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TUESDAY, JUNE 7
7:45 am Registration and Morning Coffee
8:45 Chairperson’s Opening Remarks
Peter Hoffmann, M.D., Ph.D., Executive Director, Pre-Clinical Safety, Novartis Institutes for BioMedical Research
8:55 Expanding in vitro Biochemical and Cellular Models for Earlier Drug Safety Assessment
Mary Ellen Cvijic, Ph.D., Principal Scientist, Lead Evaluation, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Co.
We have developed a high-throughput in vitro assay panel including target classes such as GPCRs, kinases, transporters, ion channels, and nuclear hormone receptors to determine which critical targets can be used to best flag potential cardiac liability issues before compounds advance to in vivo or late-stage drug safety evaluation. We have investigated which in vitro assays offer more sensitive and physiologically-relevant read-outs for assessing compound safety profiles and have identified current gaps in harnessing state-of-art technology platforms. We can now address how to establish a comprehensive pharmacologic liability tool kit for structure liability relationship studies and how to build connectivity between cause and effect.
9:25 Stem Cell Cardiomyocyte Screening
Craig T. January, M.D., Ph.D., Professor, Medicine and Physiology, Division of Cardiovascular Medicine, University of Wisconsin, Madison
9:55 Networking Coffee Break
10:25 Development of Translatable Biomarkers for Cardiovascular Safety
Jennifer Colangelo, Ph.D., Associate Director, Drug Safety R&D, Pfizer Global Research and Development
Safety biomarkers are an integral part of the decision-making process for drug development at all stages, aiding in compound selection for early pre-clinical studies and ensuring patient safety in clinical trials. Mass spectrometry is one of the critical tools for safety biomarker discovery, development and deployment, providing assays that are often easily translatable between species. This presentation will provide examples of mass spectrometry applications to the development of biomarkers for drug-induced cardiovascular toxicity, including MS-based metabonomics for biomarker discovery and stable label approaches for the quantitation of novel proteins.
10:55 Pre-Clinical Strategies for De-Risking the Potential of Cardiovascular Toxicity
Peter Hoffmann, M.D., Ph.D., Executive Director, Pre-Clinical Safety and Co-Chair, Translational Cardiovascular Advisory Team, Novartis Institutes for BioMedical Research
The introduction of in vitro and in vivo cardiovascular safety tests as suggested by guidelines S7A and S7B was successful in preventing acute and catastrophic effects in Phase 1 studies, primarily in healthy male volunteers. On the contrary, recent experiences show that the manifestation of human cardiovascular adverse effects during late stage clinical development or post-marketing is poorly predicted. The presentation summarizes current status and emerging trends of preclinical strategies for de-risking the potential of cardiovascular toxicity in the target population, e.g., diabetic patients.
11:25 Biologicals and Cardiac Toxicity Risk: Relating Toxicity to Mechanism of Action
Noël Dybdal, Ph.D., D.V.M., D.A.C.V.P., Associate Director, Principal Scientist, Safety Assessment, Genentech, Inc.
High molecular weight biological therapeutics in general and monoclonal antibodies specifically are highly targeted in their activity and risk of off-target toxicity is low. Adverse cardiovascular effects associated with these drugs to-date result from on-target pharmacology and relate to their mechanism of action. Species specificity of biologics presents challenges that limit the extent to which cardiotoxicity risk can be assessed preclinically. However, novel approaches including in vitro strategies are increasingly offering better opportunities for focused safety assessments. This presentation will include case studies as examples of preclinical cardiac toxicity assessments for biologicals of various types.
11:55 Luncheon Presentation
Multiplex Biomarker Assays for Kidney and Liver Toxicity
Pankaj Oberoi Ph.D., Director of Scientific Services & Director of Qualified Kit Development, Meso Scale Discovery
Protein expression fingerprints of various biological samples can be used for measuring drug efficacy and toxicity and for target selection. Multiplexing has the advantage of rapidly measuring levels of multiple analytes from a limited sample volume, which is critical for preclinical and clinical studies where samples are precious and often limited. There are numerous challenges to overcome during the development and validation of biomarker assays and these challenges are magnified when considering multiplex biomarker assays. MESO SCALE DISCOVERY® is focused on the development and validation of multiplex biomarker assays to serve the safety biomarker community. A description of novel assays for human and rat kidney biomarkers as well as rat liver biomarkers will be discussed.
