Periodic Reporting for period 1 - INSPIRE (INnovation in Safety Pharmacology for Integrated cardiovascular safety assessment to REduce adverse events and late stage drug attrition.) Reporting period: 2020-01-01 to 2021-12-31 Summary of the context and overall objectives of the project New drug candidates often have off-target effects resulting in adverse events, thus representing a major limitation for drug R&D. Safety pharmacology aims to detect, understand and reduce undesirable pharmacodynamic effects early-on. Especially, cardiovascular toxicity is problematic, as it is the most prevalent reason for failure during preclinical development. Moreover, cardiovascular toxicity remains a key reason for drug attrition during clinical development and beyond. While the discipline of safety pharmacology has been successful in identifying drug-induced proarrhythmia risk, new forms of functional and structural (often more chronic) cardiovascular toxicity have emerged. These new cardiovascular liabilities call for new tools for risk identification, assessment and mitigation. Additionally, safety pharmacology uses a significant number of laboratory animals, thereby creating opportunities for a better implementation of the 3Rs in animal experimentation. The vision of INSPIRE is to extend the toolbox for preclinical safety evaluation by exploring novel technologies and by turning these into new products or services for improved evaluation of drug-induced cardiovascular toxicity. This way, INSPIRE will contribute to more efficiency in drug development and will protect patients from experiencing cardiovascular adverse events.In addition, INSPIRE constitutes a highly stimulating, multidisciplinary and intersectoral training programme for 15 early-stage researchers (i.e. PhD students). Through a balanced combination of hands-on research training, intersectoral secondments, local courses and network-wide events INSPIRE will equip the future generation of safety pharmacology scientists with a wide range of scientific knowledge and professional skills. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During the reporting period, research activities were performed along 3 axes (defined as work packages): (1) Exploring novel technologies and platforms for cardiovascular safety evaluation, (2) Investigating mechanisms of newly emerging cardiovascular safety concerns (often linked to anti-cancer therapies), and (3) Progress results towards tangible and validated solutions (commercial products or services) for cardiovascular safety screening. Additionally, a substantial number of training activities were organised to improve the scientific background of the early-stage researchers, and to develop essential professional skills and an entrepreneurial attitude.The main activities and results achieved so far can be summarized as follows:• Progress was made towards an optimized protocol for reproducible differentiation and maturation of human pluripotent cell (“human induced pluripotent stem cells, hiPSC”) into cardiomyocytes for safety evaluation. • Development and validation of hiPSC cardiomyocyte-based assays (e.g. based on high-throughput imaging, contractility assessment and molecular markers) to evaluate structural and functional cardiovascular toxicity after (chronic) drug exposure.• Comparison of different machine learning strategies to speed-up the analysis of large electrophysiology (MEA) datasets and to assess predictive value and computational cost.• Development of novel hardware and software prototypes to enable simultaneous evaluation of cardiovascular physiology and behavioural treats in awake socially interacting animals. To this end, different strategies for tracking of animals (e.g. video capture or localisation technology) were evaluated and will be combined with algorithms for automated classification of behaviours.• Prototype numerical models for in silico simulation of haemodynamics were delivered and are ready for further iteration based on real-life experimental inputs.• Mass spectrometry imaging (MSI) has been applied to quantify drug-exposure in different organs (including the heart) and will be coupled with proteomics in upcoming work.• New approaches for the evaluation of drug-induced haemodynamic changes have been explored such as arterial stiffness and local (blood)flow patterns.• Moreover, research was initiated towards mechanisms of cardiovascular toxicity related to anti-cancer drugs, such as tyrosine kinase inhibitors and doxorubicin. • Along the same line, biomarkers have been explored, both functional and molecular ones, to identify specific patient populations at risk of cardiovascular toxicity.• Regular meetings fostered interaction between scientist from academia, pharma industry, technology vendors, as well as regulatory agencies. This unique setting has provided the early-stage researchers with invaluable insights and excellent opportunities to develop themselves. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Based on the project’s progress so far, we believe that INSPIRE is on track to achieve its ambition to extent the toolbox for cardiovascular safety evaluation, add novel mechanistic insights in cardiovascular adverse events, and eventually contribute to the development of effective, yet safe, therapies for patients. Importantly, we expect an economic return as well, given the substantial engagement of industry and the promising results so far. Moreover, the complementary composition of the network (i.e. pharma companies, technology providers, CRO’s and other stakeholders) facilitates the path-to-market, given the unparalleled insights into market opportunities, possible (regulatory) hurdles and validation requirements. Finally, in addition to its direct scientific and socio-economic impact, we also anticipate a long-lasting impact of the INSPIRE network mainly by training the future generation of safety pharmacology scientist with a holistic view on safety science and an innovation-oriented attitude that have the ability to adapt to a dynamic ever-changing industry. The INSPIRE family
