ADME-Tox Strategies to Accelerate Drug Discovery 

Anders Sonesson PhD Senior Research Scientist Ferring Pharmaceuticals

Presentation Title

ADME Strategies for Peptide Drugs

Abstract

ADME strategies for peptides depend on (1) size of the peptide, (2) structure of the peptide, (3) amino acid constituents, natural or artificial amino acids, (4) the indication whether acute or chronic and (5) severity of disease for which the drug is aimed. Regulatory guidelines poorly describe requirements for peptides as they fall in the grey zone between small molecules and biopharmaceuticals. Using case studies for both agonistic and antagonistic peptide drugs, different ADME strategies will be discussed.

Biography

Anders received his PhD in Analytical Chemistry from Lund University in 1990. For the last 27 years, Anders has been working in the Pharmaceutical industry, with the last 24 years at Ferring Pharmaceuticals, and mostly within DMPK.

Paul Walker PhD VP, Head of Toxicology andInnovation Efficiency Cyprotex Discovery Ltd

Presentation Title

The Use of Toxicogenomics (TGx) in Early Pre-clinical Safety Assessment

Abstract

Drug-induced organ toxicity remains a major reason for drug attrition and a primary concern in the development of new drugs. A variety of in vitro models, such as organotypic three-dimensional (3D) microtissues combined with High-Content Imaging (HCI), have been developed to de-risk in early drug discovery. It is possible to gain an enhanced mechanistic understanding of off-target cellular effects by combining the most predictive and physiologically relevant in vitro models with analysis of the cellular transcriptome.

In this presentation, we show how predictive toxicogenomics (TGx) combined with organotypic cell-based models and machine learning can be used to profile novel chemical entities to determine their safety profile, and if a liability is observed then to provide a valuable insight into the potential mode of action implicated in a drug’s toxicity.

Biography

Paul Walker is the VP Head of Toxicology and Innovation Efficiency at Cyprotex where he is responsible for the R&D strategy, operations and study management performed within the Toxicology Group. Paul obtained his PhD from King’s College London in Molecular Toxicology and was awarded the Tadion-Rideal prize for molecular sciences (2004). Paul joined Cyprotex in 2010 with his research interests focused on the role of drug metabolism in drug toxicity and in vitro assays to predict toxicity in early drug discovery. His team is focused on: 1. Developing and evaluating novel cellular systems to improve the prediction of toxicity. 2. Evaluate current industry utilized mechanistic endpoint assays in predicting toxicity. 3. The importance of drug metabolism and appropriate cellular models in our mechanistic understanding of toxicity. 4. Integrating in vivo exposure in interpretation of in vitro data, and 5. Modelling approaches combining ADME, PK, Omics technologies and in vitro Tox assays to predict toxicity.

Janne Koch DVM, PhD Manager, Safety & Lab Animal Research LEO Pharma A/S

Presentation Title

LEO Pharma Early Toxicology Strategy

Abstract

At LEO Pharma, the early tox assessment is based on literature and in silico approaches combined with screening in cellular systems. Extensive profiling of the drug candidates is performed before testing in vivo due to both ethical concerns i.e., the 3Rs and also compound requirements.

The screening cascade is initiated by testing compounds in simple cytotoxicity assays such as HepG2. As the number of compounds are reduced and more compound is available, the complexity of the assays is increased by including more endpoints, by increasing exposure time and by moving into primary cells and 3D cell systems. Comparing outcomes from compound testing in 2D versus 3D model systems is still being performed and hence the early screening strategy is currently under revision due to new cellular test systems.

In addition, the strategy also includes an extensive off target profiling against GPCRs, kinases, transporters, enzymes etc. and an assessment in mechanistic genotoxicity assays. Ultimately the compounds are tested in rodent studies to investigate how the in vitro findings manifest in an animal.

Biography

Janne Koch is the manager of the department ‘Safety and Lab Animal Research’ in Research and Early Development at LEO Pharma. In this position she is responsible for early toxicology from target safety assessments of potential new targets to selection of a drug candidate for preclinical development. Her research interests include in vitro to in vivo translation, immunotoxicology and pathology. Prior to joining LEO Pharma in 2015, Janne received her PhD from the University of Copenhagen, where she conducted research within cancer immunology in a mouse model for cancer resistance. In addition, she has been involved in many research projects with inflammation models. Janne is an author and co-author of 19 peer-reviewed scientific publications.

Phil Butler PhD VP, Head of ADME, Physical Chemistry and Analytical Sciences Cyprotex Discovery Ltd

Presentation Title

From Small Molecules to New Modalities – The Changing Landscape of ADME Screening

Abstract

Our knowledge of the links between specific biological targets and disease has increased substantially over the last 20 years. Many of the new targets being identified are considered undruggable using traditional small molecules and this has led to the development of a variety of new modalities to address this challenge. Standard screening approaches for these new modalities are either unsuitable or irrelevant, and experimental design, screening strategies and analytical methods need to be considered carefully. In this presentation, we discuss the impact of new modalities on ADME screening strategies with a particular focus on PROTAC technology.

Biography

Phil Butler is the VP Head of ADME, Physical Chemistry and Analytical Sciences at Cyprotex where he is responsible for the R&D strategy and operations. Phil obtained his PhD from the University of Liverpool where he studied the role of drug metabolism in toxicity. In 2006, Phil joined Cyprotex, initially in the drug metabolism department and later progressing to Head of ADME before taken on his current role in 2021. Phil has been instrumental in the growth and success of the team aligning it to business needs and future strategy.