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. So what are scientists and clinicians doing to make sure that compounds fail early and cheaply? New screening technologies such as, in vitro assays and in vivo models continue to be developed, but are the right tools being used at the right time to predict and detect adverse events? Cambridge Healthtech Institute’s ninth annual conference on New Approaches 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 unexpected and costly findings in the clinic. What assays and models are being used, how reliable and predictable is the data, and how is this information impacting decisions before compounds are tested in patients? Hear experiences shared by experts and join the interactive sessions and panel discussions on issues related to drug toxicity.

Final Agenda

Wednesday, June 15

7:00 am Registration and Morning Coffee

DRUG TRANSPORTERS AND THEIR ROLE IN Drug Toxicity

8:25 Chairperson’s Opening Remarks

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

8:35 Transporter-Mediated Drug Interactions with Endobiotics, Toxins and Nutrients

Adrian Ray, Ph.D., Senior Director, Department of Drug Metabolism, Gilead Sciences, Inc.

Drug-drug interactions can arise from transporter inhibition. It is increasingly apparent that transporter inhibition can also cause effects on diverse endobiotics (e.g., signaling molecules, metabolites), toxins and nutrients. A number of drugs have been found to interfere with toxicity biomarkers, bilirubin and creatinine, used in routine clinical practice. Broader effects are now being better appreciated including the overlap of transport pathways for drugs and thiamine.

9:05 Combination of Top-Down and Bottom-Up Strategy to Elucidate Mechanistic Roles of Transporters in Organ Toxicity

Yurong Lai, Ph.D., Senior Principal Scientist, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb

Inhibition of transport processes may cause acute or chronic adverse effects in humans. As species differences in the transporter expression and substrate specificity exists, animals may not be perfect models. The presentation will discuss combining top-down and bottom-up thinking to elucidate the mechanisms of transporter associated organ toxicities, contemporary models for translational measurement and methods to predict drug exposure in targeted tissue to assess organ toxicity risk.

9:35 In vitro Human Intestinal Tissue Model to Assess and Predict Drug-Induced-GI Damage

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

9:50 Assessing Off-Target Drug Activities by Transcription Factor Profiling in FACTORIAL™ Assays. From TZDs to Statins to Proteasome Inhibitors

Sergei Makarov, Ph.D., CEO, Attagene

Using a patented reporter system, the FACTORIAL™, we developed screening assays enabling profiling activities of 50 transcription factors (TFs) within test cells. For different drug classes, we found characteristic multi-endpoint “TF signatures”, associated with their on-target activities. By evaluating distortions of the “on-target TF signatures” we can quantitatively assess off-target activities. Thus FACTORIAL™ offers a general straightforward solution for selecting optimal drug candidates.

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

UNDERSTANDING TRANSLATIONAL CHALLENGES AND INTERPRETING SAFETY GUIDELINES

10:50 The Importance of Reverse Translation for Preclinical Off-Target Mitigation

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

Secondary pharmacology is an integral part of preclinical safety assessment and off-target mitigation. However, the main challenge is how off-target effects translate into clinical ADRs. To address this issue, several approaches are conveyed; most importantly analysis of clinical side effects of marketed drugs and phenotypes of hereditary diseases. Once connections between ADRs and targets are identified, in vitro assays can be applied to detect unwanted off-target effects.

11:20 Moving beyond the S6(R1): A Snapshot of Toxicity & Safety Pharmacology Tools to Evaluate Biotherapeutics

Susan M.G. Goody, Ph.D., Senior Principal Scientist, Global Safety Pharmacology, Pfizer, Inc.

Biopharmaceuticals, such as monoclonal antibodies, growth factors, and antibody drug conjugates (ADCs), are increasingly at the forefront of treating human disease. The ICH S6(R1) provides regulatory guidance on the basic preclinical toxicity studies that are required for biopharmaceutical clinical development. This presentation will focus on instances where value can be gained by integrating specialized endpoints into toxicity studies or by the addition of dedicated safety studies with biotherapeutics.

11:50 Novel Human Cell-Based Assays for ADME/Tox Applications

David Thompson, Ph.D., Research & Development, Manager, ADME/Tox, MilliporeSigma

Attrition due to nonclinical and clinical safety issues continues to be a concern in drug development. To address these limitations, we used genome editing tools to develop improved human cell-based assays for frequently assessed endpoints in three commonly affected tissues (intestine, liver, kidney). These genetically modified cell lines are designed to improve and clarify data interpretation. Case studies illustrating how these have been used to resolve issues will be presented.

