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 such as, in vitro assays, in vivo models and computational tools continue to be developed and used, but they are often unable to predict and detect all adverse events? What are scientists and clinicians doing to make sure that drug candidates fail early and cheaply during early testing? Cambridge Healthtech Institute’s tenth annual conference on Predicting Drug Toxicity looks at the scientific and technological progress being made to better predict drug related toxicities at the early preclinical stages, 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.

Who should attend: Drug discovery scientists, high-throughput screeners, cell biologists, safety pharmacologists, toxicologists, stem cell biologists, scientists in lead optimization, ADME/DMPK, biomarker discovery and translational research

Final Agenda

Tuesday, June 13

7:00 am Registration Open and Morning Coffee

HOW WELL AND HOW EARLY CAN WE PREDICT DRUG TOXICITIES?

8:25 Chairperson’s Opening Remarks

Paul B. Watkins, M.D., Director, Institute for Drug Safety Sciences, Howard Q. Ferguson Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

8:35 KEYNOTE PRESENTATION: Predicting Liver Safety Liabilities in New Drug Candidates: Are We There Yet?

Paul B. Watkins, M.D., Director, Institute for Drug Safety Sciences, Howard Q. Ferguson Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

Drug Induced Liver Injury (DILI) remains a major adverse event leading to termination of drug development programs and regulatory actions. Recent advances in understanding mechanisms that underlie DILI, more complex organotypic liver culture systems, novel mechanistic biomarkers, and quantitative systems toxicology modeling are increasingly impacting decisions made within both industry and regulatory agencies, and should improve the efficiency of drug development in the near future.

9:05 Quantitative Systems Modeling of Tolvaptan-Induced Hepatotoxicity

Sharin Roth, Ph.D., Director, Clinical Pharmacology, Bioanalytical & Biomarkers, Otsuka Pharmaceuticals

Quantitative systems modeling of tolvaptan-induced liver injury was performed using DILIsym®. Toxicity was mechanistically multifactorial in nature according to the simulations, with contributions from both bile acid accumulation and mitochondrial electron transport chain (ETC) inhibition. Predicted risk factors include basal ETC flux, mitochondrial respiratory reserve capacity, and BSEP function. Characteristics related to exposure were less correlated with susceptibility.

9:35 Organotypic Small Intestinal Tissue Model for Prediction of Adverse Drug Reactions

Seyoum Ayehunie, Ph.D., Vice President, MatTek Corporation

Gastrointestinal adverse drug reactions (ADR) cause health problems and create a burden on the health care system and the pharmaceutical industry. Gastrointestinal ADR often lead to late-stage drug attrition. In this presentation, we will demonstrate the utility of a novel in vitro 3D primary human small intestine based system to identify biomarkers that can better predict human ADR compared to preclinical animal models, and is ideal for therapeutic candidate screening.

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

10:50 Optimizing Dose Combinations via Simultaneous Toxicity & Antitumor Efficacy Modeling

Dean C. Bottino, Ph.D., Scientific Director, Quantitative Clinical Pharmacology, Takeda Pharmaceuticals International

A key question in early clinical oncology novel-novel combination drug development is: what recommended Phase II dose (RP2D) combination will optimize the efficacy of the combination while avoiding excessive toxicity? We describe a method combining clinical toxicity data, used to derive the maximum tolerated exposure (MTE) combination curve, with preclinical efficacy data, used to determine which point along this curve will provide optimal antitumor effect.

11:20 Strategies for Integration of in silico and in vitro Data for Off-Target Safety Assessments

Terry Van Vleet, Ph.D., DABT, Head of Molecular and Computational Toxicology, Department of Preclinical Safety, AbbVie

Typically, small molecule compounds are evaluated against a screening panel of potential off-targets to determine if they interact with human proteins of interest that may have consequence for toxicities. However, it is not feasible to screen each compound for all possible off-target interactions. One way to potentially enhance the coverage of in vitro screening is with computational methods to predict potential chemical interactions with human protein targets. This strategy may fill gaps in off-target screening that could not be covered routinely with panels.

11:50  Human-Based Phenotypic Profiling Uncovers Mechanisms of Toxicity

Adam Best, Ph.D., Product Manager, DiscoverX Corporation

Human-based phenotypic profiling is an attractive method for the discovery of chemical toxicity mechanisms. Using a standardized panel of human primary cell and co-culture model systems, BioMAP® Diversity PLUS, a database was generated. We identified a biomarker signature common to skin irritants, which was shared by several reference compounds including a lead compound from a drug discovery program that was terminated due to skin toxicity in primates.

12:20 pm  Luncheon Presentation: Preclinical Considerations for Cellular Therapeutic Safety Study Designs

Shawna Jackman, Ph.D., DABT, Principal Research Scientist, Photobiology, Charles River Laboratories

Complex and comprehensive preclinical evaluations are essential to assess potential clinical risks and to meet regulatory expectations for cell therapy products and specific intended indication. These design considerations include selection of the appropriate test system, study duration, toxicological endpoints and cell fate criteria. This presentation will address the unique challenges in the design and execution of these safety studies for cellular therapeutics.

