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. So what can scientists do to make sure that the lead compounds are optimized and validated early and accurately to avoid costly mistakes from happening
later? Cambridge Healthtech Institute’s inaugural conference on Optimizing Leads and Predicting Drug Toxicity, looks at the scientific and technological progress being made to better optimize drug candidates and accurately predict drug related
toxicities, early in drug development. What assays and models are being used, how reliable and predictable is the data, and how is this information translated into knowledge that then impacts decision-making? Hear experiences shared by experts and
join the interactive sessions and panel discussions for active networking, brainstorming and collaborating.
Day 1 | Day 2 | Download Brochure | Speaker Biographies
14 - 15 November: Mastering Medicinal Chemistry
15 - 16 November: Optimizing Leads and Predicting Drug Toxicity
15 November Dinner Short Course*: (SC2) New Technologies for Improving Drug Safety Screening
*Separate registration required.
Tuesday 15 November
12:00 Registration
13:30 Chairperson’s Opening Remarks
Gerry Kenna, Ph.D., Pharmaceutical Director, Safer Medicines Trust and Drug Safety Consultant
13:35 Impact of Early Detection of Drug Side Effects on Drug Development
Berengere Dumotier, Ph.D., Secondary Pharmacology Expert, Safety Pharmacology,
Novartis Institutes for Biomedical Research
The identification of the most important targets linked to undesired side effects is a key step in compound selection process. The use of accumulated knowledge on such targets is necessary for optimizing the chemical series much before a compound reaches
the clinic. How to best share the knowledge and provide a translational value to this information will be the main topics of this presentation.
14:05 A Novel Fast Orthogonal Search Method to Identify a Compound’s Mechanism of Action
Philippe Marc, Ph.D., Global Head of Preclinical Informatics, PreClinical Safety, Novartis
Institutes for BioMedical Research
Better understanding of the mechanism of action and toxicity of small molecules would lead to a more rational drug design, and presumably also to safer and more efficacious drugs. Within Novartis, large amounts of data have been collected in service of
this goal. However, it often remains tricky to assemble a “bottom line” conclusion. I will present the MoA Central search we use to facilitate our explorations.
14:35 Pharmacogenetics of Cytochrome P450: In silico Prediction of the Impact of Amino Acid Variants of CYP2C9 for Drug Metabolism
Maxime Louet, Ph.D., Post-Doctoral Fellow, Laboratory of Dr. Bruno Villoutreix, Molécules
Thérapeutiques in silico (MTi), French National Institute for Health and Medicine Research (INSERM) / University Paris Diderot
We will present the Cytochrome P450 enzyme and its central role in drug metabolism and pharmacogenetics. The malfunction of cytochromes, due to single nucleotide polymorphism, could lead to decreased metabolism of drugs causing drug toxicity, or affected
prodrug activation. We will present an in silico protocol to predict the effect of Cytochrome P450 mutations on the drug metabolism. As an example, we will present a specific natural variant of the Cytochrome P450
2C9 on the metabolism of selected approved drugs.
15:05 Refreshment Break in the Exhibit Hall with Poster Viewing
15:45 Large-Scale Predictive Drug Safety
Jordi Mestres, Ph.D., Head, Systems Pharmacology Group, IMIM-UPF Joint Research Programme
on Biomedical Informatics, and Associate Professor at the Universitat Pompeu Fabra (UPF), Spain
The recent explosion of data linking drugs, proteins, and pathways with toxicity has promoted the development of integrative systems approaches to large-scale predictive drug safety. Beyond the traditional identification of potentially labile chemical
fragments for a limited number of selected toxicity endpoints, it will be shown that it is now possible to gain mechanistic insights for a much larger and diverse set of safety events.
