Predicting Drug-Induced Cardiotoxicity


Day 1 | Day 2 
Download World Pharma Congress Final Brochure or Download Cardiotoxicity Brochure 

About This Conference:


Cambridge Healthtech Institute’s fifth annual conference on Predicting Drug-Induced Cardiotoxicity elaborates on the mechanisms underlying cardiotoxicity, the use of stem cells, ion-channel assays, computational tools and models for early cardiac safety assessments and also delve into details for screening biological drugs, like monoclonal antibodies, antibody drug conjugates, fusion proteins and others. The pre-conference courses related to cardiac safety will also offer more in-depth education and networking opportunities with experts in the field. The CRO panel will include scientific experts from Contract Research Organizations, who will share their views on the technologies and trends that will impact cardiac safety testing going forward.


» Recommended Short Courses

Addressing Safety Concerns for Biological Drugs

Computational Tools for Predicting Toxicity

Mechanistic Insights into Cardiotoxicity

Recent Developments in Ion Channel Assays for Safety Screening

Use of Stem Cells for Safety Screening

Strategies for Safety Testing for Biologics


TUESDAY, JUNE 5

7:15 am Registration & Morning Coffee

 

EARLY ASSESSMENTS:
ASSAYS, MODELS AND MARKERS
 

8:30 Chairperson’s Opening Remarks

Gary GintantGary Gintant, Ph.D., Senior Group Leader, Department of Integrative Pharmacology, Global Pharmaceutical Research & Development, Abbott Laboratories




 

8:40 Cellular QT Screens - Probing Adult Cardiac Myocytes

Lars Kaestner, Ph.D., Principal Investigator, Institute for Molecular Cell Biology, Saarland University

Cellular action potentials can be recorded by optical approaches. To fulfill the pre-requirements to scale up for pharmacological screens, model cells need to represent target cells, optical sensors need to provide a reliable readout with minimal interaction with naive behavior of the cells and devices need to stimulate cells, read out signals with appropriate speed and throughput. In this talk scenarios for all three categories are discussed to use the power of light as a cellular equivalent for the QT-interval.  

9:10 Evaluation of Cellular Impedance Measures of Cardiomyocyte Cultures for Drug Screening Applications

Matthew Peters, Ph.D., Principal Scientist, Safety Assessment, Astrazeneca

Cardiovascular toxicity is a leading contributor to drug withdrawal and late-stage attrition. There is an urgent need for novel in vitro assays that enable earlier and broader testing for CV activity. Here, label-free impedance assays with cardiomyocytes are evaluated against criteria required for drug screening. The data reveal a novel combination of features including- sensitivity to contractile activity, versatile data analysis, robust/translatable data, and sufficient throughput to be a valuable addition to the cardiovascular in vitro screening arsenal. 

9:40 The Tell Tale Heart: Integration of Whole Heart Energetics, Proteomics, and Function to Assess Cardiac Toxicity in the Isolated Heart

Brian Roche, Ph.D., Cardiovascular Safety Pharmacologist, Safety Pharmacology, Battelle Memorial Institute

Using the isolated heart model we combined multiple modalities to assess drug induced cardiac toxicity in response to known cardiac toxicants. We monitored cardiac electrical and contractility function, combined with changes in protein regulation, and cardiac ATP production using NMR analysis of 31P. This multi scale concept in monitoring cardiac toxicity has allowed for the rapid assessment of not only acute but also the potential for delayed effects from new chemical entities. 

10:10 Coffee Break

10:40 Cardiac Contractility: Challenges in De-Risking

Jonathan Heyen, Ph.D., Principal Scientist, Global Safety Pharmacology, Pfizer Global Research & Development

Cardiac contractility or inotropy defined as the intrinsic ability of the heart to contract independent of preload and afterload is an important parameter of overall cardiovascular function and health. Direct monitoring of contractility is challenging and has lead to the use of indirect techniques such as catheterization or imaging techniques as surrogates in toxicology and safety pharmacology studies. However, these techniques are influenced by multiple factors of the cardiovascular system and care must be given when interpreting effects observed on contractility. 

11:10 Translating Cardiotoxicity: Can Stem Cells “Swim” Like Humans?

Gary GintantGary Gintant, Ph.D., Senior Group Leader, Department of Integrative Pharmacology, Global Pharmaceutical Research & Development, Abbott Laboratories

Numerous innovative in vitro approaches, ranging from swimming zebrafish to stem cells from different species, are available to interrogate human cardiotoxicity. A challenge faced by all approaches is the ability to translate results to correctly identify potential hazards and asesss potential clinical risk of drug candidates as safety assays move upstream in drug discovery. This presentation will discuss considerations critical in selecting appropriate assay(s) to enhance compound safety in a sea of uncertainty.