12:50 Session Break

HOW GOOD ARE THE NEW IN VITRO MODELS FOR EARLY TOXICITY SCREENING?

1:40 Chairperson’s Remarks

Mary Ellen Cvijic, Ph.D., Director, Lead Evaluation & Lead Profiling, Department of Lead Discovery and Optimization, Bristol-Myers Squibb

1:50 Human on a Chip Systems as Phenotypic Models for Drug Toxicity and Efficacy Evaluation

James J. Hickman, Ph.D., Professor, Nanoscience Technology, Chemistry, Biomolecular Science, and Electrical Engineering, University of Central Florida

We are establishing functional in vitro systems to create organs and subsystems to model organ function and diseases, such as cancer and neurological deficits. The idea is to integrate microsystems fabrication with protein and cellular components, offering biologically, mechanically and electronically interactive functional multi-component systems. Some of the more advanced body-on-a-chip systems being developed will be discussed, as well as the results of workshops held to explore what is needed for validation and qualification of these systems.

2:20 Inotropy and Chronotropy Screens in Human Engineered Myocardium

Malte Tiburcy, M.D., Research Fellow, Institute of Pharmacology and Toxicology, University Medical Center Goettingen

Tissue engineered organ surrogates evolve rapidly as advanced tools for safety and efficacy screens. We developed engineered human myocardium (EHM) from defined cell populations under serum-free culture conditions in collagen type 1-hydrogels for applications in phenotypic drug screens. An automated tissue culture and analysis platform for high throughput screening of inotropic and chronotropic effects is presented. Validation of the EHM screening platform by test compounds with known and unknown pharmacologic profiles is discussed.

2:50 ZeGlobalTox - An Innovative Approach to Address Organ Drug Toxicity using Zebrafish

Javier Terriente, Ph.D., CSO, Research & Development, ZeClinics

Cardio-, neuro- and hepatotoxicity are major attrition causes during drug development. Drug-induced organ-toxicity can be assessed using zebrafish larvae, which provides high predictivity on possible human drug-induced liabilities; bridging the gap between preclinical in vitro safety evaluation and rodent models in a fast and cost-effective manner. ZeGlobalTox is an innovative assay that integrates sequential cardio-, neuro- and hepatotoxicity assessment in the same animal, allowing an strong impact in 3R implementation.

3:05 The Innovation Hub - Simplifying Access to the Latest Models and Innovative Strategies

Gursatya "Guru" Singh, PSM, Director, Scientific Content, Scientist.com

The Innovation Hub is a dedicated section of the Scientist.com marketplace in which we highlight and provide access to cutting-edge research tools, technologies and services. In the Innovation Hub, you can search for the latest CRISPR/Cas9 gene editing services, find new toxicity assays, browse a growing list of 3D tissues and access the latest in silico models of disease.

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 The Need for Increased Sensitivity in in vitro Drug Toxicity Testing

Ian Sweet, Ph.D., Associate Professor, Department of Medicine, University of Washington

In this talk, I will first consider the theoretical underpinnings of the ideal in vitro test of drug effects and toxicity. The second half will focus on very sensitive technology we have developed that continuously measures detailed time courses of pharmacologically relevant drug effects on solid tissue samples. The accuracy and throughput positions this technology as an important investigational component of a drug discovery strategy.

4:35 Further Defining the Role of Human Stem Cell Derived Cardiomyocytes to Assess Proarrhythmia

Gary Gintant, Ph.D., Senior Research Fellow, Integrative Pharmacology, Integrated Science and Technology, AbbVie

The availability of human stem cell derived cardiomyocytes (representing normal as well as diseased phenotypes) provides unique opportunities and challenges for evaluating cardiac safety of drug candidates. This presentation describes present and future roles of these cardiomyocytes as an in vitro proarrhythmia assay, and within the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative to guide the efficient development of safe drugs and reshape regulatory expectations.

5:05 High Content Screening for Predictive Safety/Toxicity Assays

Mary Ellen Cvijic, Ph.D., Director, Lead Evaluation & Lead Profiling, Department of Lead Discovery and Optimization, Bristol-Myers Squibb

High content imaging (HCI) is emerging as an important tool for safety and efficacy studies to advance drug discovery efforts. Due to its multi-parametric nature, this technology enables the identification of subtle changes in cell phenotypes which otherwise would be missed by conventional toxicity assay technologies. Here, we present case studies for HCI screening to investigate toxicity targets, mode-of-action and safety biomarkers for organ toxicities.

5:35 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Day

Wednesday, June 14

7:00 am Registration Open

7:30 Interactive Breakout Discussion Groups with Continental Breakfast

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. Continental breakfast is available for all participants.

Studies in the “Proclinical” Space: Risks and Benefits of Human- and Human-Derived Cells, Tissues, and In Silico Models in Preclinical Studies to Supplement (or Replace) Traditional Toxicity Models

Moderator: Gary Gintant, Ph.D., Senior Research Fellow, Integrative Pharmacology, Integrated Science and Technology, AbbVie

• Good (and not so good) Examples of “Proclinical Studies”
• Exploratory vs. Regulatory Expectations
• Gaps to Future Adoption

Competitive Safety – A Winning Formula for Drug Discovery

Moderator:
Laszlo Urban, M.D., Ph.D., Global Head, Preclinical Secondary Pharmacology, Novartis Institutes for BioMedical Research, Inc.