16:15 KEYNOTE PRESENTATION:
Using Quantitative Systems Toxicology (QST) to Assess and Manage Drug Safety
Paul B. Watkins, M.D., Director, Institute for Drug Safety Sciences, Howard Q. Ferguson Distinguished
Professor, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
Translating safety data obtained by in vitro systems into quantitative risk assessments in specific patient populations remains a challenge. The DILI-sim Initiative is a public-private partnership that consists of scientists
from 12 major pharmaceutical companies, the FDA, and academia. The models resulting from this effort have successfully employed QST approaches to predict incidence and severity of hepatotoxicity in patients, and to inform risk management strategies.
17:00 Evaluation of the Applicability of Microsampling for Metabolite Identification
Janne Mannila, Ph.D., Senior Scientist, Permeability and in vivo DMPK, Admescope
17:15 Interactive Breakout Discussion Groups
Topic: Lost in translation?
Moderator: Philippe Marc, Ph.D., Global Head of Preclinical Informatics, PreClinical Safety, Novartis Institutes for BioMedical Research
- Integrating early safety data. What are the goals? How to get translational?
- In silico modeling for safety. What works today? Where are we going tomorrow?
Topic: Novel In vitro Tools for Safety Testing
Moderator: Philip Hewitt, Ph.D., Head of Early Investigative Toxicology, Non-Clinical Safety, Merck KGaA
- Experience with stem cell derived models for early toxicological assessments
- Microphysiological systems: what are they good for?
Topic: How and When To Use "Non-standard" Toxicity Assessment Tools
Moderator: Gerry Kenna, Ph.D., Pharmaceutical Director, Safer Medicines Trust and Drug Safety Consultant
- Compound design. Are there useful toxicology structural alerts?
- What to prioritize?
- When? Routine high volume screens vs. bespoke low throughout methods. Integrating in vitro toxicity assessment alongside ADME profiling/optimization
18:15 Close of Day
18:30 – 21:00 Recommended Dinner Short Course*
(SC2) New Technologies for Improving Drug Safety Screening
* Separate registration required
Day 1 | Day 2 | Download Brochure | Speaker Biographies
Wednesday 16 November
8:00 Registration
8:25 Chairperson’s Remarks
Paul B. Watkins, M.D., Director, Institute for Drug Safety Sciences, Howard Q. Ferguson Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
8:30 Integrating Data from Multiple in vitro Methods Enables Prediction of Serious Human Adverse Drug Reactions
Gerry Kenna, Ph.D., Pharmaceutical Director, Safer Medicines Trust and Drug Safety Consultant
Although Adverse Drug Reactions (ADRs) are a leading cause of human illness, they cannot be detected from toxicity studies undertaken in animals. ADRs are initiated by chemical insults, which can be assessed using in vitro methods. I shall describe a multi-parametric test cascade that enables highly sensitive and specific identification of unsafe drugs and has the potential to aid the development of safe new drugs.
9:10 Key Challenges and Opportunities Associated with the Use of in vitro Models to Detect Human Drug Associated Liver Injury (DILI)
Franck Atienzar, Ph.D., Associate Director in silico, in vitro Toxicology, Non-Clinical
Development, UCB BioPharma SPRL
Despite considerable efforts, limited improvements in drug-induced liver injury prediction have been made during the last decade. Efforts to improve existing preclinical models or develop new test systems remain a high priority. The presentation will
provide an overview of some of the key challenges associated with data interpretation, practical considerations, model limitations, and the need for an integrated risk assessment. Opportunities exist for improvement and harmonization of
in vitro systems.
9:50 Human-on-Chip Systems for Lead Optimization in Drug Discovery
James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and
Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
Phenotypic screening systems for pre-clinical applications have the advantage of providing useful information without a known target for the compounds to be tested. Human-on-chip systems can potentially bridge the gap between current phenotypic animal
models and human systems. They also give the possibility of target identification, thus making the process of lead optimization more efficient, which could lead to a higher number of successful clinical trials.
10:30 Coffee Break in the Exhibit Hall with Poster Viewing
11:15 The Application of Stem Cells in Drug Safety Science: What Do We Need and Why Do We Need Them?
Christopher Goldring, Ph.D., Professor, Molecular and Cellular Pharmacology,
MRC Centre for Drug Safety Science, University of Liverpool, U.K.
