In silico human-based methodologies for evaluation of drug cardiac safety and efficacy
Lead Research Organisation:
University of Oxford
Department Name: Computer Science
Abstract
Cardiotoxicity is one of the leading causes of failure during drug development and also, more worryingly, after marketing approval. Withdrawal due to cardiotoxicity has increased from 5.1 to 33%, including compounds to treat cardiovascular problems as well as drugs not intended to affect the heart. Cardiotoxicity manifest itself as adverse effects on cardiac electrophysiology such as arrhythmias and sudden death, and alterations on contractility and structure including, for example, increased incidence of heart failure and myocardial infarction. In spite of the variety of animal methods for preclinical screening for drug safety, 20-50% of all advanced candidates have to be abandoned due to adverse outcomes, even late in the drug development process. These figures could be drastically reduced, and at a smaller cost of animal experimentation, by the adoption of in silico technologies in the earlier phases of the drug development process.
The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings.
The specific objectives include:
1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico models for specific disease conditions such as heart failure, myocardial ischemia, genetic disorders and cardiomyopathies.
2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings.
3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes.
4) Planning and development of workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings.
The proposal will consider as an important focus the fact that cardiotoxic adverse events are more likely to occur in patients with compromised cardiac electromechanical function due to coronary artery disease, myocardial infarction and/or heart failure. These are rarely reproduced in animals, which are however systematically used for drug evaluation. We will create the infrastructure required to facilitate access to expertise and in silico multiscale human cardiac models from ion channels to the whole organ, for a range of conditions including heart failure, myocardial ischaemia, and genetic mutations. This amazing technology has the obvious advantage of a focus in human, but also the ability for personalisation to specific patients' conditions, with a potential 3Rs impact in drug safety and efficacy evaluation in industry, and also in clinical applications that also rely on animal testing. In addition, to delivering in silico modelling technology, the project will facilitate inter-sectorial working groups including academics, clinicians and industrial partners for the definition of evaluation criteria to increase the credibility and refine the in silico human models for cardiotoxicity, and to design strategies to overcome barriers for their uptake to refine, replace and reduce animal experimentation for drug safety and efficacy evaluation. The project is strongly supported by wide membership across regulatory, industrial, clinical and academic sectors located in at least ten countries, who will contribute to raising the profile of the in silico models for the 3Rs in animal experimentation, internationally.
The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings.
The specific objectives include:
1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico models for specific disease conditions such as heart failure, myocardial ischemia, genetic disorders and cardiomyopathies.
2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings.
3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes.
4) Planning and development of workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings.
The proposal will consider as an important focus the fact that cardiotoxic adverse events are more likely to occur in patients with compromised cardiac electromechanical function due to coronary artery disease, myocardial infarction and/or heart failure. These are rarely reproduced in animals, which are however systematically used for drug evaluation. We will create the infrastructure required to facilitate access to expertise and in silico multiscale human cardiac models from ion channels to the whole organ, for a range of conditions including heart failure, myocardial ischaemia, and genetic mutations. This amazing technology has the obvious advantage of a focus in human, but also the ability for personalisation to specific patients' conditions, with a potential 3Rs impact in drug safety and efficacy evaluation in industry, and also in clinical applications that also rely on animal testing. In addition, to delivering in silico modelling technology, the project will facilitate inter-sectorial working groups including academics, clinicians and industrial partners for the definition of evaluation criteria to increase the credibility and refine the in silico human models for cardiotoxicity, and to design strategies to overcome barriers for their uptake to refine, replace and reduce animal experimentation for drug safety and efficacy evaluation. The project is strongly supported by wide membership across regulatory, industrial, clinical and academic sectors located in at least ten countries, who will contribute to raising the profile of the in silico models for the 3Rs in animal experimentation, internationally.
Technical Summary
Cardiotoxicity is one of the leading causes of failure during drug development and also, more worrying, after marketing approval. Withdrawal due to cardiotoxicity has increased from 5.1 to 33%, including compounds to treat cardiovascular problems as well as drugs not intended to affect the heart such as antihistamines. Current used strategy to screen for adverse contractility effects involves a combination of preclinical in-vitro pharmacological profiling, cardiomyocyte assays and in-vivo cardiovascular (CVS) studies, and uses a variety of animal species (rats, mice, rabbits, guinea-pigs, dogs, pigs and non-human primates).
In spite of the variety of animal methods for preclinical screening for drug safety, 20-50% of all advanced candidates have to be abandoned due to adverse outcomes, even late in the drug development process.
The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings. The specific objectives include:
1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico multiscale mechanistic models for specific cardiac disease conditions.
2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings.
3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes.
4) Workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings.
Project membership involves key partners across 11 countries who will raise the profile of in silico human models for the 3Rs.
In spite of the variety of animal methods for preclinical screening for drug safety, 20-50% of all advanced candidates have to be abandoned due to adverse outcomes, even late in the drug development process.
The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings. The specific objectives include:
1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico multiscale mechanistic models for specific cardiac disease conditions.
2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings.
3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes.
4) Workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings.
Project membership involves key partners across 11 countries who will raise the profile of in silico human models for the 3Rs.