• Safety assessment of targets and associated drugs is a priority during all phases of drug discovery
• Integration of in silico, in vitro and in vivo aspects of toxicology should be aligned with clinical observations and reverse translation
• PK/PD aspects should not be left last in the drug discovery process

Susceptibility Factors in Drug Toxicity

Patricia Ganey, Ph.D., Professor, Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University

• What genetic and environmental factors influence susceptibility?
• Should toxicity testing incorporate determinants of susceptibility? If so, how and to what extent?
• How can individual susceptibility be incorporated into predictive in vitro toxicity assays?

HOW CAN WE BETTER UNDERSTAND & IDENTIFY DRUG-INDUCED ORGAN TOXICITIES?

8:35 Chairperson’s Remarks

Laszlo Urban, M.D., Ph.D., Global Head, Preclinical Secondary Pharmacology, Novartis Institutes for BioMedical Research, Inc.

8:45 Excipient Related Adverse Events

Laszlo Urban, M.D., Ph.D., Global Head, Preclinical Secondary Pharmacology, Novartis Institutes for BioMedical Research, Inc.

While regulatory agencies monitor the use of excipients, there is little knowledge about their broad biological behavior. Sporadic studies have highlighted safety concerns with some excipients, however, no systematic and rigorous safety investigations which are applied to drug candidates are required for these molecules. Here we present data from a broad scale investigation of biological effects of excipients in a variety of in vitro assays and possible implications of positive findings.

9:15 Prediction of Metabolism Mediated Drug Toxicity: Where Are We Now?

Jayaprakasam Bolleddula, Ph.D., Senior Scientist II (Associate Director), Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals

Idiosyncratic adverse drug reactions (IADRs) are one of the major causes of drug attrition at various stages of development and even after marketing. The mechanisms of IADRs are complex and poorly understood. Circumstantial evidence suggests that most IADRs are due to formation of reactive metabolites through bioactivation of drug molecules and their subsequent covalent binding to biological macromolecules. The current strategies followed across the pharmaceutical industry to mitigate reactive metabolites and future perspectives will be presented.

9:45 Drug-Cytokine Interaction in Idiosyncratic Hepatotoxicity

Patricia Ganey, Ph.D., Professor, Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University

Interaction with cytokines likely contributes to idiosyncratic liver injury from nonsteroidal anti-inflammatory drugs. We found that NSAIDs synergize with tumor necrosis factor (TNF) and interferons (IFN) to cause hepatocellular killing in vitro. The kinases JNK and ERK are critical mediators of cell death, but their roles differ depending on NSAID structure. Findings suggest that, even within the same pharmacologic class, synergy with cytokines occurs by different kinase signaling mechanisms.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 A Current Industry Perspective on Assessing Hepatotoxicity Risk in Drug Discovery

William Proctor, Ph.D., DABT, Senior Scientist, Head of Investigative Toxicology, Department of Safety Assessment, Genentech, Inc.

Extensive efforts are made to assess hepatotoxicity risk in drug discovery, which is difficult as there is poor concordance of preclinical species to identify human hepatotoxicants. Genentech employs a panel of in vitro models to investigate potential DILI risk with additional consideration for indication and projected dose/exposure. This talk will focus on standard and emerging technologies to assess hepatotoxicity risk and will demonstrate through case studies how the data can be used in a weight-of-evidence approach to characterize risk for DILI in small molecules.

11:30 Genetically Heterogeneous Mouse Populations Enable Study of Idiosyncratic Hepatotoxicity

Alison Harrill, Ph.D., Geneticist, National Toxicology Program Division, National Institute for Environmental Health Sciences

Diversity Outbred mice were specially bred to encompass a large degree of well-randomized genetic diversity across individuals, providing an opportunity to model idiosyncratic toxicities and to identify pharmacogenetics risk factors that confer susceptibility. This presentation will demonstrate the utility of Diversity Outbred mice for detection and study of idiosyncratic hepatic adverse reactions, as well as translation of mouse-derived pharmacogenetic risk factors to the clinic.

12:00 pm Bridging Luncheon Presentation: 3D Bioprinted Tissue Models for Predictive Toxicology and Disease Modeling

Jeff Irelan, Ph.D., Director, Scientific Applications, Tissue Operations, Organovo

Translation of preclinical data to clinical outcomes remains a challenge in drug development. Organovo’s ExVive™ 3D Bioprinted Human Liver and Kidney Tissues are positioned to bridge the gap by providing tissue-like responses in vitro through spatially-controlled, automated deposition of cells. Multicellular tissues preserve native cellular interactions for assessment of biological responses at the biochemical, transcriptional, and histological levels. Examples of toxicological applications and capacity for disease modeling will be discussed.

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing

1:30 PLENARY KEYNOTE SESSION

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Close of Conference