Industry Hosted Sessions

Monday, September 19, 2022

12:00 PM - 13:00 PM

Chairperson(s): Abby Li (Exponent, Inc., USA)

Glyphosate products are widely used to combat weeds in agriculture and horticulture. Neurological outcomes spanning the age spectrum, including neurodevelopmental disorders and chronic neurodegenerative diseases such as Parkinson disease, have become increasingly prominent issues in human health risk assessments of pesticides, including glyphosate. Since glyphosate is measured in a number of food products and water sources, systematic reviews of the human epidemiological and animal neurotoxicology studies are needed to evaluate the potential neurotoxicity of glyphosate. This symposium will begin with a brief introduction of exposure considerations that are key to evaluating the quality and relevance of human and animal studies for risk assessment purposes. This will be followed by two lectures on the current state of the human and animal literature on the effects of glyphosate exposures on neurological outcomes. A weight-of-evidence approach with a priori quality criteria will be described, the results of the analysis by two separate panels of epidemiologists and neurotoxicologists will be summarized, and recommendations for how future studies can be more useful for risk assessment purposes will be discussed.


Abby Li (Exponent, Inc., USA):
The Who What Why of Glyphosate Exposure in Evaluating Neurotoxicology Studies for Risk Assessment (Intro)

Ellen Chang (Exponent, Inc., USA):
Application of US EPA Office of Pesticide Programs (OPP) Framework for Evaluation of Human Epidemiological Literature on Glyphosate Neurotoxicity

Virginia Moser (Independent Consultant, USA); Jason Richardson (Robert Stempel College of Public Health and Social Work at Florida International University, USA); Keith Morris-Schafer (Exponent, Inc., USA); Abby Li (Exponent, Inc., USA):
Expert Panel Review of the Neurotoxicology of Glyphosate in Mammalian Systems for Risk Assessment Purposes

Chairperson(s): Thierry Langer (University of Vienna, AT), Jacques Richard (Sanofi Aventis, FR)

The adverse effects of pharmaceuticals on the central or peripheral nervous systems are poorly predicted by the current in vitro and in vivo preclinical studies performed during Research and Development (R&D) process. Therefore, increasing the predictivity of the preclinical toolbox is a clear need, and would benefit to human volunteers/patients (safer drugs) and Pharmaceutical Industry (reduced attrition). By combining top level scientists in neurobiology/toxicology with successful software developers, the NeuroDeRisk | Neurotoxicity De-Risking in Preclinical Drug Discovery Consortium will aim at tackling three of the most challenging adverse effects: seizures, psychological/psychiatric changes, and peripheral neuropathies. Our approach will be global, starting with an in-depth evaluation of knowledge on mechanisms of neurotoxicity (biological pathways as well as chemical structures and descriptors, using in particular historical data). Then we will search
for innovative tools, assays and studies covering in silico, in vitro and in vivo approaches. This will include in particular:
molecular design platform, artificial intelligence, human induced pluripotent stem cells, blood-brain-barrier models, immunohistochemistry, transcriptomics, RNA editing biomarkers, video-monitoring and telemetry of animals, pharmacokinetics, etc. The last step will aim at combining these tools in an integrated platform for better risk-assessment and decision-points throughout R&D process, and thus better protection of human volunteers and patients.


Thierry Langer (University of Vienna, AT):
Overview of the Innovative Medicines Initiative NeuoDerisk Project

Ludmilla Mazelin-Winum (Sanofi R&D, FR):
Work Package 1 – Improving the Preclinical Prediction of Seizures

JoĂŁo Pedro Silva (UCIBIO-REQUIMTE, Faculty of Pharmacy, University of Porto, PT):
Work Package 2 – Improving the Preclinical Prediction of Psychological/Psychiatric Adverse Effects

Lorenzo Do Cesare Mannelli (University of Florence, IT):
Work Package 3 – Improving the Preclinical Prediction of Peripheral Neuropathies

Sharon Bryant (Inte:Ligand Software Enwicklungs und Consulting GmbH, AT):
The NeuroDeRisk Toolbox: DeRisking Chemical Structures for Neurotoxic Adverse Outcomes

Chairperson(s): Janet Kelly (WuXi AppTec, USA)

What is animal welfare and why is it important during your toxicology program? There are excellent opportunities to advance the welfare of animals by eliminating pain and distress, and systematically reducing the number of animals necessary for individual studies by implementing the 3Rs.


Janet Kelly (WuXi AppTec, USA):
The Importance of Animal Welfare During Your Toxicology Program

