Adverse drug events such as cardiotoxicity, hepatotoxicity and other organ toxicities, keep surfacing in the clinic and idiosyncratic drug toxicity continues to haunt the drug development process. New screening technologies, in vitro assays, in vivo models and computational tools continue to be developed, but scientists are still unclear on which models to use, how reliable the data is, and how predictive the translation is from in vitro to in vivo. Cambridge Healthtech Institute’s Eleventh Annual Predicting Drug Toxicity conference looks at the scientific and technological progress being made to predict drug-induced toxicities and to better translate these findings to the clinic. Join us to hear experiences shared by experts and participate in the interactive sessions and panel discussions on issues related to drug toxicity.

Final Agenda

Wednesday, June 20

11:00 am Registration Open (America Foyer)

11:50 Bridging Luncheon Presentation: Use of a Collaborative Tool to Simplify the Outsourcing of Preclinical Safety Studies

Amanda Benjamin, Head, Alliance and Project Management, Drug Safety and Metabolism, AstraZeneca

Ruth Maclean, Senior Client Manager, Charles River

In 2012, AstraZeneca entered into a strategic relationship with Charles River whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, and pharmacokinetics studies were outsourced. Processes were created to ensure seamless workflows in order to accelerate the delivery of new medicines to patients. This session explores the preclinical safety outsourcing model and how a collaborative tool helped translate processes into simpler integrated workflows across two companies.

12:20 pm Dessert and Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)


2:30 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

St. George AB 

3:10 Chairperson’s Opening Remarks

Laszlo Urban, MD, PhD, Global Head, Preclinical Secondary Pharmacology, NIBR

3:15 Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Models of Cardiotoxicity

Gary_GintantGary Gintant, PhD, Senior Research Fellow, Department of Integrative Pharmacology, Integrated Science and Technology, AbbVie

The promise (and limitations) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as models of toxicity continue to be refined as experience with these preparations grow (along with variations in the preparations themselves). This presentation will discuss the evolving roles of hiPSC-CMs in assessing electrophysiologic as well as structural cardiotoxicity of novel pharmaceutical candidates, along with paths forward for their implementation in drug development and regulatory arenas.

3:45 Bridging the Gap between Determining Hepatotoxicity Potential Using in vitro Assays and Clinical Outcomes

Renato (Ron) Scialis, PhD, Senior Research Investigator, Preclinical Candidate Optimization, Bristol-Myers Squibb

In terms of hepatotoxicity, certain assays focus on discrete endpoints, however what is more relevant are toxicity models that can holistically cover a spectrum of pathways that are modulated by the compound and/or metabolites. This underscores the importance that observing toxicity preclinically involves the right experimental conditions to elicit a physiological response. This talk will focus on such an integrated model and relate in vitro findings to clinical results.

4:15 Zebrafish: An Alternative Model for Toxicity Screening in Early Discovery and Development

Arantza Muriana, MBA, CEO, Biobide USA

The many advantages that zebrafish presents make it a suitable alternative model for toxicity screening in Drug Discovery. As a powerful High Content Analysis tool, during this presentation we will provide a better understanding of how zebrafish relates to mammalian systems, and the strengths and challenges of using this model in the early preclinical phase, specifically for developmental, cardiovascular, neurological and hepatic safety evaluation, consequently minimizing risks and cost.

4:45 Identifying Non-Targeted Uptake Mechanisms of Antibody Drug Conjugates (ADCs) Using in vitro Platforms

Terry_Van_VleetTerry Van Vleet, PhD, DABT, Head of Molecular and Computational Toxicology, Department of Preclinical Safety, Abbvie

Unintended interactions are common with small molecule drugs, especially at higher exposures and concentrations. With the development of ADCs, non-targeting interactions of antibody based biologics (leading to uptake in unintended tissues) have become more apparent and consequential as well. This presentation outlines the careful characterization and use of in vitro platforms and technologies to identify these routes of uptake.

5:15 Challenges in Assessing Mitochondrial Toxicities and Liabilities in Drug Discovery

Will_ProctorWilliam Proctor, PhD, Senior Scientist, Head of Investigative Toxicology, Department of Safety Assessment, Genentech

Early identification of compounds that induce mitochondrial toxicities is an important part of lead-optimization. This talk will focus on mitochondrial toxicity assessment and included in here will be a cross-comparison of popular assays using a test set of commercial drugs with known clinical toxicities, as well as, data from a novel live-cell imaging approach to detect mitochondrial toxicities. Case studies of how these assays informed hepatotoxicity risk assessment as well as mechanistic understanding or preclinical toxicities will be presented.

