New screening technologies, in vitro assays and in vivo models continue to be developed, but is the right tool being used at the right time to predict and detect adverse events? Cambridge Healthtech Institute’s eighth annual conference on New Models for Predicting Drug Toxicity, looks at the scientific and technological progress being made to better predict drug-related toxicities at the preclinical stage, and avoid costly mistakes in the clinic.

Final Agenda

Wednesday, June 10

7:00 am Registration and Morning Coffee

HOW USEFUL ARE CURRENT IN VITRO AND IN VIVO MODELS

8:00 Chairperson’s Opening Remarks

Gary Peltz, M.D., Ph.D., Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine

8:05 Current Use of Stem Cell-Derived Cardiomyocytes to Assess QT Prolongation and Proarrhythmia

Bernard Fermini, Ph.D., Associate Research Fellow, Global Safety Pharmacology, Pfizer Global Research & Development

An increasing number of published studies support the use of human embryonic and iPSC derived cardiomyocytes for the assessment of drug-induced QT prolongation. While some of the studies conclude that these cells represent a suitable predictive model, others question their value based on reports of mixed phenotype, unforeseen pharmacology, and conflicting ion channel profile. In this presentation we review some of the more controversial issues and attempt to provide a holistic view of the field.

8:35 How Useful Are IN VITRO Tools to Predict Hyperbilirubinemia: Utility of UGT1A1, OATP1B1, OATP1B3, MRP2 and BSEP Inhibition Assays

Jae Chang, Ph.D., Senior Scientist, DMPK, Genentech, Inc.

Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body, a multifaceted process consisting of uptake of bilirubin into hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. This talk would 1) provide justification on the potential role of drug transporters in hyperbilirubinemia, 2) show inhibition data against UGT1A1, OATP1B1, OATP1B3, MRP2 and BSEP with marketed drugs and 3) discuss the application of IN VITRO assays for prediction of hyperbilirubinemia.

9:05 Proteomic Approaches to the Discovery of Preclinical Biomarkers of Toxicity

Li-Rong Yu, Ph.D., Associate Co-Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration

Advances of proteomics and its application to toxicological studies have led to the development of a new discipline, toxicoproteomics. One of the major research areas of toxicoproteomics is to identify novel biomarkers of toxicity. Mass spectrometry-based quantitative proteomic approaches have been applied to the identification of biomarkers of multiple organ toxicity in preclinical models.

9:35 Predictivity of IN VITRO Models Including Co-Cultures for the Detection of Hepatotoxic Drugs in Humans

Franck Atienzar, Ph.D., Associate Director, In Silico, IN VITRO Toxicology, Non Clinical Development, UCB BioPharma SPRL

Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better IN VITRO tools for predicting hepatotoxicity in humans. The presentation will focus on the predictivity of different human IN VITRO models such as primary hepatocytes, HepG2 and co-culture models. Toxicity and metabolism data will be presented to better judge the relevance of such IN VITRO models.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

11:35 Irinotecan Toxicity: 11 Novel Organ and Drug-specific Non-PK/PD, Non-DNA Repair Genes Detected in Mice Are Predictors of Individual Toxic Reactions

Peter Demant, M.D., Ph.D., Distinguished Member and Professor, Roswell Park Cancer Institute

Irinotecan serves as an important paradigm of pharmacogenetics of host toxicity. Although many homozygotes for UGT1A1 variants deficient in inactivation of irinotecan’s toxic metabolite SN-38 develop severe neutropenia, 75% of all such neutropenias affect UGT1A1 wild-type patients, indicating additional genes. A linkage analysis in mice detected 11 novel Adri (Adverse drug reactions-irinotecan) genes controlling tolerance to irinotecan. They are distinct from known PK/PD and DNA-repair genes and cumulatively determine individual susceptibility to irinotecan toxicity.

