Cambridge Healthtech Institute’s 12th Annual

Predicting Drug Toxicity

Innovative Tools and Strategies for Early Drug Safety Assessments

June 19-20, 2019

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 of results from in vitro to in vivo. Cambridge Healthtech Institute’s 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.

Final Agenda

Wednesday, June 19

12:00 pm Registration Open

12:00 Enjoy Lunch on Your Own

12:30 Transition to Plenary


2:20 Booth Crawl and Dessert Break in the Exhibit Hall with Poster Viewing

2:25 Meet the Plenary Keynotes

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3:05 Chairperson’s Remarks

Laszlo Urban, MD, PhD, Global Head, Preclinical Secondary Pharmacology, Novartis Institutes for Biomedical Research (NIBR)

3:10 Safety Differentiation: Emerging Competitive Edge in Drug Development

Urban_LaszloLaszlo Urban, MD, PhD, Global Head, Preclinical Secondary Pharmacology, Novartis Institutes for Biomedical Research (NIBR)

With increasing expectations to provide evidence of drug efficacy, safety and cost-effectiveness, best-in class drugs are a major value driver for the pharmaceutical industry. Superior safety is a key differentiation criterion that could be achieved through better risk-benefit profiles, safety margins, fewer contraindications, and improved patient compliance. To accomplish this, comparative safety assessments using outcome-based approaches should be undertaken, and continuous strategic adjustments must be made as risk-benefit evolves.

3:40 Defining Predictivity: The Dilemma Facing Hepatotoxicity Risk Assessment in Drug Discovery

Proctor_WilliamWilliam Proctor, PhD, DABT, Associate Director/Senior Scientist, Investigative Toxicology, Department of Safety Assessment, Genentech Inc.

Drug-induced liver injury (DILI) is a leading cause of drug attrition. Numerous retrospective studies have identified physiochemical and in vitro hazards associated with DILI; yet there is no consensus for which parameters are truly predictive as varying statistical approaches, test sets, and DILI classification approaches. This talk will focus on evaluating the predictivity of each hazard individually or in combination employing a large test set with consistent classification and statistical analysis.

4:10 Adult Human Ex-Vivo Models for Preclinical Cardiac Safety Assessment of Drugs

Abi-Gerges_NajahNajah Abi-Gerges, Vice President, Research & Development, AnaBios

Reliable assessment of the cardiac safety of drugs is a critical requirement of pharmaceutical development. However, current approaches have significant limitations, whereby toxic drugs can still escape detection, or potential life-saving therapies are abandoned due to false positive signals. Therefore, AnaBios has established a novel, reliable and predictive, preclinical drug safety paradigm that uses ex-vivo human cardiac tissues and cells derived from donor hearts to provide a predictive assessment of drug-induced cardiotoxicity in humans.

4:40 Q&A with Session Speakers

5:10 4th of July Celebration in the Exhibit Hall with Poster Viewing

5:30-5:45 Speed Networking: Oncology

6:05 Close of Day

5:45 Dinner Short Course Registration

6:15 Dinner Short Course*

*Separate registration required.

Thursday, June 20

7:15 am Registration Open

7:15 Breakout Discussion Groups with Continental Breakfast 

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8:10 Chairperson’s Remarks

Terry Van Vleet, PhD, DABT, Head of Molecular and Computational Toxicology, Department of Preclinical Safety, AbbVie

8:15 Evaluating ADC-Related Peripheral Neuropathy with Advanced in vitro Models

Van_Vleet_TerryTerry Van Vleet, PhD, DABT, Head of Molecular and Computational Toxicology, Department of Preclinical Safety, AbbVie

Peripheral neuropathy has been observed clinically following chronic treatment with some microtubule inhibitors (MTIs), but is difficult to detect during early preclinical testing. Similar effects have been observed with some antibody drug conjugates (ADCs) using MTIs, but not all MTIs. A series of experiments using in vitro neural models were conducted to better understand the process of peripheral neuropathy with MTIs and identify models useful in predicting this adverse clinical outcome at early stages of preclinical testing.