12:25 pm Luncheon Presentation II
(Sponsorship Opportunitiy Available)
1:30 Chairperson’s Remarks
Vivek Kadambi, Ph.D., Senior Director, Drug Safety Evaluation, Millennium, The Takeda Oncology Company
1:35 Evolving Trends in Pre-Clinical Cardiac Safety: Gazing into the Crystal Ball
Gary Gintant, Ph.D., Senior Group Leader, Integrative Pharmacology, Global Pharmaceutical Research & Development, Abbott Laboratories
Increasing emphasis on the safety of novel drug candidates demands more efficient discovery and development efforts with a balanced focus on risk/benefit considerations. This goal will be realized only with a) early “frontloading” of appropriate assays to derisk compounds early in discovery, b) an understanding of the strengths and limitations of present (and evolving) assays, and c) an appreciation of present and emerging cardiac safety issues within the context of drug efficacy in development. This presentation will provide some instructive preclinical examples of where we have succeeded present-day gaps in our understanding, and future challenges for pre-clinical cardiac safety.
2:05 Does it Help or Hurt to Know Cardiovascular Biology?
Douglas B. Sawyer, M.D., Ph.D., Lisa M. Jacobson Professor of Medicine and Chief, Cardiovascular Division, Vanderbilt University Medical Center
2:35 You Don’t Give Drugs to Normal People, so Why Search for Toxicity in Normal Animals?
Robert Hamlin, Ph.D., Professor, Veterinary Biosciences, Ohio State University
It is important to search for potential risks of drugs in subjects possessing the clinical substrates for which they are indicated. Heart failure, ventricular hypertrophy, and diabetes are present in many persons manifesting drug toxicity, therefore it appears reasonable to search for potential toxicity in animals afflicted with them. Furthermore it is essential to interrogate all physiological parameters that if, affected by a drug may translate to morbidity and/or mortality. In models of rabbits and dogs possessing hypertophy and heart failure, sensitivity to detect drug toxicity is improved dramtically over studies conducted in normals, and specificity does not appear to be reduced signficantly.
3:05 Innovative Approaches for Monitoring Cardiotoxicity
Abdel-Ilah El Amrani, Ph.D., Head, Safety and General Pharmacology, CiT-Safety & Health Research Laboratories
Cardiovascular toxicity is one of the major causes for drug attrition in the pre-clinical or clinical phases. An overview of the most significant surrogate biomarkers in early safety pharmacology screening, in safety endpoints in regulatory toxicology and in safety pharmacology will be presented. These surrogates have actively contributed to a significant reduction in drug discontinuation for cardiovascular safety reasons in clinical phase I.
3:20 Sponsored Presentation (Opportunity Available)
3:35 Grand Opening Refreshment Break in the Exhibit Hall
4:35 FEATURED PRESENTATION: Pre-Clinical Strategies for Predicting and Preventing Cardiotoxicity
Thomas Force, M.D., Professor of Medicine and Clinical Director of the Center for Translational Medicine, Thomas Jefferson University
Despite intense interest in strategies to predict which tyrosine kinase inhibitor (TKI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Herein I will explore a variety of pre-clinical models, starting with “best guess” approaches (virtual cardiotoxicity) based on what we do, and do not know about the role of protein kinases in maintaining homeostasis in the heart. I will also discuss various pre-clinical models, highlighting pros and cons of each. Finally, I will focus on the zebrafish as a pre-clinical model, and present some recent data suggesting it may be a viable tool for prediction and for defining mechanisms of cardiotoxicity.
5:05 PANEL DISCUSSION: Minimizing the Disconnect Between the In Vitro and In Vivo Worlds
Moderator: Vivek Kadambi, Ph.D., Senior Director, Drug Safety Evaluation, Millennium, The Takeda Oncology Company
5:35 - 6:30 Happy Hour in the Exhibit Hall
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