2017 Archived Content
The conference on Optimizing Leads and Predicting Drug Toxicity looks at the scientific and technological progress being made to better optimize drug candidates and accurately predict drug related toxicities. What assays and models are being used, how
reliable and predictable is the data, and how is this information translated into knowledge that can impact decision-making? Hear experiences shared by experts and join the interactive sessions and panel discussions for active networking, brainstorming
and collaborating.
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Final Agenda
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Wednesday 15 November
7:00 Registration and Morning Coffee
8:25 Chairperson’s Opening Remarks
Christopher Goldring, Ph.D., Senior Lecturer, Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool
8:30 Evaluation of Lead Optimization and Toxicity Risk Assessment with Human-on-a-Chip Systems
James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor,
Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
Phenotypic screening systems for lead optimization have the advantage of providing useful information without a known target. Human-on-chip systems can potentially establish a therapeutic index before evaluation in animal models or clinical trials and
also give the possibility of target identification. These innovative platforms can make lead optimization more efficient which can lead to a greater number of successful clinical trials and de-risk the process.
9:00 All Optical Cardiac Toxicity Testing with Optogenetics and Calcium Imaging
Matthew J. Daniels, MA, Ph.D., MRCP, Wellcome Trust Intermediate Clinical Fellow,
Principal Investigator, Division of Cardiovascular Medicine, and BHF Oxbridge Centre of Regenerative Medicine, Oxford University
Detection of QT prolongation pre-clinically requires measurements reflecting the action potential duration (APD). Since the APD is influenced by beat frequency methods to control the cell are also needed. Normally this is achieved with electrical stimulation
and patch clamp. These require contact with the cell and with the dish, constraining throughput. We replace those with genetically encoded tools to make this possible in a microscope.
9:30 2017 – Growing Confidence in Use of hiPSC-Cardiomyocyte Assays in Early Drug Hazard Identification
Ard C.H. Teisman, Ph.D., Scientific Director, Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development
Selecting the best candidates for a drug-pipeline is a desirable but challenging process. Safety assessment from preclinical models is often essential within this selection process. Nevertheless, accurately predicting clinical effects remains a challenge with many of the existing preclinical models. Human stem cells at least bridge the “species difference gap”, and therefore hiPSC-cardiomyocyte are becoming more accepted within safety testing and drug candidate selection.
10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Update on IMI MIP-DILI Consortium Efforts: Stem Cells and More
Christopher Goldring, Ph.D., Senior Lecturer, Molecular and Clinical Pharmacology,
Institute of Translational Medicine, University of Liverpool
Drug-induced injury is a major cause of drug attrition, leading to the withdrawal of potentially valuable therapies. A particular problem is drug-induced liver injury (DILI), and our work in the MIP-DILI consortium (Mechanism-Based Integrated Systems
for the Prediction of Drug-Induced Liver Injury) will form the basis of this talk, which will cover the range of different model systems (simple and complex cell models, including stem cells) that have been evaluated for their relevance to man as
well as mechanisms of DILI.
11:15 Evaluation of Toxicogenomics Models Using the Literature on Human Toxicity
Miguel Andrade, Ph.D., Professor, Bioinformatics, Johannes Gutenberg University of Mainz
and Adjunct Director, Institute of Molecular Biology
Toxicogenomics resources describe the effects of toxic compounds in system models that can be
in vitro (including human cell lines) or in vivo (including rat and mouse whole organs). A problem remains that is to evaluate how these models recapitulate toxicity in humans. I will present approaches that we proposed that evaluate
toxicogenomics models comparing compound-induced gene expression profiles with the literature on human toxicity.
11:45 Enjoy Lunch on Your Own
13:45 Chairperson’s Remarks
Jordi Mestres, Ph.D., Head, Systems Pharmacology Group, IMIM-UPF Joint Research Programme on Biomedical Informatics; Associate Professor, Universitat Pompeu Fabra (UPF), Spain
13:50 In silico Prediction of Hepatotoxicity – Use of eTOX in vivo Data for Development of New in silico Tools
Alexander Amberg, Ph.D., Computational Toxicologist, R&D Preclinical Safety,
Sanofi
Within the eTOX consortium, in vivo data were extracted from legacy toxicity reports of 13 participating companies. With this approach, a database containing high detail toxicity results (histopathology, clinical chemistry,
etc.) from 1414 compounds was compiled. This presentation will show how hepatotoxicity data was extracted from this database, and how it was used for the development of new in silico tools for the prediction of
DILI.
14:20 Drug Safety Prediction in the Era of Precision Medicine
Jordi Mestres, Ph.D., Head, Systems Pharmacology Group, IMIM-UPF Joint Research Programme
on Biomedical Informatics; Associate Professor, Universitat Pompeu Fabra (UPF), Spain
14:50 Refreshment Break in the Exhibit Hall with Poster Viewing
15:30 The Emerging Role of MicroRNAs in Toxicity Detection
Rachel Church, Ph.D., Research Assistant Professor, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, and Head, Hamner-UNC Organ Injury Biomarker Core
Safety concerns, identified when pharmaceutical compounds reach clinical trials, are a major cause for drug attrition, highlighting the need for novel biomarkers with improved translatability. MicroRNAs (miRNAs) are non-coding RNAs that post-transcriptionally
regulate gene expression, are highly conserved across species, and released into biofluids (blood, urine) in response to organ toxicity. The potential for miRNAs to serve as translational biomarkers of organ toxicity will be discussed.