8:45 In vitro Models and Assays to Predict Drug-Induced Kidney Toxicity During Drug Discovery

anna-karin-sjogrenAnna-Karin Sjögren, PhD, Drug Safety Scientist, Drug Safety and Metabolism, Astra Zeneca

Drug attrition related to kidney toxicity remains a challenge in drug discovery and development. Kidney toxicity is typically detected late, which reflects a lack of in vitro assays to identify early and screen away from the risk. Therefore, we have developed a multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced kidney toxicity during drug discovery. We also employ advanced culture models, including kidney microphysiological systems (MPS) and organoids to aid mechanistical investigations.

9:15 Human and Animal-derived Organoids to Model Drug Toxicity

Robert Vries, PhD, CEO, Hubrecht Organoid Technology (HUB)

Key to the development of the Organoid Technology was the discovery of LGR5+ intestinal adult stem cells by the lab of Hans Clevers. When provided with the appropriate growth factors, the adult stem cells were found to form a polarized epithelium in which stem cells, and their off spring such as differentiated cells maintain their natural hierarchical and functional role. Importantly, organoids proved to be both genetically and phenotypically stable during cell culture. After the discovery of the method for intestinal cells we developed methods for many other organs such as liver, lung and pancreas. HUB (Hubrecht Organoid Technology), implements the Organoid Technology in pre-clinical drug development as well as a clinical platform for patient stratification in clinical trials, biomarker discovery and as a companion diagnostic.

9:45 Ultrasound and Its Applications in Preclinical Drug Discovery and Development

Dunn_MichaelMichael Dunn, PhD, Senior Staff Scientist, Cardiovascular Research, Regeneron Pharmaceuticals

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

10:45 Poster Winner Announced

11:00 “Tissues-on-Chips”: Innovative Approach to Preclinical Toxicity Testing on Human Tissue

Lee_Bo_YeonBo Yeon Lee, PhD, Scientific Program Manager, Office of the Director, Tissue Chip for Drug Screening Program, National Center for Advancing Translational Sciences, National Institutes of Health

Microphysiological systems (also known as “Tissues-on-Chips”) is an alternative approach that would enable early indications and potentially more reliable readouts of toxicity and efficacy. Tissues-on-Chips are in vitro, three-dimensional organ systems from human cells on bioengineered platforms that mimic in vivo tissue architecture and physiological conditions. They are useful tools for predictive toxicology and efficacy assessment of candidate therapeutics and can be utilized to inform human clinical trial design and implementation.

11:30 Mouse Population-Based Approaches to Understand and Predict Adverse Drug Reactions

Mosedale_MerrieMerrie Mosedale, PhD, Assistant Director, Institute for Drug Safety Sciences, Research Assistant Professor, University of North Carolina Eshelman School of Pharmacy

This talk will describe genetically diverse mouse populations and provide examples of their utility in investigating adverse drug response. It will also introduce recent efforts to adapt mouse population-based approaches to in vitro platforms thereby enabling the incorporation of genetic diversity and the identification of genetic risk factors and mechanisms associated with drug toxicity susceptibility at all stages of drug development.

12:00 pm Five Cases of Clozapine-Associated Cardiotoxicity and Implications for Monitoring

Rhee_DavidDavid Rhee, MD, House Staff, Department of Internal Medicine, New York University School of Medicine

Clozapine-associated myocarditis is a rare but potentially life-threatening complication. There are no guidelines for monitoring, but the reaction most often occurs within 2-3 weeks of medication initiation. This is an observational case series of five patients who developed clozapine-associated myocarditis at Bellevue Hospital and discusses the clinical features and trends of these patients as well as their implications for monitoring for myocarditis during clozapine initiation.