5:45 Close of Day and Dinner Short Course Registration*

*Separate registration required.

Thursday, June 21

7:30 am Registration Open (America Foyer) and Morning Coffee (Foyer)

St. George AB

8:00 Chairperson’s Remarks

William Proctor, PhD, Senior Scientist, Head of Investigative Toxicology, Department of Safety Assessment, Genentech

8:05 Accurate Prediction of Clinical Parameters Utilizing Multi-Organ Human Systems

James_HickmanJames J. Hickman, PhD, Founding Director, NanoScience Technology Center; Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida

Our human-on-a-chip systems utilize functional models to capture multi-organ complexity to produce relevant modeling information related to drug responses in clinical settings. We have evaluated multi-organ toxicity and efficacy under continuous flow in a serum-free defined medium utilizing a pumpless platform for 28 days. The pharmacological relevance was evaluated with drugs and compared to human and animal data and these results will be presented.

8:35 The NIH Tissue Chips Program for Toxicity and Efficacy Testing

Danilo A. Tagle, PhD, Associate Director for Special Initiatives, National Center for Advancing Translational Sciences, National Institutes of Health

The current drug development process has a failure rate of 90% in being able to predict safety and efficacy of candidate drugs. To address this challenge in drug development, the NCATS Tissue Chip for Drug Screening program supports the development of alternative approaches for more reliable readouts of toxicity and efficacy. By emulating human physiology, tissue chips can increase the predictive power of preclinical modeling, for modeling human diseases, and for studies in precision medicine and environment exposures.

9:05 ZeCardio, An Innovative Zebrafish High Throughput Screening Platform for Cardiovascular Assessments

Simone Calzolari, MSc, PhD, Co-Founder, Chief Commercial Officer, ZeClinics S.L.

We present ZeCardio, a zebrafish larvae platform for the in vivo study of cardiotoxicity and cardiomyopathy therapy discovery. ZeCardio allows for the high throughput, fully automatized image acquisition of multiple cardiovascular parameters in living individuals, including readouts which are costly, time-consuming or simply unattainable with conventional methods.

9:20 Development of a Semi-Automated Segmentation Tool for High Frequency Ultrasound Image Analysis of Mouse Echocardiograms  

Raymond Chang, PhD, Imaging Research Scientist, Cardiovascular Research, Regeneron Pharmaceuticals

Echocardiography is a widely used and clinically translatable imaging modality for the evaluation of myocardial structure and function in preclinical drug discovery and development. The objectives of this study were to develop a robust analysis algorithm for semi-automated segmentation of left ventricle (LV) ultrasound images acquired from control and cardiovascular disease model mice.

9:35 Find Your Table and Meet Your Moderator

9:40 Interactive 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.

Gaps in Translating Preclinical Findings to the Clinic

William Proctor, PhD, Senior Scientist, Head of Investigative Toxicology, Department of Safety Assessment, Genentech

  • Model/assay sensitivity – What level (or magnitude) of change can we detect?
  • Do we have appropriate study design, data analysis, statistical analysis, and statistical power?
  • How predictive are our preclinical findings/models to the clinic?
  • What is it we are missing? Are there other useful models? Are there gaps in our translation knowledge?

Using iPSC for Drug Safety Screening

Gary Gintant, PhD, Senior Research Fellow, Department of Integrative Pharmacology, Integrated Science and Technology, AbbVie

  • What are concerns for using human induced pluripotent stem cell (iPSC)-derived cells to assess drug safety screening?
  • How to consider standardizing assays and comparing results? Assay reproducibility?
  • Generation of patient derived hiPSC-derived cardiomyocytes: present and future roles.
  • The role of newer co-cultures and 3D structures in present and future efficacy and safety studies.
  • How to best adapt hiPSCs for high-throughput phenotypic screening.

10:20 Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

11:05 High-Throughput Toxicokinetics for Rapid Risk Prioritization

John_WambaughJohn Wambaugh, PhD, Physical Scientist, National Center for Computational Toxicology, U.S. Environmental Protection Agency

Chemical prioritization based on potential human health hazard requires exposure, toxicity, and toxicokinetic (TK) data which are unavailable for thousands of chemicals. To provide TK estimates, high-throughput, in vitro TK (HTTK) pharmaceutical methods have been adapted for environmental chemicals. Systematically comparing HTTK predictions to in vivo data allows quantification of model uncertainty enabling chemical prioritization. This abstract does not necessarily reflect U.S. EPA policy.

