MDC Connects is a series of informative webinars covering the drug discovery process, from our own experts and experts at our CRO network partners.
Lack of efficacy is one of the most important causes of failure in clinical trials. Therefore identifying the biological target for a drug discovery project is one of the most important decisions the project team will make. The safest and most potent molecule will still fail if a team is working on the wrong target for the disease of interest.
In this first webinar, we consider what makes a good target and how we identify them. Dr Davide Gianni from AstraZeneca describes the importance of selecting the right target and the approaches used by AstraZeneca. and Prof. John P. Overington from MDC shows how informatics and data mining demonstrates which targets and target classes have the best chance of success.
The identification of high quality leads is an important step in the discovery of a new drug, but in order to achieve a relevant starting point there are several factors to consider in the design of the assays, the reagents and the compound collection.
In this webinar, Trevor Askwith from Domainex outlines the important factors to consider when embarking on a hit identification programme and the development of a screen. The importance of quality protein, a quality compound collection and good assay design.
Gary Allenby from Aurelia Bioscience provides examples of assays with case studies, focusing on cell based assays and taking a look to the future describing the use of complex assays at this early stage.
And finally, Andrew Pannifer from MDC describes the importance of building and then maintaining a compound collection against which to screen.
Structural biology is a vital tool in the drug discovery pipeline. Proteins are the targets for most marketed drugs, and so uncovering the molecular structure of the biological target to high resolution, researchers can directly visualise the interactions of the target with ligands and compounds, information vital to structure-based drug design.
In this webinar we discuss protein production, compare structural approaches and how structural data may be exploited to support chemistry. Derek Ogg from Peak Proteins describes the ins and outs of generating good quality protein suitable for structural studies with particular reference to X-Ray crystallography. Rebecca Thompson from Astbury BioStructure Laboratory shows how the emerging field of CryoEM can be applied to generate structural information for a wide range of targets, and Martin Slater from Cresset Discovery Services describes how structure based and ligand based software tools can be used to virtually discover, design and optimise compounds.
For a molecule to be worthy of entering preclinical development it needs to have the desired biological activity, as well as DMPK properties and a safety profile appropriate for the targeted therapeutic indication. In this phase of the drug discovery process biologists and chemists work to optimise the properties of the compounds by utilising computational modelling, chemical reactions and synthetic transformations and a suite of biological in vitro assays and in vivo models.
In this webinar we will focus on the methodologies used to establish and optimise the DMPK properties and biodistribution of the molecules. Firstly, Al Dossetter from MedChemica describes how multiple data sources can be used to improve the properties of compounds using in silico drug design and how this method can lead to a good quality candidate drug in fewer iterations. Richard Weaver from XenoGesis outlines examples of DMPK properties of the molecule, how they are assessed, and common mistakes made, providing illustrations of how the issues can be resolved. Finally, Juliana Maynard from MDC describes how imaging technologies can be used to establish the biodistribution and accumulation of the compounds in vivo.
The chemistry discipline is instrumental at all stages of drug discovery, from the creation of diverse or targeted libraries for screening, through design, synthesis, formulation and ultimately the scale up and manufacture of the final drug product.
In this webinar we hear from three chemists. Trevor Perrier from Domainex describes how fragment based drug design can be applied, taking us through a case study which illustrates how low molecular weight fragment hits can be turned into drug candidates. James Hitchin from Charnwood Molecular focusses on synthetic chemistry and the different skills required from early Drug Discovery to Development phases, with particular reference to the way in which transformation maps can be applied to guide decision making. Alison Foster from Quay Pharma describes how the formulation of a compound can be optimised to maximise dose and absorption in preclinical studies and enhance the properties of the API to meet the Target Product Profile in the clinic.