Planned Impact
Drug discovery and their safety evaluation before first use in humans heavily rely on animal experimentation. Still, current rates of drugs withdrawn from the market are about 40%, evidencing clear differences in human physiology compared to animals, an unnecessary waste of hundreds of thousands of animal lives per year, incurring billions of loss for the pharmaceutical sector and, most importantly, putting human lives in danger. This has called into question the reliability of animal-safety testing paradigms and has led to demands for more predictive human-based tools.
By bringing together an intersectorial pharmaceutical, regulatory, clinical, technological and research initiative, our project aims at accelerating the intake of human-based computational methodologies for an effective reduction, refinement and replacement of animal experimentation in cardiac drug safety and efficacy. The following sectors will benefit from our research:
1) Industrial: despite advances in medicine, the cost of bringing new drugs to the market is becoming prohibitive, putting the pharmaceutical sector under unprecedented needs for cost cutting efficiencies. Direct cost savings as outcomes of this research are due to arise from a drastic reduction in animals usage in early drug development, safer selection of leading compounds to reduce failure rates for development programs, reduced duration of clinical trials, and the minimisation of implementation costs in the uptake of these new technologies.
2) Governmental: we will work in close collaboration with regulatory agencies to facilitate the adoption of in silico methodologies into the safety approval process. Our research will be closely based on their expert choice of compounds of interest, whereas our periodic evaluation reports will define the capabilities of human-based models compared to animal methods, but importantly also their limitations and needs for improvements.
3) Clinical: current trends in medicine point towards patient-specific treatments, meaning the development of therapies optimised to a group of individuals. However, drug screening is performed in healthy animals, which cannot recapitulate the complexity of human disease. Our research will develop and quantify human-based models for the prediction of adverse outcomes for specific disease conditions. This will also support the integration of human models into clinical support systems, to establish advisory courses of action ahead of treatments, tailoring therapies and optimising healthcare resources.
4) Technological: a successful adoption of computational medicine is expected to generate a whole new economic sector, primarily driven by SMEs. Through the dissemination of models, tools and expertise, our research will support the development of this sector, reducing barriers hindering access to computational methods, and minimising the entry costs of implementing new technologies within their business processes.
5) Research: the experimental, clinical and computational research communities will benefit worldwide from the proposed research, by giving them access to robust, reliable and reusable human-based in silico technologies, and by consolidating an international research community with closer intersectorial links. The integration of computational methods with experimental and clinical research will also contribute to the replacement, refinement and reduction of animal experimentation, contributing to a drastic reduction in animal costs in the biomedical academic and commercial sectors.
6) Society: least, but never last, patients are the ultimate beneficiaries of our research. Together with contributing to health system sustainability and adequacy of care, the proposed human-based technologies will also lead to improved outcomes for patients, enhancing their health and wellbeing, reduced risk during clinical trials, and faster and safer access to more effective drugs for patients who urgently need them.
By bringing together an intersectorial pharmaceutical, regulatory, clinical, technological and research initiative, our project aims at accelerating the intake of human-based computational methodologies for an effective reduction, refinement and replacement of animal experimentation in cardiac drug safety and efficacy. The following sectors will benefit from our research:
1) Industrial: despite advances in medicine, the cost of bringing new drugs to the market is becoming prohibitive, putting the pharmaceutical sector under unprecedented needs for cost cutting efficiencies. Direct cost savings as outcomes of this research are due to arise from a drastic reduction in animals usage in early drug development, safer selection of leading compounds to reduce failure rates for development programs, reduced duration of clinical trials, and the minimisation of implementation costs in the uptake of these new technologies.
2) Governmental: we will work in close collaboration with regulatory agencies to facilitate the adoption of in silico methodologies into the safety approval process. Our research will be closely based on their expert choice of compounds of interest, whereas our periodic evaluation reports will define the capabilities of human-based models compared to animal methods, but importantly also their limitations and needs for improvements.
3) Clinical: current trends in medicine point towards patient-specific treatments, meaning the development of therapies optimised to a group of individuals. However, drug screening is performed in healthy animals, which cannot recapitulate the complexity of human disease. Our research will develop and quantify human-based models for the prediction of adverse outcomes for specific disease conditions. This will also support the integration of human models into clinical support systems, to establish advisory courses of action ahead of treatments, tailoring therapies and optimising healthcare resources.
4) Technological: a successful adoption of computational medicine is expected to generate a whole new economic sector, primarily driven by SMEs. Through the dissemination of models, tools and expertise, our research will support the development of this sector, reducing barriers hindering access to computational methods, and minimising the entry costs of implementing new technologies within their business processes.
5) Research: the experimental, clinical and computational research communities will benefit worldwide from the proposed research, by giving them access to robust, reliable and reusable human-based in silico technologies, and by consolidating an international research community with closer intersectorial links. The integration of computational methods with experimental and clinical research will also contribute to the replacement, refinement and reduction of animal experimentation, contributing to a drastic reduction in animal costs in the biomedical academic and commercial sectors.
6) Society: least, but never last, patients are the ultimate beneficiaries of our research. Together with contributing to health system sustainability and adequacy of care, the proposed human-based technologies will also lead to improved outcomes for patients, enhancing their health and wellbeing, reduced risk during clinical trials, and faster and safer access to more effective drugs for patients who urgently need them.