Cambridge Healthtech Institute’s seventh annual conference on Functional Screening for Drug Safety Testing focuses on innovative tools, assays, models and biomarkers that are being used for detecting and predicting idiosyncratic and drug-induced toxicities. This conference will bring together leading experts in drug safety, from industry, academia and government/regulatory agencies, to discuss the appropriate use of in silico, in vitro and in vivo tools, leading to informed decision-making.
Day 1 | Day 2 | Safety/Screening Brochure | Speaker Bios
Wednesday, May 21
7:00 am Registration and Morning Coffee
8:00 Chairperson's Opening Remarks
Chair: Bettina Bertram, Scientist, Axiogenesis AG
8:05 In vitro Cardiac Safety: Current Issues and Emerging Challenges
Bernard Fermini, Ph.D., Ion Channel Discipline Lead, Associate Research Fellow, Global Safety Pharmacology, Pfizer Global Research & Development
Following the adoption of the S7B guidance document (2005), pharma has invested significant resources in establishing strategies to identify compounds that may cause prolongation of the QT interval. However, with increasing diversity of the portfolio, current strategies often fail to address emerging non-QT related issues, such as hypertrophy and heart failure. In this presentation we review current and future strategies to address these safety issues.
8:35 Drug Cardiotoxicity Screening by Microelectrode Arrays
Sonia Grego, Ph.D., Senior Research Scientist, Research Triangle Institute (RTI) International
Driven by rapid advancement in stem cell technologies and measurement techniques, in vitro cardiotoxicity assays are under intense development. We have carried out functional screenings of iPS cardiomyocytes by a multiwell microelectrode array (MEA) system. Results will be presented of a customized analysis of the rich dataset produced by MEA for reliable extraction of multiple drug response parameters.
9:05 FEATURED PRESENTATION: Patient-Specific iPSCs for Cardiac Safety Assessments
Joseph Wu, M.D., Ph.D., Director, Stanford Cardiovascular Institute; Professor, Department of Medicine and Radiology, Stanford
School of Medicine
Cardiac toxicity is a side effect of many pharmaceutical compounds and is a leading cause for drug withdrawal from market because of safety concerns. Current preclinical methods to measure cardiotoxicity are inefficient and rely on genetically altered cell lines, which do not accurately resemble human heart cells. Recent technological advancement has enabled the generation of patient-specific human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in vitro. The iPSC-CMs generated in this fashion carry all the genetic information from the individuals from whom they are derived. Here I will discuss the generation of iPSC-CMs from patients with cardiovascular diseases. I will also give examples showing how iPSC-CMs can detect drug-induced cardiac toxicity more accurately than the conventional hERG testing used by most pharmaceutical companies. I will also discuss the potential applications of iPSC-CMs for drug discovery.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 FEATURED PRESENTATION: Microscale Engineered Liver Tissue for Modeling Human Disease
Sangeeta Bhatia M.D.,Ph.D., John J. and Dorothy Wilson Professor of Health Sciences and Technology/Institute for Medical Engineering and Science, and Professor, Electrical Engineering and Computer Science, Massachusetts Institute of Technology
10:50 Contribution of BSEP Inhibition and Mitochondrial Toxicity to Drug Induced Liver Injury - New Assays, New Insights
Michael Aleo, Ph.D., Research Fellow, Pfizer Global Research & Development
In this talk I will discuss vesicle based and cell based assays for the assessment of BSEP inhibition and the learning’s we have had regarding species specificity. In addition, I will speak to the contribution of mitochondrial toxicity to DILI and will provide proof that the dual effect on BSEP and mitochondria will correlate with severe liver injury, whereas BSEP inhibition alone does not lead to liver injury per se.
11:20 Multiple Ion Channel Effects (MICE) and the New Era of Safety Pharmacology
Arthur M “Buzz” Brown, MD, PhD, President and CEO ChanTest Corp.
The Comprehensive in vitro Proarrhythmia Assay (CIPA) shifts the emphasis in cardiac risk assessment from measurement of QT to measurement of ventricular arrhythmias e.g., Torsade de Pointes and from measurement of hERG to measurement of cardiac ion channels and transporters that shape the cardiac action potential(MICE). A strategy for implementing, executing and validating this program will be described.