16:00 Interference of Drugs with Canalicular Bile Formation
Bruno Stieger, Ph.D., Group Leader, Department of Clinical Pharmacology and Toxicology,
University Hospital, Zurich
Bile is rich in phosphatidylcholine and bile salts. The latter are detergents and are cytotoxic. Canalicular bile formation involves an array of ABC-transporters. Interference of drugs with selected ABC-transporters may lead to the impairment of canalicular
bile formation followed by accumulation of bile salts in hepatoctyes. Such an accumulation leads to drug-induced cholestasis and, if persistent, to severe liver disease. This presentation will present evidence that some drugs may inhibit BSEP and/or
MDR3, two key transporters for canalicular bile formation.
16:30 Breakout Discussion Groups
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active
networking.
TOPIC: Cardiotoxicity Assessments: New Tools and Strategies
Moderators:
James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
Matthew J. Daniels, MA, Ph.D., MRCP, Wellcome Trust Intermediate Clinical Fellow, Principal Investigator, Division of Cardiovascular Medicine, and BHF Oxbridge Centre of Regenerative Medicine, Oxford University
- Maturity of human cardiomyocytes
- Functional Measurements as opposed to biomarker and viability assays
- Integration with other organs
- Use of induced pluripotent stem cells for cardiotoxicity assessments
TOPIC: Early Predictions of Hepatotoxicity and Idiosyncratic Toxicity
Moderator: Christoph Funk, Ph.D., Head Mechanistic ADME, Roche Innovation Center Basel, F. Hoffmann-La Roche
- Experimental approaches: Mechanistic tools (reactive metabolites, transporter inhibition, mitochondrial toxicity) versus holistic tools (3D cultures; organs on chips)
- In vitro to in vivo extrapolation (role of compound concentration, host-specific factors)
TOPIC: Lead Optimization for Drug Safety
Moderator: Bruno Stieger, Ph.D., Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
- Understanding drug transport and role of drug transporters
- Role of reactive drug metabolites in drug toxicity
- Methodologies: What experimental systems are available?
17:30 Welcome Reception in the Exhibit Hall with Poster Viewing
18:30 Close of Day and Dinner Short Course Registration
19:00 Recommended Dinner Short Course*
(SC1) New Technologies for Improving Drug Safety Screening
*Separate registration required
Day 1 | Day 2 | Speaker Biographies | Download Brochure
Thursday 16 November
8:00 Registration and Morning Coffee
8:25 Chairperson’s Remarks
Nigel Greene, Ph.D., Director, Head of Predictive Compound Safety and ADME, AstraZeneca
8:30 Summary of Breakout Discussions
Participants: Moderators of the Breakout Discussions Hosted on Nov 15
9:00 Impact of Secondary Pharmacology Data: Integration of Translational Information in Research to Better Mitigate the Risk of Adverse Clinical Effects
Bérengère Dumotier, Ph.D., Secondary Pharmacology Expert,
Safety Pharmacology, Novartis Pharma AG
Adverse Drug Reactions (ADRs) still often cause drug development failure or withdrawal. Considering the molecular pathways involved in the most severe clinical side effects is an integrated part of the early drug development phases. How to best share
translational information based on analysis of marketed drugs plasma exposure/ADR relationship and use this information to minimize the risk of severe adverse effects in later phases will be the main topics of this presentation.
9:30 ZeGlobalTox - An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish
Davide D'Amico, Ph.D., CEO, Management Board, ZeClinics
Assessments of drug-induced organ-toxicity using zebrafish larvae can provide high predictivity and effectively bridge the gap between preclinical in vitro safety evaluation and rodent models. ZeGlobalTox is an innovative assay that integrates sequential
cardio-, neuro- and hepatotoxicity assessment in the same animal, allowing a strong impact in 3R implementation.
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Implications of Reactive Metabolite Formation for Lead Optimization in Drug Discovery
Andreas Brink, Ph.D., Principle Scientist Drug Metabolism, Roche Pharma Research and Early
Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
Bioactivation of drugs to chemically reactive metabolites is a potential safety liability. A practice often applied to minimize the bioactivation potential of lead structures is to guide rational drug design based on the detection of stable trapping
products of reactive metabolites with e.g. glutathione. This contribution illustrates this strategy, exemplified by experiences at F. Hoffmann-La Roche over the last decade.
11:15 Target Tissue-Focused ADMET
Christoph Funk, Ph.D., Head Mechanistic ADME, Roche Innovation Center Basel, F.
Hoffmann-La Roche
Active targeting of drugs to particular target organs such as liver, tumor and brain can be achieved by targeting drug transporters or specific enzymes for prodrug activation. This approach can significantly enlarge the therapeutic window by increasing
efficacy at reduced drug exposure/safety. However, target-tissue specific ADMET properties, such as polymorphism, regulation and ontogeny of involved mechanisms, disease state as well as compound distribution, have to be assessed in order to reliably
predict safety and efficacy in different patient populations.
11:45 Using 21st Century Science in the Design of Safer Medicines
Nigel Greene, Ph.D., Director, Head of Predictive Compound Safety and ADME, AstraZeneca
Technological advances in the last decade have greatly enhanced our ability to screen larger and larger numbers of compounds for a variety of safety endpoints of concern in pharmaceutical development. These large data sets have led to an increased
understanding of trends in chemical features and properties that lead to an increased likelihood of seeing adverse events. This presentation will provide an overview of these properties of compounds and the challenges of using high-throughput
assays in the design of novel therapeutics.
12:15 Close of Conference
Day 1 | Day 2 | Speaker Biographies | Download Brochure