This webinar forms part of the CRACK IT 10 year anniversary celebrations and will showcase the technologies and platforms developed to address the 2013 InPulse CRACK IT Challenge to develop a human-based in vitro system to assess cardiotoxicity in new drugs. The Challenge was sponsored by GlaxoSmithKline (GSK).
The InPulse CRACK IT Challenge aimed to develop a physiologically relevant cardiac contractility platform to identify early in development novel drugs with potential cardiovascular (CV) safety liabilities, one of the most common causes of drug attrition. Multiple different technologies and platforms were developed or advanced to meet this technically demanding challenge. These include three-dimensional engineered heart tissues, fully functional human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a new software platform for the measurement of cardiomyocyte and cardiac muscle contraction. Different lines of hiPSC-CMs, in combination with different platform technologies, were each tested using the same set of compounds provided by the Sponsor. Using this approach it was possible to establish the optimum configuration to assess the cardiotoxic potential of drugs with a focus on cardiac contractility. A typical investigative animal study to assess cardiac contractility of drugs prior to clinical trials would use at least 12 – 24 dogs. Applying the developed in vitro platforms early in drug development could significantly reduce these numbers.
During the webinar, which is free to attend, you will hear from the project leader of the InPulse Challenge and the Sponsor who supported the development and validation of the platforms. There will be an opportunity to ask questions after the webinar presentation.
Professor Chris Denning, Director of the University of Nottingham Biodiscovery Institute and Professor of Stem Cell Biology. Chris led the project team that delivered the Challenge and will describe the various technology platforms developed, their validation and how CRACK IT supported this process. He will also highlight how the technologies have been further developed since the Challenge was completed and their application across different disciplines and sectors.
Dr Peter Clements, Global Head, Comparative and Translational Sciences at GSK. Peter was lead Sponsor of the InPulse Challenge and will describe the rationale behind the Challenge and how GSK will apply the technologies developed to support their decision making relevant to cardiac safety liabilities of new drugs. He will also describe the wider scientific and 3Rs benefits of these models compared to traditional in vitro and in vivo approaches.
The InPulse Challenge, sponsored by GSK and launched in 2013, was to develop a physiologically relevant contractility platform for assessing the cardiotoxic potential of new drugs, one of the leading causes of drug attrition. The model had to use cells that are phenotypically ‘mature’, possess a robust contractile apparatus, move calcium between intracellular and extracellular spaces and metabolically generate substantive amounts of energy.
Current approaches for preclinical assessment of CV safety liabilities rely on highly invasive animal models which provide only indirect measures of contractility. There is no currently validated/qualified human-derived in vitro system for assessing drug-induced changes in contractility under varying levels of physiologic load. The ability to study changes in cardiac contractility in vitro would allow the investigation of potential drug-induced structural and functional changes that may lead to clinical heart failure. This would allow a more accurate prediction of potential drug-induced cardiac toxicity in preclinical and clinical settings and reduce attrition.
The InPulse Challenge was awarded to a team led by Professor Chris Denning (University of Nottingham) to deliver the project: ‘Engineered 2D & 3D hiPSC-CM platforms to detect cardiovascular safety liabilities’.
Further information about the InPulse platforms can be found on the NC3Rs Innovation Platform.