12:20 pm Luncheon Presentation: CiPA: How Comprehensive Does It Have to Be?

James Kramer, Ph.D., Principal Scientist, Discovery, Charles River

Many potentially valuable therapeutics have been inadvertently prevented from reaching the clinic due to the overly sensitive nature of the current nonclinical cardiac safety testing paradigm. The comprehensive in vitro proarrhythmia assay (CiPA) is a newly proposed strategy that shifts emphasis away from QT prolongation and focuses on predicting torsadogenic hazard through ion channel testing, in silico modeling and stem cell-derived cardiomyocyte testing.

12:50 Session Break

IN VIVO TECHNIQUES FOR MONITORING Drug Toxicity

1:40 Chairperson’s Remarks

Todd Wisialowski, MS, Associate Research Fellow, Global Safety Pharmacology, Pfizer Inc.

1:50 A Disruption of Autonomic Balance: Use of Heart Rate Variability (HRV) in Cardiovascular Safety Pharmacology

Carrie Northcott, Ph.D., Senior Principal Scientist, Global Safety Pharmacology, Pfizer Inc.

Changes in heart rate and blood pressure are often observed within in vivo pre-clinical cardiovascular studies following administration of a test article. The heartbeat, while continuous, is not periodic and can change in frequency due to autonomic influence. HRV provides a non-invasive methodology to determine if test article-induced changes in cardiovascular parameters are due to modulation of the autonomic nervous system.

2:20 Whole-Body Imaging of Drug-Induced Toxicity

Ming Zhao, Ph.D., Associate Professor, Feinberg School of Medicine, Northwestern University

Apoptosis is an important manifestation of drug-induced toxicity. We report the development of a whole-body non-invasive imaging technique to assess the spatiotemporal distribution of apoptosis as a novel indicator for systemic toxicity. With a proof of feasibility, it has the potential to provide an important companion diagnostic tool in human patients.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing

NEW IN VITRO SCREENING APPROACHES FOR SAFETY TESTING

3:35 Combination of Screening Assays for Assessing Drug-Induced Liver Injury in Humans

Christoph Funk, Ph.D., Vice Director, Pharmaceutical Sciences, F. Hoffmann-La Roche

Drug-induced liver injury (DILI) is one of the leading causes for acute hepatic failure and drug withdrawal. The potential DILI risk can be identified early-on by assessing multiple endpoints contributing to human DILI (metabolic activation, cytotoxicity and transporter inhibition) in conjunction with compound exposure. The approach was validated using 125 marketed or withdrawn compounds with different degree for DILI and exhibited an overall sensitivity and specificity of 80 and 86%.

4:05 In vitro Approach to Classify Drugs According to Their Idiosyncratic, Drug-Induced Liver Injury Liability

Robert A. Roth, Ph.D., DABT, Professor of Pharmacology and Toxicology and Director, Graduate Program in Environmental and Integrative Toxicological Sciences, Michigan State University

Current preclinical safety testing fails to identify drug candidates with the potential to cause idiosyncratic, drug-induced liver injury (IDILI). We found that logistical regression modeling applied to cytotoxic, drug-cytokine interactions in vitro yielded models with remarkable ability to categorize drugs according to their IDILI liability in humans. These initial results suggest a highly promising, in vitro approach that could be used preclinically to identify drug candidates with the potential to cause IDILI in human patients.

4:35 Generation of Complex Disease Phenotypes in 3D Bioprinted Human Liver Tissues for the Assessment of Drug-Induced Injury

Leah Norona, Doctoral Candidate Curriculum in Toxicology, University of North Carolina at Chapel Hill

Compound-induced hepatotoxicity leading to fibrosis remains a challenge for human risk assessment. Latency to detection and limitations of conventional model systems make it difficult to characterize dynamic and complex intercellular interactions that occur during progressive injury. Here we discuss the utility of 3D bioprinted liver for studying chronic exposure using fibrosis as a case study and provide a comprehensive approach to examine key initiating events and progression of tissue injury.

5:05 Drug-Induced Vascular Injury (DIVI)- Historical Review of Non-Clinical DIVI and Development of an Early Screening Strategy

Todd Wisialowski, MS, Associate Research Fellow, Global Safety Pharmacology, Pfizer Inc.