12:05 pm Experiences with the Comprehensive In Vitro Proarrhythmia Assay (CiPA)

Arthur M. "Buzz" Brown, M.D., Ph.D., Managing Director, ChanTest, a Charles River Company

The regulatory paradigm for nonclinical cardiac risk assessment has shifted from delayed repolarization, hERG block and QT prolongation to involvement of major human cardiac ion channels and proarrhythmic effects on human cardiomyocytes. Please join the discussion to learn more about our experiences with this multi-faceted approach.

12:20 LUNCHEON PRESENTATION: E Unum Pluribus: Evolution of iPSC Technologies from Cell Lines to Functional Tissues

Greg Luerman, Ph.D., Head, N.A. Applications, Axiogenesis AG

iPSC technology is a rapidly evolving, increasingly accessible tool helping to humanize science. Axiogenesis „ready-to-use“ cell types, exhibiting mature electrophysiological and primary tissue-like function, have been adopted into pre-clinical compound screens, safety/tox assessment, and phenotypic assay development. This presentation will demonstrate how Axiogenesis is tackling the next frontier: engineering functional tissues to more accurately reflect in situ drug environments.

1:00 Refreshment Break in the Exhibit Hall with Poster Viewing

EXPLORING ENGINEERED MODELS

1:30 Chairperson’s Remarks

Michael Shuler, Ph.D., Samuel B. Eckert Professor of Chemical Engineering and James and Marsha McCormick Chair of Biomedical Engineering, Cornell University

1:35 Body-on-a-Chip Devices for Drug Testing: Opportunities and Limitations

Michael Shuler, Ph.D., Samuel B. Eckert Professor of Chemical Engineering and James and Marsha McCormick Chair of Biomedical Engineering, Cornell University

Human surrogates for drug testing can be created using tissue engineered constructs, microfabrication, and PBPK (Physiologically Based Pharmacokinetic) models and may be used to make better decisions about which drugs to select for human clinical trials. We will describe our “pumpless” system, results with multi-organ models, and progress toward a 10+ organ human model. We will discuss the limitations of such technologies and potential solutions.

2:05 Human Contractile Engineered Muscle for Drug and Toxicity Studies

Nenad Bursac, Ph.D., Rooney Family Associate Professor, Department of Biomedical Engineering, Duke University

Current in vitro models of human muscle do not exhibit contractile behavior. We engineered electrically and chemically responsive, contractile human muscle tissues (“myobundles”) made of primary myogenic cells. These biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers, and a satellite cell pool, and respond to electrical stimuli with twitch and tetanic contractions. Use of GCaMP6-reported calcium responses enables long-term non-invasive tracking of myobundle function and response to drugs and provides a platform for predictive drug and toxicology screening.

2:35 Towards Organoid Microarrays for Screening Within Neural Tissues

Krishanu Saha, Ph.D., Assistant Professor, Biomedical Engineering and Bioethics, University of Wisconsin, Madison

Current human pluripotent stem cell-derived neural models consist of 2D disorganized cultures of cell phenotypes representative of only one or a few regions of endogenous tissues. This ignores the vast diversity of cell phenotypes and structured 3D niches that exist IN VIVO and thereby limits their modeling capacity in regulatory science settings. To overcome these limitations, we used emerging microfabrication methods to generate an array of 3D neural tissues (e.g., organoids) within standard multi-well plates for screening purposes.

3:05 The Impact of Assay Technology as Applied to Safety Assessment in Reducing Compound Attrition in Drug Discovery 

Yvonne Will, Ph.D., Senior Director, Drug Safety, and Head, Science and Technology Strategy, Pfizer R&D  

Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies.

3:35 Utility of an In Vitro Platform to Assess Neuronal Toxicity Using Human iPSC-Derived Neurons

Dinah Misner, Ph.D., DABT, Senior Scientist and Group Leader, Investigative Toxicology, Safety Assessment, Genentech Inc.

