra-Zeneca
This presentation will define and provide models and examples of functional toxicities. Additionally, it will explore the question of “QT interval duration – a surrogate of drug-induced Torsades de Pointes?” And provide a review of existing data and on-going initiatives in the translation of non-clinical data to humans. Lastly, we will review various case studies demonstrating the utilization of biomarkers to assess functional toxicities; successes, threats and opportunities.

9:40 Assessing Cardiac Inotropic Liabilities of Early Discovery Compounds: A Practical Preclinical Approach
Zhi Su, M.D., Ph.D., Associate Research Investigator, Department of Integrative Pharmacology, Abbott Laboratories
Reliable evaluation of cardiac inotropic liabilities of evolving discovery compounds is still challenging. There is a substantial need to improve in achieving this mission in the early phase of drug discovery. This presentation will briefly review the advantages and disadvantages of selected in vivo and in vitro models currently used to assess preclinical inotropic liabilities, and focus on how these models were employed through two case studies.

10:10 Networking Coffee Break

NEW STUDIES IN CARCINOGENICITY TESTING: BETTER WORK WITH RODENTS

10:40 FDA Perspective
Speaker to be Announced

11:10 Interlaboratory Evaluation of Genomic Signatures for Predicting Carcinogenicity in the Rat
Michael McMillian, Ph.D., Principal Scientist, Mechanistic Toxicology, Preclinical Drug Evaluation, Johnson & Johnson
A few years ago, we published a six gene expression signature for non-genotoxic carcinogens (NGTCs), based on results from a 1500 gene cDNA microarray (Nie et al, 2006). More recently data from the same set of rat liver RNA samples have been derived from full genomic microarrays, resulting in improved signatures. Other groups have derived their own versions of NGTC signatures, with considerable overlap of predictive genes. Acting via the Carcinogenicity Working Group of the Predictive Safety Testing Consortium of C-Path, these data, samples and approaches have been shared and critiqued in hope of cross-validating the more useful predictive genes for NGTCs. Despite subtle effects in short-term rat studies, NGTCs can be accurately predicted, and their mechanisms of action better understood.

11:40 Sources of Variation Toxicogenomics Study Control Animals Across Multiple Labs
Chris Corton, Ph.D., Senior Research Biologist, Environmental Carcinogenesis Division, National Health and Environmental Effects Research Lab, US Environmental Protection Agency
Determining normal variation in gene expression is an important precursor to interpreting changes due to treatment. However, the appropriate meta-data has not been available on the necessary scale. Towards this end we have created a public resource of microarray data from control rodents used in toxicological experiments. More than 500 Affymetrix arrays conducted at a wide variety of institutions under different experimental conditions were assembled and analyzed. 35 Biological and laboratory factors were tracked and examined as potential sources of large variability using univariate and multivariate analysis. Major potential sources of variability included organ section, gender, strain and fasting-state and should be included as minimal information in toxicogenomics experiments.

12:10 pm Enjoy Lunch on Your Own

1:10 Session Break

ZEBRAFISH & OTHER ALTERNATIVE MODELS: THE LATEST AND GREATEST

1:40 Chairperson’s Remarks
Ernie Bush, Ph.D., Vice President of Collaboration, Drug Safety Executive Council

1:45 Zebrafish Assays as Early Safety Pharmacology Screens: Paradigm Shift or Red Herring?
Jean-Pierre Valentin, Ph.D., Senior Director, Head of Safety Pharmacology, Astra-Zeneca
The recent flurry of interest in the potential use of the zebrafish in Drug Discovery has also led to the development of a range of assays purported to be useful as early screens in safety pharmacology. This presentation will take stock of the available zebrafish assays in the context of alternative mammalian cell-based assays, and of the validation outcomes to date. In addition, the results of a recent survey of the membership of the Safety Pharmacology Society regarding their views on zebrafish assays will be reported. The survey data indicate that the preferred way forward would be a collaborative effort between the pharmaceutical/biotechnology industry (as potential/eventual customers), and the zebrafish contract research companies (as suppliers), with expert input from academia.

2:15 Using the 3Rs to Develop Predictive Models for Preclinical Safety Assessment
Kathryn Chapman, Ph.D., Program Manager, National Centre for the Replacement, Refinement and Reduction of Animals in Research, NC3R’s
Traditional animal models of toxicity are not always predictive of toxicity in humans, and are considered a major bottleneck in the drug development pipeline. The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) has developed a broad programme of work with the pharmaceutical industry to investigate the added value of animal models and opportunities for the use of in vitro alternatives. This presentation will focus on how we work with the scientific and regulatory communities to achieve this mission.

Sponsored by

2:45 Validation of an Automated Screening Platform in Zebrafish
Carles Callol-Massot, Scientific Director , Biobide S.L.
Biobide has developed a HTS system that allows fully automated testing of libraries of compounds in zebrafish. The zebrafish model possesses many features that facilitate large-scale experimental approaches.
1. How to implement a totally automated platform for cardiotoxicity detection in zebrafish
2. Factors affecting the embryos heart rate in the QT prolongation prediction
3. Possible automatic classification of cardiac effects of drugs in zebrafish based on their predominant effects
4. Identifying type 2:1 arrhythmia as a marker of zERG blockade and consequently be able to predict QT interval prolongation.
5. Improving potency of the assays

3:00 Grand Opening Refreshment Break in the Exhibit Hall

3:40 The Other Side of the Coin: Screening Environmental Toxicants Using Zebrafish Embryos
Stephanie Padilla, Principal Investigator, Cellular & Molecular Toxicology Branch, Neurotoxicology Division, Environmental Protection Agency

4:10 Panel Discussion: Emerging Impact of Zebrafish
Moderator: Ernie Bush, Ph.D., Vice President of Collaboration, DSEC

The current trend of moving towards zebrafish technology in an assortment of preclinical screens?
The importance of HT in the evaluation process of new screens.
The advantages of testing in vivo with zebrafish vs. other in vivo & in vitro screens and profiling tools
Concerns surrounding the possibility of zebrafish being incorporated into preclinical safety assessment paradigms

5:10 Happy Hour in the Exhibit Hall

6:10 End of Day

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Drug Safety Executive Council

The Drug Safety Executive Council (DSEC) is a peer-to-peer membership of drug safety leaders with the common objective of advancing the development of better and safer medicines worldwide. Membership in DSEC is limited to leaders representing companies who develop small and large molecule pharmaceuticals only.