The occurrence of drug-induced vascular injury (DIVI) in preclinical toxicology studies often has a significant impact on compound development. This presentation will highlight efforts to summarize and characterize toxicity findings observed with internal compounds in a ‘DIVI Database’. In addition, we have studied compound effects in relevant exploratory in vitro and ex vivo assays, and sought to understand relationships between DIVI and hemodynamic changes.

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

6:45 Close of Day

Thursday, June 16

7:00 am Registration.

USE OF iPS CELLS FOR DRUG TOXICITY SCREENING

8:35 Chairperson’s Remarks

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

8:45 Utilization of iPSCs in Developing Human-on-a-Chip Systems for Phenotypic Screening Applications

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

Our lab is developing multi-organ human-on-a-chip systems for evaluating toxicity and efficacy compounds for drug discovery applications. Validation of the systems has already indicated good agreement with previous literature values, which gauges well for the predictive power of these platforms. Applications for neurodegenerative diseases, metabolic disorders as well as cardiac and muscle deficiencies will be highlighted in the talk.

9:15 Human-Induced Pluripotent Stem Cells Recapitulate Breast Cancer Patients’ Predilection to Doxorubicin-Induced Cardiotoxicity

Paul W. Burridge, Ph.D., Assistant Professor, Department of Pharmacology, Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine

The ability to predict which patients are likely to experience cardiotoxicity as a result of their chemotherapy represents a powerful clinical tool to attenuate this devastating side-effect. We report our progress towards this aim using the hiPSC cell model, a battery of in vitro assays, and machine learning.

9:45 Utilization of Induced Pluripotent Stem Cells to Understand Tyrosine Kinase Inhibitors (TKIs)-Induced Hepatotoxicity

Qiang Shi, Ph.D., Principal Investigator, Division of Systems Biology, National Center for Toxicological Research (NCTR), U.S. FDA

For cancer patients, the benefits of anti-cancer agents are often countered by hepatotoxicity. The purpose of current study is to predict tyrosine kinase inhibitors (TKIs)-induced toxicity using rat primary hepatocytes and human induced pluripotent stem cell (iPSC) -derived hepatocytes. Multi-parameter cellular endpoints have been used to examine the utilization of iPSC in safety screening. Data on cross-species comparison from rodent to human will be presented.

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

UNDERSTANDING MECHANISMS TO BETTER PREDICT Drug Toxicity

11:00 Predict Tyrosine Kinase Inhibitors (TKIs)-Induced Cardiotoxicity Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Xi Yang, Ph.D., DABT, Principal Investigator, Division of Systems Biology, National Center for Toxicological Research (NCTR), U.S. FDA

The utility of tyrosine-kinase inhibitors (TKIs) is limited by their structural cardiotoxicity, an effect not monitorable with current biomarkers of myocardial toxicity. This talk will present the progress to predict TKI-induced structural cardiotoxicity using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Multi-parameter cellular endpoints were used to help identify mechanism-based biomarkers to predict cardiotoxicity before loss of contractility.

11:30 Prediction of Transporter-Related Drug-Induced Liver Injury (DILI) Using Integrated Approaches

Mingxiang Liao, Ph.D., Senior Scientist I, DMPK, Takeda Pharmaceutical Intl. Company

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in patients and drug withdrawal from market. It is becoming increasingly evident that the inhibition of hepatic transporters by drugs and their metabolites can lead to the cholestatic forms of DILI. However, the prediction of hepatotoxicity in humans from preclinical data is a significant challenge. In the present study, the integrated models were used to understand the mechanisms and to improve the prediction of transporter related DILI.

12:00 pm Bridging Luncheon Presentation: Case Studies in Cardiac and Neuro Safety / Toxicity Assessment Using Human iPSC-Derived Cell Systems

Greg Luerman, Ph.D., Head, Applications Development, Axiogenesis Inc.

A major challenge in drug development is identifying novel cellular tools that more accurately reflect human biology while providing a significant advance over current methods. Here we provide several snapshots/case studies that utilize human-induced pluripotent stem cell-derived cardiomyocytes and neurons. These cells provide a flexible, high value human cellular system that offers a highly translational and typically more predictive cellular environment than immortalized cell lines or even primary rodent models.

12:30 Session Break

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

1:45 PLENARY KEYNOTE SESSION

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

4:15 Close of Conference