Understanding the pharmacokinetic-pharmacodynamic (PK-PD) relationship in preclinical models is crucial to predicting an efficacious dose regime in man. Preclinical PK-PD analysis investigates the dose-response relationship of exposure and biological effect. The exposure levels of a drug following dosing is quantified using PK analysis in the plasma or target tissue and the measurement of a PD marker show how the drug is acting at the biological target.
In this webinar, Graham Trevitt from XenoGesis describes and explains the principles of PK-PD modelling, how it can be applied in early stage drug discovery and how it supports decision making throughout the life time of the project, increasing in complexity and accuracy with time. Jenny Worthington from AxisBio outlines what a successful PK-PD study should include and draws on case studies to demonstrate the benefit of PK-PD models prior to efficacy studies in preclinical animal models; and finally Neill Gingles from MDC describes the approaches for evaluation of PD endpoints, using non-invasive imaging modalities to visualise and quantify clinical response to a drug.
Project failure due to lack of clinical efficacy during development remains an issue and can in part be attributed to inadequate pre-clinical target validation or clinical translation data.
Target validation is required to build confidence in the biological hypothesis, and the strength of the hypothesis is increased as the complexity of the system increases; from validation in cell lines, to primary cells, to complex cell systems and animal disease models before ultimately efficacy is tested in human clinical studies.
In this webinar, Matt Burnham from MDC describes the importance of confirming target engagement, the ligand-target interaction and its mechanism, and provides examples of methods to measure this. He explains the importance of understanding target engagement in the event of a lack of efficacy to establish whether this is due to the compound not engaging with the target or a failure of hypothesis. Amanda Woodrooffe from Precision for Medicine discusses the advantages and disadvantages of in vitro cell models using primary cells and the importance and relevance of these approaches in modelling native biology in human systems prior to the clinic; and finally Lorraine Mooney from Sygnature Discovery outlines the considerations for in vivo proof of concept studies with reference to experimental design and model choice based on the molecule’s mode of action.
Safety plays a huge part during preclinical development, and any drug must be extensively tested to regulatory standards before approval to test in humans. Safety-related hazards can arise from target-mediated risk, off-target activity, pharmacodynamic effects on the major body systems such as cardiovascular, central nervous and respiratory systems, as well as gross behaviour and pathological changes in animals. Comprehensive testing strategies, combining in vitro and in vivo safety studies enable liabilities of a new molecule to be identified and assessed in line with the clinical patient setting and can significantly influence compound selection, ensure the safety of clinical trial candidates and increase the chances of success.
In this webinar, Richard Knight from Apconix highlights the importance of thinking about safety early in the drug discovery programme; considering target, mechanistic and compound related safety. Pauline Garner from Sequani provides a practical guide to the design of safety studies and considerations of formulation, toxicokinetics, species selection and regulatory requirements. Finally, Malcolm Haddrick from MDC discusses the challenges and opportunities of using complex cell models in early de-risking strategies and toxicity testing.
A common theme throughout our MDC Connects series is that of building confidence in a hypothesis and improving the chances of success in the clinic. To achieve success, the project team needs to understand the key clinical questions and build testable and scientific evidence throughout the preclinical phase employing a clear biomarker strategy. The biomarkers used to transition from the preclinical into the clinical setting will ensure development of robust clinical studies, enabling the monitoring of effects and an understanding of the outcomes.
In this webinar, Gayle Marshall from MDC to sets out the importance of thinking about biomarkers early in your drug discovery project and defining a clear biomarker strategy to address a range of clinical questions. Helen Hind from MDC outlines the importance of clinical samples in R&D and how to access them and finally Russell Garland from Charles River Laboratories discusses biomarkers in the context of immunology and provides examples of how biomarkers can be identified and measured using different platforms and what does validation of a biomarker look like.
Gayle Marshall is Lead Scientist for Biomarkers at MDC. She has extensive experience in clinical and pre-clinical biomarkers, previously leading a translational science laboratory team within large pharma. At MDC, she is responsible for delivering biomarker strategies and developing robust assays for clinical utility through delivering key data to support clinical development.