Elsevier-square 12:30 Co-Presentation: Modeling and Predicting Toxicity Using Extracted Regulatory Data

Pooja JainPooja Jain, Senior Product Manager, Life Science Solutions, Elsevier

Tsaioun_KatyaKatya Tsaioun, Director, Evidence-Based Toxicology Collaboration, Johns Hopkins Bloomberg School of Public Health

Predicting toxicity early during development helps to prevent late stage failure, reduce clinical development costs and protect patient safety. Progress has been hampered by poor data quality and lack of predictive power of current models. During this session we will discuss recent data and analytical developments at Elsevier that support predicting toxicity, animal to human translation and pharmacokinetic profiling.

1:00 Enjoy Lunch on Your Own

1:35 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing

1:45-2:00 Speed Networking: Last Chance to Meet Potential Partners and Collaborators!

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2:20 Chairperson’s Remarks

Gary Gintant, PhD, Senior Research Fellow, AbbVie

2:25 The Evolving Roles of Evolving Human Stem-Cell Derived Cardiomyocyte Preparations in Cardiac Safety Evaluations

Gintant_GaryGary Gintant, PhD, Senior Research Fellow, AbbVie

Human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for preclinical cardiac safety testing. Recent applications focus on drug effects on cardiac electrophysiology, contractility, and structural toxicities, with further complexity provided by the growing number of hiPSC-CM preparations being developed that may promote myocyte maturity. The evolving roles (both non-regulatory and regulatory) of these preparations will be reviewed, along with considerations for their use in cardiac safety studies.

2:55 Pharmacogenomic Prediction of Drug-Induced Cardiotoxicity Using hiPSC-Derived Cardiomyocytes

Burridge_PaulPaul W. Burridge, PhD, Assistant Professor, Department of Pharmacology, Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine

We have demonstrated that human induced pluripotent stem cell-derived cardiomyocytes successfully recapitulate a patient’s predisposition to chemotherapy-induced cardiotoxicity, confirming that there is a genomic basis for this phenomenon. Here we will discuss our recent work deciphering the pharmacogenomics behind this relationship, allowing the genomic prediction of which patients are likely to experience this side-effect. Our efforts to discover new drugs to prevent doxorubicin-induced cardiotoxicity will also be reviewed.

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3:25 Exploring the Utility of iPSC-Derived 3D Cortical Spheroids in the Detection of CNS Toxicity


Qin Wang, PhD, Scientist, Drug Safety Research and Evaluation, Takeda

Drug-induced Central Nervous System (CNS) toxicity is a common safety attrition for project failure during discovery and development phases due low concordance rates between animal models and human, absence of clear biomarkers, and a lack of predictive assays. To address the challenge, we validated a high throughput human iPSC-derived 3D microBrain model with a diverse set of pharmaceuticals. We measured drug-induced changes in neuronal viability and Ca channel function. MicroBrain exposure and analyses were rooted in therapeutic exposure to predict clinical drug-induced seizures and/or neurodegeneration. We found that this high throughput model has very low false positive rate in the prediction of drug-induced neurotoxicity.


3:55 Linking Liver-on-a-Chip and Blood-Brain-Barrier-on-a-Chip for Toxicity Assessment

lelievre_sophieSophie Lelievre, DVM, PhD, LLM, Professor, Cancer Pharmacology, Purdue University College of Veterinary Medicine

One of the challenges to reproduce the function of tissues in vitro is the maintenance of differentiation. Essential aspects necessary for such endeavor involve good mechanical and chemical mimicry of the microenvironment. I will present examples of the management of the cellular microenvironment for liver and blood-brain-barrier tissue chips and discuss how on-a-chip devices may be linked for the integrated study of the toxicity of drugs and other molecules.

4:25 Close of Conference

Arrive early to attend Tuesday, June 18 - Wednesday, June 19

Optimizing Drug Metabolism & Pharmacokinetics

Recommended Short Course

SC2: Optimizing Drug Metabolism, Drug Clearance and Drug-Drug Interactions