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 PLENARY KEYNOTE PANEL

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

Thursday, June 11

PREDICTIVITY OF COMPUTATIONAL TOOLS

8:35 Chairperson’s Remarks

Yvonne Will, Ph.D., Senior Director, Drug Safety and Head, Science and Technology Strategy, Pfizer R&D

8:45 eTOX: Assembling Animal Study Data from 6000 Reports From 13 Pharmaceutical Companies

Philippe Marc, Ph.D., Global Head, Informatics, Preclinical Safety, Novartis Institutes for BioMedical Research

In 2010, within the Innovative Medicines Initiative, the eTOX project started to extract data from legacy preclinical toxicology reports with the objective of creating a collaborative preclinical study database. The current version of the database contains data for 1791 small molecule drugs and drug candidates extracted from 6105 reports donated by 13 pharmaceutical companies. The database is currently growing by approximately 180 studies per month, and we envisage the creation of the largest preclinical database available.

9:15 Enhanced Prediction of Drug-Induced Liver Injury by the Development of Liver Toxicity Knowledge Base

Minjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration

Here, we will introduce our efforts to develop the Liver Toxicity Knowledge Base (LTKB), which focuses on collecting drug properties data and aims to develop predictive models for assessing DILI risk in humans. We will discuss some simple rules derived from drug physiochemical and toxicological properties and its significant association with DILI risk in humans. After confirmation and validation, these DILI predictive rules may support decision-making in drug development or regulatory processes to reduce potential DILI liability.

9:45 An In silico Approach to Predict Intrinsic In Vitro Cytotoxicity for Compounds in Primary Human Hepatocytes

BinQing Wei, Ph.D., Scientist, Discovery Chemistry, Genentech, Inc.

We present work in progress in the development of a computational model that is used to predict the outcome of hepatocyte screening for a set of preclinical compounds with significant accuracy. We show that this model proved very useful in reducing compound attrition for internal projects. Furthermore, the physicochemical property space that this work has implicated as being associated with toxicity may also provide clues toward understanding the underlying mechanism(s) of toxicity.

10:15 Tissue Chips for Drug Discovery and Screening

Kristin Fabre, Ph.D., Scientific Program Manager, Tissue Chip for Drug Screening Program, National Center for Advancing Translational Sciences (NCATS), NIH

The Tissue Chip Program is supporting development of platforms to mimic human physiology that will recapitulate the complex environment for human multi-cellular tissues to be studied. Within five years, major organs systems will be developed and applied to the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to clinical trials. It will deliver a valid alternative to standard methodologies and will produce human-physiologically relevant findings, reduce animal experimentation, and improve translational research efficacy.

10:45 Coffee Break in the Exhibit Hall with Poster Viewing

NEW PARADIGMS FOR SAFETY TESTING

11:30 Bioinformatic and Cheminformatic Approaches to Assess Cardiac Arrhythmias

Siobhan Malany, Ph.D., Chemical Biology Team Leader, Chemical Genomics Center, Sanford Burnham Medical Research Institute

The combination of hiPSC-cardiomyocytes and real-time cellular impedance measurements has provided for higher throughput toxicological screening in physiologically-relevant cellular assays. We have monitored dose-dependent changes in beat rhythm of hiPSC-cardiomyocytes induced by pharmaceutical compounds. For compounds that induce atypical beat patterns, we apply bioinformatic approaches, limit cycle analysis and autocorrelation, and present quantitative results to examine irregular beat patterns induced by channel blockers and provide automated solutions to analyze large kinetic datasets for web-based reporting.

12:00 pm Assay Platforms for Toxicity Evaluation in Small Molecules and Nanomaterials

Robert Damoiseaux, Ph.D., Scientific Director, Molecular Screening Shared Resource, California Nanosystems Institute, University of California, Los Angeles

Small molecule and nano-toxicity can follow quite different paradigms, requiring thoughtful use of adequate assay platforms for toxicity evaluation. In this talk we will have a look at the differences in paradigms and their corresponding assay platforms. We will give examples for each and also present a novel laser scanning cytometry based platform for the direct quantification of genotoxic potential of a substance via quantification of the DNA damage response by quantifying H2AX phosphorylation.

12:30 Close of Conference