11:40 Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Understand Mechanisms of Cardiotoxicity

Dinesh Puppala, Ph.D., Senior Scientist, Compound Safety Prediction Group, Pfizer, Inc.

Cardiotoxicity is one of the leading causes of early and late stage drug attrition and induced pluripotent stem cell-derived cardiomyocytes offer the promise for early safety assessment. In here, we evaluate the value of induced pluripotent stem cell-derived cardiomyocytes (iCell CM) in comparison to conventional immortalized cell lines using different in vitro end points (ATP depletion, transcriptomics etc.,) for identifying underlying molecular mechanisms of cardiotoxicity. 

QUINTILES 12:10pm Translational Cardiovascular Safety: Optimizing the Integration of Preclinical and Clinical Safety Data
Sarah S. Bacus, Ph.D., CSO & Senior Vice President, Innovation, Quintiles Pacific, Inc.
This is broad enough--- and descriptive enough-- to cover whatever the precise content of the presentation is at the time of the conference. It also conveys that we are on the cutting edge of translational safety science.

 

Sigma_NEW12:40 Luncheon Presentation
Using Stem Cell-derived Cardiomyocytes in Drug Screening and Predictive Cardiotoxicity 
Silke Schwengberg, Ph.D., Senior Scientist, Research and Development, Axiogenesis AG
Cardiomyocytes derived from pluripotent stem cells are an attractive in vitro model due to standardized large scale production process, stability in long-term culture, and relevant physiology. In combination with advanced assay technologies, cardiac drug efficacy and safety assessment data have become more predictive. Cor.At® cardiomyocytes have been functionally validated for several cardiototoxicity assays including drug-induced cardiac-specific cytotoxicity as well as mitochondrial toxicity of different compound classes including anthracyclines as well as tyrosine kinase inhibitors.

12:55 Luncheon Presentation (Sponsorship Opportunity Available)  

New Insights Into The Role Of Ion Channels 

1:30 Chairperson’s Remarks

Peter HoffmannPeter Hoffmann, M.D., Ph.D., Executive Director, Preclinical Safety and Translational Cardiovascular Advisory Team, Novartis Pharmaceuticals Corporation




 

1:40 Cardiac Sodium Channel Inhibition: A Risk Marker During Early Drug Development

Peter Hoffmann, M.D., Ph.D., Executive Director, Pre-Clinical Safety and Translational Cardiovascular Advisory Team, Novartis Pharmaceuticals Corporation

Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity. Therefore, detection and mitigation of hNav1.5 liabilities early in drug discovery is important. In this presentation, a pre-clinical strategy is described that identifies hNav1.5 liabilities incorporating in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development. 

2:10 What is New About hERG Channel Inhibition? Atypical hERG Inhibition and Mitigation Strategies

Gul Erdemli, M.D., Ph.D., DABT, Head, Ion Channel Group, Novartis Institutes for BioMedical Research, Inc.

It is believed that the vast majority of low molecular weight hERG inhibitors block the channel by binding to the canonical binding site within the conduction pathway. However, we recently discovered different classes of novel hERG channel blockers, atypical hERG inhibitors that may be interacting with the channel in an unconventional manner. These inhibitors include gating modifiers, close channel blockers and indirect inhibitors of the hERG channel. They are likely to escape from traditional detection methods such as radioligand displacement assays and may not follow QSAR models based on these in vitro methods. This talk will describe the atypical hERG inhibition and discuss strategies for early detection and mitigtaion. 

2:40 Regional Genomic Regulation of Cardiac Ion Channels by Estrogen and its Implications to Sex Differences in Arrhythmia Risk

Guy Salama, Ph.D., Professor, Department of Medicine, University of Pittsburgh, School of Medicine

Women are at a greater risk than men of long QT types 1 and 2 and bradycardia-dependent arrhythmias. We will review the role of estrogen in the genomic upregulation of L-type Ca2+ channels and Na-Ca exchanger and their currents, I_Ca,L and I_NCX . The latter imply that during prolonged action potential durations or delayed repolarization by bradycardia or LQT 1 or 2, Ca influx exceeds Ca efflux resulting in Ca overload, spontaneous Ca release and triggered activity. The spatial heterogeneities of ion channel expression caused by estrogen is also responsible for the enhanced dispersion of repolarization and a more arrhythmogenic substrate.

Chantest3:10 Channeling Cardiac Risk
Arthur M. "Buzz" Brown, M.D., Ph.D., Executive Chairman & CSO, ChanTest Corporation

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:40 Interactive Discussion Groups

Concurrent problem-solving discussions on specific topics, to provide a forum for exchanging ideas, voicing opinions and meeting potential collaborators. Discussions will be led by a moderator/s, limited to 15 participants per table, and open to all attendees and exhibitors.

5:40 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 End of Day



Day 1 | Day 2 
Download World Pharma Congress Final Brochure or Download Cardiotoxicity Brochure