There have been rapid changes in technology and approaches being utilized to bring safer and more effective drugs to the clinic. Despite those efforts, 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. What can scientists do to ensure that the lead compounds are optimized and validated early and accurately to avoid costly mistakes from happening later in drug development? Cambridge Healthtech Institute’s 3rd Annual Optimizing Leads and Predicting Drug Toxicity conference looks at the scientific and technical advancements being made to better optimize drug candidates and accurately predict drug-related toxicities. What assays and models are being used, how physiologically relevant are they, how reliable and predictable is the data, and how is this information translated into knowledge that can impact decision-making? Hear experiences shared by experts and join the interactive sessions and panel discussions for active networking, brainstorming and collaborating.

Final Agenda

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Recommended All Access Package:

27 November: Organ-on-a-Chip and MicroPhysiological Systems

27 November Dinner Course: SC2: Understanding Key Concepts in Drug Metabolism and Drug Transport

28-29 November: Optimizing Leads and Predicting Drug Toxicity

29-30 November: 3D Cellular Models

29 November Dinner Course: SC5: Humanized Mouse Models: Technology and Applications in Preclinical Assessment of Cancer Immunotherapy

Wednesday 28 November

7:00 Registration and Morning Coffee

INTEGRATING LEAD OPTIMIZATION AND RISK ASSESSMENT STRATEGIES

8:50 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

8:55 Chairperson’s Remarks

Bernard Faller, PhD, Director, PK Sciences-In vitro ADME, Novartis Institutes for BioMedical Research

9:00 Transport Systems: Victims or Perpetrators in Drug Safety?

Bruno Stieger, PhD, Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland

Adverse drug actions are typically caused after the drugs have entered the cells. This is the standard situation, where drug transporting uptake systems act as perpetrators of adverse drug action. Outside of the cells, drug uptake may be impaired by drug-drug interactions and lead to pharmacokinetic drug-drug interactions with uptake systems being victims. At epithelial barriers like the intestine, drugs may interfere with efflux systems, e.g., which become victims. In hepatocytes, drugs or their metabolites can also interfere with the canalicular efflux of bile salts, making BSEP a victim.

9:30 Screening Strategies for Cellular Uptake

Bernard Faller, PhD, Director, PK Sciences-In vitro ADME, Novartis Institutes for BioMedical Research

Intra-cellular concentration is an important parameter to assess target engagement, especially for teams working outside the traditional LMW property space where permeability might be rate-limiting. What are the assays that can be used to assess intracellular concentration? How long does one need to incubate? How can one most effectively remove non-specific binding? How are efflux and uptake transporters shifting the equilibrium between medium and intra-cellular compartments?

10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Reactive Drug Metabolites in Safety Testing of Novel Drug Candidates

Christine K. Maurer, PhD, Head of Laboratory Discovery Biotransformation, Research & Development, Global Early Development, Merck KGaA

Many drugs withdrawn from the market undergo bioactivation to reactive metabolites (RMs). These can form covalent bonds to proteins and/or DNA potentially leading to organ toxicity and/or carcinogenesis. Thus, detection, risk minimization, and integrated risk assessment of RM formation is important in drug discovery and development. In this talk, current methods for RM detection and strategies for risk assessment in oncology projects are discussed in connection with the Merck RM strategy.

11:15 Drug Bioactivation: The Good, The Bad And The Ugly

Axel Pähler, E.R.T., DMPK/PD Leader, Pharmaceutical Sciences (PS), Roche Pharmaceutical Research and Early Development, Roche Innovation Center

Bioactivation is generally considered a risk factor for drug induced toxicities such as DILI. This presentation will highlight cases of reactive metabolite formation linked to safety failures and the key learnings Pharma has derived from that. Also highlighted are bioactivation reactions that determine the pharmacological mode of action. In this context learnings from old drug as well as from novel strategies to design selective covalent t inhibitors for safe use will be presented.

11:45 Idiosyncratic Drug Toxicity: Can in silico Tools Predict Bioactivation?

John C. L. Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.