Tuesday, September 20, 2022

12:00 PM - 13:00 PM

Chairperson(s): Lorna Ewart (Emulate, Inc., USA) There is no doubt that scientific progress has accelerated the discovery and development of innovative medicines, a phenomenon acutely visible through the rapid advancement of vaccines against SARS-CoV-2. Outside of dealing with a global pandemic, the process of drug discovery and development remains painfully slow, extremely costly and can, despite appropriate measures, result in patient-safety concerns. Because only around 12% of drugs that enter clinical trials make it to approval, governments in the United States and Europe are taking steps towards modernizing the process of drug discovery and development. Whilst several solutions will ultimately be required, there are growing calls for the utilization of 21st century tools within drug discovery pipelines. One such tool is organ-on-a-chip technology that employs microfluidic systems engineering to recapitulate in vivo cell and tissue microenvironments in an organ-specific context. This is achieved by recreating tissue-tissue interfaces and providing fine control over fluid flow and mechanical forces, optionally including supporting interactions with immune cells and microbiome, and reproducing clinical drug exposure profiles. This seminar will showcase the Emulate Organ-Chip platform and will present the findings of the first of its kind Organ-Chip study which utilized the pharma consortium Innovation and Quality (IQ) roadmap for developing in vitro liver models for the prediction of drug-induced liver injury1. Using 780 Liver-Chips across a test set of 27 small molecule drugs, data will be presented indicating that the Liver-Chip has a 87% sensitivity and 100% specificity, thus making it a highly predictive tool compared to animal models and prior preclinical in vitro models. The seminar will complete with an overview on how such a tool can be implemented into drug discovery workflows whilst providing adopting organizations a significant productivity gain. Reference: 1. Baudy et al., (2020) Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry Lab Chip, 20, 215 Presentations: Sasha Berdichevski (Emulate, Inc., USA) Modernizing Drug Discovery & Development with Organ-Chip Technology

Chairperson(s): Andy Forreryd (SenzaGen AB, SE)

The field of in vitro skin sensitization assessment is rapidly evolving, and novel methods are developed to increase predictivity, broaden the applicability and to provide reliable quantitative and qualitative potency assessments. This symposium will introduce the audience to GARD®, the genomic-based technology, and discuss the new opportunities it brings to the field of in vitro skin sensitization testing.

The session will start with an introduction to the key elements of the GARD technology followed by reviewing the performance and applicability of the GARDskin assay for in vitro skin sensitization testing. Results from the assessment of “difficult-to-test” samples including metals, complex mixtures, pre- and pro-haptens, surfactants and hydrophobic substances will be presented. Moreover, the capability of GARD for quantitative skin sensitizing potency assessment will be exemplified by several industry-sponsored case studies.

In summary, this symposium will highlight the performance and applicability domain of GARD and discuss its potential for addressing remaining challenges within R&D and regulatory skin sensitization testing.

Learning objectives
The participants will have the opportunity to learn more about the following:

  • Key elements of the GARD technology.
  • Quantitative potency assessments on a continuous scale for use as point-of-departure in already established risk assessment procedures.
  • The applicability domain of GARDskin and its performance for “difficult-to-test” samples including metals, complex mixtures, pre- and pro-haptens, surfactants and hydrophobic substances.
  • User cases from industry-sponsored studies to exemplify how GARD can be used for R&D and regulatory testing.

About the GARD technology platform
GARD – Genomic Allergen Rapid Detection® – is a next-generation, non-animal-based testing platform for identification and potency assessment of chemical sensitizers. The GARD platform brings novel elements to the field of regulatory toxicology, and integrates state-of-the-art technological components, including human immunological cells, specific genomic biomarker signatures and machine learning-assisted classification models. As a result, GARD comprises an accurate, cost-effective and efficient method for assessment of skin sensitizing properties of neat chemicals, complex mixtures and medical devices and may successfully be applied throughout the product life cycle.


Andy Forreryd (SenzaGen AB, SE):
In vitro skin sensitization testing: new opportunities for hazard and quantitative potency assessment using genomics and machine learning technolog

Chairperson(s): Adrian Rea (CN-Bio Innovations Ltd, UK) Adverse drug reactions in the liver remain a major clinical problem, causing unforeseen late-stage failures in the clinical phases of drug development and post-approval. It is clear from the statistics that the standard preclinical in vitro and in vivo drug-induced-liver-injury (DILI) models are poorly predictive, particularly for molecules with highly human-specific mechanisms of toxicity. DILI as it occurs in humans, is a multi-cellular and multi-stage process. Simple tools, such as single-cell culture-screening strategies, lack the physiological relevance required to model this process in vitro. In vivo animal studies capture the complexity of a living organism but lack human-relevance. What’s missing is a complimentary tool to bridge this “relevance” gap and improve the predictability of data from the laboratory into the clinic. In response, the last decade has seen a rapid rise in the development of 3D, multi-cellular and microfluidic-based tools for modelling the human liver, including the development of organ-on-a-chip (OOC), also known as microphysiological systems. Liver OOC enable the culture of primary human liver cell types for extended periods of time in a physiologically relevant microenvironment to recapitulate tissue and organ-level functionality more accurately. OOC provide unique capabilities and insights over and above what is possible using the current preclinical toolbox to:
  • Derive clinically relevant translational end point measurements
  • Avoid missing rare or human-specific metabolites
  • Generate mechanistic signatures of toxicity
  • Model the effects of acute and chronic dosing regimens
  • Assess DILI responses of specific patient populations (e.g. patients with fatty liver disorders)
  • Understand interactions between organs, such as inflammation, which drive disease and enhance certain toxicities
In this session, the challenges of predicting DILI as well as some of the new tools available for understanding the mechanistic basis of human responses will be discussed from the perspective of the pharmaceutical industry and an organ-on-a-chip developer. Presentations: Tomasz Kostrzewski (CN-Bio Innovations Ltd, UK): Predicting human responses to drug toxicants using liver-on-a-chip technology Sebastian Prill (Safety Innovation, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, SE): Enhancing the early detection of safety liabilities of new therapies to advance drug development
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