11:35 The IQ DruSafe Nonclinical to Clinical Translational Database: Value of Animal Data in Drug Safety Testing

Vivek_KadambiVivek (Vic) Kadambi, PhD, Vice President, Nonclinical Development, Blueprint Medicines

The safety assessment of new drugs requires the conduct of animal toxicology studies, based on the assumption that the results provide translational value in identifying potential human hazards. Results of the IQ Consortium nonclinical to clinical translational database for Phase I trials will be presented, highlighting both the positive and negative predictive value of animal studies that support the safe entry of new drugs into the clinic.

12:05 pm Possible Regulatory Considerations for Secondary Pharmacology Related Adverse Drug Events (ADRs)

Laszlo_VaskoLaszlo Urban, MD, PhD, Global Head, Preclinical Secondary Pharmacology, Novartis Institutes for Biomedical Research

In this presentation, I will describe how off-target pharmacology became a mainstream tool to mitigate and manage unwanted ADRs and to be considered for guidance in regulatory affairs. Ongoing discussions with FDA focus on the determination of safety margins for off-target activities of drug candidates and their anticipated side effects in the clinical setting. Thus off-target pharmacology can help shaping the design of clinical trials.


12:35 Networking Luncheon in the Exhibit Hall with Poster Viewing (America Ballroom)

St. George AB

1:55 Chairperson’s Remarks

S. Joshua Swamidass, MD, PhD, Assistant Professor, Department of Immunology and Pathology, Division of Laboratory and Genomic Medicine; Faculty Lead, Translational Informatics, Institute for Informatics, Washington University

2:00 Managing Drug Toxicity Risks with Deep Learning Models of Bioactivation

Joshua_SwamidassS. Joshua Swamidass, MD, PhD, Assistant Professor, Department of Immunology and Pathology, Division of Laboratory and Genomic Medicine, Washington University

Many medicines become toxic only after bioactivation by metabolizing enzymes, sometimes into chemically reactive species. Idiosyncratic reactions are the most difficult to predict and often depend on bioactivation. Recent advances in deep learning can model bioactivation pathways with increasing accuracy, and these approaches are giving us deeper understanding of why some drugs become toxic, and others do not. At the same time, deep learning can be used to understand drug toxicity as it arises in clinical data, and why some patients are are affected, but not others.

2:30 Predicting Likelihood of in vivo Interaction Using High-Throughput Screening Data and High-Throughput Toxicokinetics

Nisha_SipesNisha S. Sipes, PhD, Health Science Evaluator, Biomolecular Screening Branch/Toxicoinformatics Group, National Toxicology Program Division, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health

In vitro-in vivo extrapolation (IVIVE) facilitates translation of data on hundreds of high-throughput screening (HTS) assays on thousands of diverse chemicals (e.g., pharmaceuticals and environmental chemicals) toward human relevance. An intuitive framework has been proposed using a generalized freely available high-throughput toxicokinetics model with parameters obtained from in silico and in vitro methods to estimate the plausibility of the biological interactions seen using HTS.

3:00 INTERVALS, A Data & Results Sharing Platform, Can Improve Transparency in Industry-Funded Research

Stephanie_BoueStéphanie Boué, Manager Scientific Transparency & Verification, PMI R&D, Philip Morris Products S.A., Part of Philip Morris International Group

INTERVALS was developed to allow a proactive sharing of the data from assessment studies examining the potential of harm reduction of modified risk tobacco products. INTERVALS enables data analysis by independent third parties and browsing the data by product, study, mechanism or endpoint. It also gives relevant information related to study design, methods, and the most important results from preclinical as well as clinical studies.

3:30 Advances in Humanized Animal Models For Prediction of Drug Safety and Disposition

Jayaprakasam Bolleddula, PhD, Associate Director, Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals

The translation of ADME parameters and toxicity from preclinical species to humans is challenging due to physiological differences between species. In order to overcome these limitations humanized animal models haven been developed and they are becoming useful tool to bridge the gap in translation. Recent advances along with application of these models for drug metabolism and related toxicity will be discussed.

4:00 Close of Conference

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