Periodic Reporting for period 2 - INSPIRE (INnovation in Safety Pharmacology for Integrated cardiovascular safety assessment to REduce adverse events and late stage drug attrition.)
Berichtszeitraum: 2022-01-01 bis 2024-05-31
New drug candidates often have off-target effects resulting in adverse events, thus representing a major challenge 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 was 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 aimed to contribute to more efficiency in drug development and will protect patients from experiencing cardiovascular adverse events. In addition, INSPIRE constituted a stimulating, multidisciplinary and intersectoral training programme for 15 early-stage researchers (ESRs, i.e. PhD students).
Important outcomes of INSPIRE include: i) refinement of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes assays to evaluate structural cardiotoxicity upon long(er)-term drug exposure, ii) improving in vivo telemetry studies by adding automated blood sampling and behavioural monitoring capabilities, iii) exploration of additional hemodynamic parameters beyond blood pressure and iv) delivering new mechanistic insights in the field of cardio-oncology. Finally, through a balanced combination of hands-on research training, intersectoral secondments and network-wide events INSPIRE has equipped a future generation of safety scientists with a wide range of scientific knowledge and professional skills.
Important outcomes of INSPIRE include: i) refinement of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes assays to evaluate structural cardiotoxicity upon long(er)-term drug exposure, ii) improving in vivo telemetry studies by adding automated blood sampling and behavioural monitoring capabilities, iii) exploration of additional hemodynamic parameters beyond blood pressure and iv) delivering new mechanistic insights in the field of cardio-oncology. Finally, through a balanced combination of hands-on research training, intersectoral secondments and network-wide events INSPIRE has equipped a future generation of safety scientists with a wide range of scientific knowledge and professional skills.
During the project, 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 (products or services) for cardiovascular safety screening. Additionally, a substantial number of training activities were organised to improve the scientific background of the ESR fellows, and to develop essential professional skills and an entrepreneurial attitude.
Main activities and results can be summarized as follows:
• Progress was made towards 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.
• For data-analysis of hiPSC-cardiomyocytes assays, different machine-learning strategies were implemented to speed up analysis of large electrophysiology (MEA) datasets and to assess predictive value and computational cost.
• Software and hardware prototypes were developed to enable behavioural monitoring of awake socially interacting animals through either video acquisition analysis or tracking devices.
• Additionally, an automated (dry) blood sampler device was implemented and validated in an in vivo safety pharmacology study to enable pharmacokinetic-pharmacodynamic (PK-PD) modelling.
• A numerical model of the vessel wall (including dynamic regulation of vascular tonus) was established and benchmarked against experimental data.
• Mass spectrometry imaging (MSI) has been applied to quantify drug-exposure in different organs (including the heart) and has been coupled with proteomics for molecular insights.
• New approaches for the evaluation of drug-induced haemodynamic changes have been explored such as arterial stiffness, local (blood)flow patterns, as well as a novel method (SPAR) to analyse subtle morphological changes in (pressure) waveforms over time.
• Research on cardiac and vascular toxicity related to anti-cancer drugs, such as VEGF-targeting tyrosine kinase inhibitors and doxorubicin pointed towards roles of endothelin and SERPINA3 respectively, that require further investigation in clinical research.
• Along the same line, biomarkers have been explored, both functional and molecular ones, to identify specific patient populations at risk of cardiovascular toxicity. The protein SERPINA3 appeared to be upregulated in plasma of patients developing anthracycline chemotherapy-related cardiovascular disease.
• Regular meetings fostered interaction between scientists from academia, pharma industry, technology vendors, as well as regulatory agencies. This unique setting has provided the ESRs with invaluable insights and excellent opportunities to develop themselves.
• At the end of the project, a few ESR fellows have already successfully defended their PhD thesis (PhD degree), while the remainder ESRs are preparing their PhD thesis.
Main activities and results can be summarized as follows:
• Progress was made towards 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.
• For data-analysis of hiPSC-cardiomyocytes assays, different machine-learning strategies were implemented to speed up analysis of large electrophysiology (MEA) datasets and to assess predictive value and computational cost.
• Software and hardware prototypes were developed to enable behavioural monitoring of awake socially interacting animals through either video acquisition analysis or tracking devices.
• Additionally, an automated (dry) blood sampler device was implemented and validated in an in vivo safety pharmacology study to enable pharmacokinetic-pharmacodynamic (PK-PD) modelling.
• A numerical model of the vessel wall (including dynamic regulation of vascular tonus) was established and benchmarked against experimental data.
• Mass spectrometry imaging (MSI) has been applied to quantify drug-exposure in different organs (including the heart) and has been coupled with proteomics for molecular insights.
• New approaches for the evaluation of drug-induced haemodynamic changes have been explored such as arterial stiffness, local (blood)flow patterns, as well as a novel method (SPAR) to analyse subtle morphological changes in (pressure) waveforms over time.
• Research on cardiac and vascular toxicity related to anti-cancer drugs, such as VEGF-targeting tyrosine kinase inhibitors and doxorubicin pointed towards roles of endothelin and SERPINA3 respectively, that require further investigation in clinical research.
• Along the same line, biomarkers have been explored, both functional and molecular ones, to identify specific patient populations at risk of cardiovascular toxicity. The protein SERPINA3 appeared to be upregulated in plasma of patients developing anthracycline chemotherapy-related cardiovascular disease.
• Regular meetings fostered interaction between scientists from academia, pharma industry, technology vendors, as well as regulatory agencies. This unique setting has provided the ESRs with invaluable insights and excellent opportunities to develop themselves.
• At the end of the project, a few ESR fellows have already successfully defended their PhD thesis (PhD degree), while the remainder ESRs are preparing their PhD thesis.
INSPIRE has achieved its overall ambition to extent the toolbox for cardiovascular safety evaluation and to stimulate innovation to the field of safety pharmacology. Additionally, INSPIRE has provided new mechanistic insights into cardiovascular adverse events. Eventually, INSPIRE will contribute to the development of effective, yet safe, therapies for patients.
An economic return is expected 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.
In addition to its direct scientific and socio-economic impact, we anticipate a long-lasting impact of the INSPIRE network. The network has initiated new and consolidated existing relationships between the participants that offer exciting opportunities for follow-up research. Further, INSPIRE has trained a future generation of safety pharmacology scientists. In this view, the INSPIRE Summer School will continue (5th edition in 2024) and present an important and sustainable legacy of the project.
An economic return is expected 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.
In addition to its direct scientific and socio-economic impact, we anticipate a long-lasting impact of the INSPIRE network. The network has initiated new and consolidated existing relationships between the participants that offer exciting opportunities for follow-up research. Further, INSPIRE has trained a future generation of safety pharmacology scientists. In this view, the INSPIRE Summer School will continue (5th edition in 2024) and present an important and sustainable legacy of the project.