Idiosyncratic drug toxicity (IDT) remains a concern to pharmaceutical firms and patients. Bioactivation of drugs to reactive metabolites is integral to the Hapten hypothesis. Bioactivation is traditionally investigated experimentally in vitro together with mass spectrometry. Bioactivation has also be investigated computationally. Approaches include quantum chemical calculations, docking with P450 enzymes and more recently, neural networks. In this talk, in silico approaches will be illustrated using drugs that have caused IDT.

12:15 Enjoy Lunch on Your Own

IMPROVING IN VITRO TO IN VIVO TRANSLATION

13:45 Chairperson’s Remarks

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

13:50 Use of a Quantitative Systems Pharmacology (QSP) Model to Predict Liver Toxicity in Simulated Populations

Christina Battista, PhD, Postdoctoral Fellow, University of North Carolina Institute for Drug Safety Sciences

DILIsym®, the result of an ongoing public-private partnership, has been developed to investigate drug-induced liver injury (DILI). The model employs mathematical representations of mechanistic interactions following drug administration through the release of serum biomarkers to accurately predict clinical observations in simulated patient populations. This talk will outline DILIsym and discuss applications to date.

14:20 On-/Off-Target and Class Effects of Different Biological Classes and How to Use Them for in silico Modelling of Biologics

Alexander Amberg, PhD, Computational Toxicologist, R&D Preclinical Safety, Sanofi

A wide variety of biotherapeutic modalities are used as drugs, many of them are a relatively new class of therapeutics. There is an uncertainty regarding the adverse effects of the different biological classes, for some people they are just a result of exaggerated pharmacology. This presentation will summarize results of an analysis of on-/off-target and class effects of different biological classes and will try to answer the question if and how they could be used for in silico modelling approaches of biologics.

14:50 Interactive Breakout Discussion Groups - View Details

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.

• Bioactivation as a risk factor for drug induced toxicities such as DILI
• Case studies of reactive metabolite formation linked to safety failures and key learnings
• Bioactivation reactions that determine the pharmacological mode of action
• Key learnings from old drugs and novel strategies to design selective new inhibitors for safe use

Use of Modeling Tools and Strategies for Predicting ADME-Tox Properties

Maria A. Miteva, PhD, Research Director, Molécules Thérapeutiques in silico (MTi), Inserm Institute

• Machine-learning or structure-based approaches for ADME-Tox prediction and optimization?
• Should the modeling tools for toxicity predicting be specific for xenobiotics and drugs?
• Quantum-mechanics methods for drug metabolism prediction

16:00 Refreshment Break in the Exhibit Hall with Poster Viewing

16:45 Microphysiological Systems for Safety and Efficacy Studies

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

Approximately 30% of drugs have failed in human clinical trials due to adverse reactions despite promising pre-clinical studies, and another 60% fail due to lack of efficacy. The NIH Tissue Chips program is developing alternative approaches for more reliable readouts of toxicity or efficacy during drug development. Tissue chips are bioengineered microphysiological systems utilizing chip technology and microfluidics that mimic tissue cytoarchitecture and functional units of human organs. These microfabricated devices are useful for modeling human diseases, and for studies in precision medicine and environment exposures.

17:15 Development of Quantitative Systems Pharmacology (QSP) for Improved Association of Preclinical and Clinical Treatment Phenotypes

Bérengère Dumotier, PhD, Secondary Pharmacology Expert, Safety Pharmacology, Novartis Pharma AG

Inadequate balance between therapeutic efficacy and adverse events is a major reason for high attrition rates. Majority of adverse events are related to undesirable drug pharmacology (off-target pharmacology, complex pharmacokinetics), and disease-specific pathophysiology of patients. Off-target engagements can be determined at the very early phase of drug discovery processes; however, their translation to AEs is dependent on the two other components mentioned above. The talk will focus on the best way to integrate preclinical and clinical data for small molecules, into a knowledge-based platform for preclinical risk mitigation.

