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

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

Wednesday, June 19

12:00 pm Registration Open

12:00 Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Transition to Plenary


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


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

Laszlo 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

William 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 Update on the Findings of the IQ Consortium for Nonclinical Safety Testing

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

4:40 Adult Human Ex-Vivo Models for Preclinical Cardiac Safety Assessment of Drugs

Najah 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.

5:10 Networking Reception in the Exhibit Hall with Poster Viewing

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


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

Terry 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 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 Multicenter Comparison of Hepatic 3D Culture Models

Volker Lauschke, PhD, MBA, Associate Professor, Group Leader in Personalized Medicine and Drug Development, Department of Physiology and Pharmacology, Karolinska Institutet

When cultured as 2D monolayers, primary human hepatocytes (PHH) rapidly lose crucial hepatic functions within hours. In this talk, I will present our multicentre benchmarking efforts in which we compared various emerging cell models and 3D culture platforms. Using integrated multi-omics analyses, we found that molecular signatures of PHH in 3D spheroid cultures most closely resembled the livers from which the cells originated and, consequently, exhibited the best functionality and highest predictive power.

9:45 Presentation to be Announced

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

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

Bo 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

Merrie 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

David 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.

12:30 Sponsored Presentation (Opportunity Available)

1:00 Transition to Lunch

1:05 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

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


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

Gary 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

Paul 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.

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

Colin Choi, PhD, Scientist, Drug Safety Research and Evaluation, Takeda

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 developed a CNS toxicity-detection strategy using a human iPSC-derived 3D microbrain model. Measuring viability and imaging-based functional endpoints, we conducted validation studies using compounds associated with neurodegeneration and seizure.

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

Sophie 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

* The program is subject to change without notice, due to unforeseen reason.

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