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.
Wednesday, June 10
7:00 am Registration and Morning Coffee
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
10:50 KEYNOTE PRESENTATION: MICE WITH ‘HUMANIZED’ LIVERS: FROM SAFER DRUGS TO LIVER REGENERATION
Gary Peltz, M.D., Ph.D., Professor of Anesthesiology, Perioperative and Pain Medicine,
Stanford University School of Medicine
Drug-induced liver injury (DILI) has become a leading cause of acute liver failure, and for regulatory actions after drug approval. Drugs that produced minimal toxicity in animals sometimes caused significant DILI in humans. The fatalities
occurring in 7 of 15 patients treated with fialuridine provides a tragic example of this. We have developed chimeric TK-NOG mice, where transplanted human liver cells replace mouse liver. We recently demonstrated that DILI caused by fialuridine
and bosentan were easily detected in chimeric TK-NOG mice, which indicates that their use in preclinical studies could improve drug safety.
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.
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.
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
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.
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
7:30 am Interactive Breakout Discussion Groups with Continental Breakfast
Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking.
TABLE 9: Understanding Role of Drug Metabolites and Transporters in Drug Toxicity
David Stresser, Ph.D., Program Manager, Corning Gentest Contract Research Services
John Erve, Ph.D., D.A.B.T., Jerve Scientific Consulting, Inc.
Mingxiang Liao, Ph.D., Senior Scientist I, DMPK, Takeda
Pharmaceutical Intl. Company
- Biotransformation and the role of metabolism in drug toxicity
- Metabolism-based drug-drug interactions
- Drug transporters relevant for drug toxicity studies
TABLE 10: Computational Tools and How They Can be Used to Predict Safety Concerns
BinQing Wei, Ph.D., Scientist, Discovery Chemistry, Genentech
Minjun Chen Ph.D., Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration
Philippe Marc, Ph.D., Global Head of Preclinical Informatics, Preclinical Safety, Novartis Institutes for BioMedical Research
- How predictive are current in silico models and databases?
- Knowledge and information gaps in current in silico tools
- How to use in silico predictions for strategic decision-making
TABLE 11: Effective Utilization of Predictive In Vitro Models for Safety
Bernard Fermini, Ph.D., Ion Channel Discipline Lead, Associate Research Fellow, Global Safety Pharmacology, Pfizer Global Research & Development
Gary Gintant, Ph.D., Research Fellow, Integrative Pharmacology,
- In vitro models for cardiac safety testing
- Stem cells for cardiotoxicity assessments
- Update on the CiPA initiative
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)
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
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
12:30 Close of Conference