17:45 Summary of Breakout Discussions

Axel Pähler, E.R.T., DMPK/PD Leader, Pharmaceutical Sciences (PS), Roche Pharmaceutical Research and Early Development, Roche Innovation Center

Maria A. Miteva, PhD, Research Director, Molécules Thérapeutiques in silico (MTi), Inserm Institute

18:15 Welcome Reception in the Exhibit Hall with Poster Viewing

19:15 Close of Day

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Thursday 29 November

8:00 Registration and Morning Coffee

USE OF STEM CELLS FOR DRUG SAFETY ASSESSMENTS

8:25 Chairperson’s Remarks

Chris Denning, PhD, Professor and Head, Department of Stem Cell Biology, University of Nottingham

8:30 Importance of Phenotyping Your Model to Know What Purpose It Is Fit For:

Focus on Increasing Complexity of In vitro Models

Praveen Sharma, PhD, Lecturer, Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool

Focus on Mitotoxicity

Amy Chadwick, PhD, Lecturer, Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool

It is estimated that 38% and 51% of compounds showing liver injury in man do not show similar effects in animals. The work of the IMI MIP-DILI and TransQST consortia shows how a roadmap is being developed based for the integration of established and emerging test systems and illustrates the increasing complexity of models from 2D to multi-cell 3D systems that are used in a logical fashion to assess DILI liabilities of new drugs before they are given to man.

9:00 Bioengineering Human Pluripotent Stem Cell Derived 3D Models for Drug Toxicity and Disease Modeling

Paula M. Alves, PhD, Unit Director, Cell Bioprocesses Laboratory, Instituto de Biologia Experimental e Tecnologica (iBET)

The development and validation of human in vitro models with physiological relevance, robustness, reproducibility and scalability are still a need in toxicology. Our strategy combines human stem cells, 3D culture strategies and computer-controlled bioreactors in perfusion operation modes. Results concerning the establishment and refinement of culture systems for efficient stem cell differentiation and maturation into cardiac, neural and hepatic cells, as well as their applicability for long-term toxicity testing will be presented and discussed.

9:30 Rethinking the Translational – The use of Highly Predictive hiPSC-Derived Models in Pre-clinical Drug Development

Alexandre Fouassier, Business Development & Sales, Southern Europe, NCardia

Current drug development strategies are failing to increase the number of drugs reaching the market. One reason for low success rates is the lack of predictive models. Join our talk to learn how to implement a predictive and translational in-vitro disease model, and assays for efficacy screening at any throughput.

10:00 Coffee Break in the Exhibit Hall. Last chance for poster viewing.

10:45 Exploring the Relationship Between Myofilament Calcium and Force Production in the Single iPS-Cardiomyocytes

Matthew J Daniels MA PhD, MRCP, Wellcome Trust Intermediate Clinical Fellow, Principal Investigator, Division of Cardiovascular Medicine, and BHF Oxbridge Centre of Regenerative Medicine, Oxford University

The in vitro survival of iPS-CMs should aid cardiotoxicity studies of contractility. As contraction depends on depolarisation, both parameters should be measured in these assays. We find that all classes of chemical dye (voltage, calcium and sodium) impair contractility, and when used in combination with drugs known to act on the myofilament produce confusing composite results making them unreliable for this purpose. We describe how we have overcome this problem.

11:15 Phenotypic Analysis for Cardiotoxicity Evaluation on Human iPSC

Anthony Perrier, PhD, Study Director, In vitro Toxicology, Biologie Servier

To improve the early prediction of cardiac toxicity, we developed in vitro tests using High Content Analysis using human iPSC cardiomyocytes. The readouts were qualified using Receiver Operating Characteristic curves and a ranking algorithm was developed to obtain an overall multiparametric cardiotoxicity evaluation for each compound. This cardiotoxicity phenotypic analysis and ensuing improvements will be used for early safety evaluation in the drug development process at Servier.

11:45 Evaluating Cardiovascular Liability and Genetic Disease with hiPSC-Cardiomyocytes

Chris Denning, PhD, Professor and Head, Department of Stem Cell Biology, University of Nottingham

We will review the results from a public-private partnership (NC3Rs-GSK), termed the “CRACK-IT InPulse Challenge” and the software developed to facilitate analysis of cardiac contractility. This sought to evaluate hiPSC-cardiomyocytes in 2D and 3D formats in the blinded evaluation of 28 drugs that were associated with positive or negative inotropy in heart tissue, or no effect. Finally, we will show data on the coupling of hiPSC-CMs and Cas9/CRISPR-mediated gene editing to model hypertrophic cardiomyopathy.

12:15 Close of Conference

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