Preclinical testing does not predict some adverse reactions. Efforts at improving predictability of drug-induced injury include stem cell technology to generate cells for drug screening. This talk will explain the background to this area, using liver
as a paradigm. The issue of what kind of cells we need will be discussed in the context of what we understand of human drug-induced injury, and why this is important to ensure that the cells are relevant.
11:45 Physiological and Toxicological Evaluation of Advanced in vitro 3D Liver Models for Toxicological Profiling
Philip Hewitt, Ph.D., Head of Early Investigative Toxicology, Non-Clinical Safety,
Merck KGaA
Drug induced liver injury remains a burden to the public, the pharmaceutical industry and regulators. Therefore, there is an urgent need for better, reliable mechanistically-based predictive cell-based assays. Hepatocytes grown in 3D (e.g., spheroids)
have improved morphology and hepatotoxicity-specific responses and are now being used to assess inflammatory related DILI, choleastasis, steatosis and mitochondrial dysfunction. In addition, the use of iPSC derived hepatocytes will be discussed.
12:15 PANEL DISCUSSION: Breaking Down Silos: Updates on New Initiatives, Consortia & Collaborations
Moderator: Paul B. Watkins, M.D., Director, Institute for Drug Safety Sciences, Howard Q. Ferguson Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
Panelists:
Franck Atienzar, Ph.D., Associate Director in silico, in vitro Toxicology, Non-Clinical Development, UCB BioPharma SPRL
Philip Hewitt, Ph.D., Head of Early Investigative Toxicology, Non-Clinical Safety, Merck KGaA
Philippe Marc, Ph.D., Global Head of Preclinical Informatics, Preclinical Safety, Novartis Institutes for BioMedical Research
12:45 Enjoy Lunch on Your Own
14:15 Chairperson’s Remarks
Maria L.H. Vlaming, Ph.D., Vice President Technoogy, Pluriomics BV
14:20 Validation Results of a Multiscale Simulation Model for the in silico Prediction of Cardiosafety
Alexander Amberg, Ph.D., Computational Toxicologist, R&D Preclinical
Safety, Sanofi, Germany
The CiPA initiative proposes the assessment of the proarrhythmic potential of drugs combining ion channel in vitro data coupled to in silico reconstructions of the cardiac action
potential. The eTOX consortium has developed such a multiscale simulation in silico model based on O’Hara/Rudy. This presentation will show that this in silico model
can successfully be applied in R&D based on a validation using Purkinje fiber results from 500 in-house drug candidates.
14:50 Characterization of hiPSC-Cardiomyocyte Calcium Transient Technology and Its Application in Safe Drug Selection
Ard C.H. Teisman, Ph.D., Scientific Director, Global Safety Pharmacology, Discovery
Sciences, Janssen Research & Development
Currently, the field of cardiovascular safety pharmacology is rapidly evolving. Due to the CIPA initiative, there’s a drive to explore human iPSC derived cardiomyocytes to predict proarrhythmic liabilities. Multiple methods to assess cardiomyocyte
function have been explored, among which calcium transient technology is one. This presentation illustrates our approach taken to build confidence in the predictive value for cardiovascular safety of this stem cell technology.
15:20 A Multiparameter Approach to Assess Anti‐cancer Drug Induced Toxicity in hiPSC‐derived Cardiomyocytes
Maria L.H. Vlaming, Ph.D., Vice President Technoogy, Pluriomics BV
Cardiotoxicity is a major cause of attrition during (pre)clinical anti-cancer drug development and a growing concern with increasing survival of cancer patients. An important issue in early cardiotoxicity screening is the lack of relevant models
and assays that can mimic the human cardiovascular system. Using tyrosine kinase inhibitors as an example, I will show how a combination of novel hiPSC-derived cardiomyocyte-based assays can be used for cardiotoxicity testing of pharmaceuticals.
15:50 Close of Conference
Day 1 | Day 2 | Download Brochure | Speaker Biographies