11:50 Systems Level Approaches to Organ Specific Toxicities in Zebrafish
Calum MacRae, M.D., Ph.D., Physician-Scientist, Department of Medicine, Cardiovascular Research Center, Brigham and Women’s Hospital; Associate Professor, Harvard Medical School
Many drug effects are a result of complex phenomena that are not recapitulated even in the most sophisticated in vitro systems. Using the larval zebrafish, it is possible to model much of drug efficacy and toxicity in a native context and to do this at high throughput. We have exploited a range of assay approaches to move towards a ‘TOX’ reporter zebrafish line capable of the interrogation of core organ specific toxicities in a manner that ultimately may allow efficacy and toxicity to be balanced in the early phases of drug discovery.
12:20 pm Neurotoxicity and Cardiotoxicity in Zebrafish Embryos: Phenotype-Based Mechanistic Studies for Drug Safety Testing
Jyotshna Kanungo, Ph.D., Senior Investigator, Lead Scientist, Zebrafish HTS Laboratory, National Center for Toxicological Research, U.S. Food and Drug Administration
Manifestations of drug–drug interactions arising from the use of combination drugs could be monitored in vivo in zebrafish. Live monitoring of multiple organ/tissue toxicities is an advantage since embryos/larvae express key enzymes involved in drug metabolism including the cytochrome P450 family. Our studies show that the drug effects (alone or in combination with other drugs) in these embryos are similar to those in humans and therefore, provide an excellent platform for mechanistic studies for translatability and therapeutic intervention purposes.
12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:30 Session Break
2:00 Chairperson’s Remarks
Chair: Michael Aleo, Ph.D., Research Fellow, Drug Safety, Pfizer Global Research & Development
2:05 Application of Knockout Animal Models for Toxicological Safety Assessments
Andrew Olaharski, Ph.D., Associate Director, Toxicology, Agios Pharmaceuticals
Knockout animals are an underutilized model for assessing the safety of pharmacological targets. Despite the inherent caveats, valuable toxicological information can be gleaned from their study. Two case studies exhibiting their utility will be presented: Firstly, a host-resistance study of LRRK2 knockout rats to assess the potential immunological liabilities associated with LRRK2 inhibition and, secondly, the evaluation of selective PLK2 inhibitors in PLK2 knockout mice to assess the impact of pharmacological inhibition on causing genotoxicity.
2:35 Utilizing Mouse Population Models to Understand and Predict Drug Toxicity in Humans
Merrie Mosedale, Ph.D., Research Scientist, Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences
Failure to accurately model clinical drug safety liabilities is, in part, due to a lack of genetic diversity present in traditional nonclinical models. Previous studies have demonstrated the ability of genetically defined mouse populations to more accurately model drug toxicity responses in humans. This presentation will describe recent findings utilizing a Mouse Diversity Panel to investigate mechanisms of drug-induced liver injury and identify risk factors that underlie drug toxicity susceptibility.
3:05 Challenges When Working With Juvenile Animal Models
Georg Schmitt, Ph.D., Head, Toxicology, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center
Studies in immature animals have dramatically increased following the pediatric drug legislations. These juvenile animal models have value, and are sometimes a unique approach to gather information critically needed for risk-benefit assessment in children. However, there are numerous challenges and pitfalls which need to be considered when juvenile animal models are engaged. The presentation will highlight scientific, regulatory, technical and ethical challenges when using immature animals for the safety assessment of pediatric drugs.
3:35 Human Cardiomyocytes - An iPSC-Derived Cell Model for Pre-Clinical Safety Studies
Bettina Bertram, Scientist, Axiogenesis AG
Axiogenesis AG is the leading expert for high quality stem cell derived, in vitro differentiated cell types. Our ready-to-use human iPSC-derived Cor.4U cardiomyocytes display an ideal cell model for pre-clinical compound screenings and safety assay needs, due to the authentic cardiac phenotype, including normal electrophysiology, pharmacology, protein expression and morphology. Successful establishment of Cor.4U cells on LTS and HTS show the great potential of these cells to permanently substitute simple cell lines to assess cardiotoxicity.
4:05 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 Plenary Keynote Presentation:
Catalyzing Translational Innovation
Christopher P. Austin, M.D., Director, National Center
for Advancing, Translational Sciences, National Institutes of Health
6:00 Networking Reception in the Exhibit Hall with Poster Viewing
7:00 Close of Day
Day 1 | Day 2 | Safety/Screening Brochure | Speaker Bios