Periodic Reporting for period 5 - DeCISIoN (Drug CandIdates ScreenINg)
Período documentado: 2018-07-01 hasta 2018-12-31
Ncardia (former Pluriomics) is an international Dutch/Belgian/German biotech company with the mission to implement stem cell technology in drug discovery and development. The company is specialized in developing stem cell-based cellular systems and assays for cardiac safety pharmacology and drug discovery and development. Ncardia developed a unique proprietary protocol to differentiate heart muscle cells derived from human induced pluripotent stem cells (hiPSCs). Ncardia provides its customers with reliable cell technology systems to test potential drugs in the preclinical phase with high predictive value.
Safety issues remain a key problem in drug development. This is amongst others emphasised by the case of AstraZeneca where 82% of pre-clinical and 62% of phase I project closures where related to safety issues (Cook D., Nat Rev Drug Discov, 2014). Out of the safety related failures the cardiovascular system is involved in 17% of the preclinical failures and 24% of the clinical failures. Examples of cardiovascular effects, include arrhythmias, hypertrophy, hypertension and reduced ventricular function, which may lead to increased cardiac risk and possibly death. Additional reasons for the decline in success rates are related to the lack of predictive models for early drug efficacy screening. These high attrition rates contribute considerably to the total costs of drug development, and since these costs need to be compensated by the earnings of marketed drugs this impacts the prices of drugs.
Ncardia has developed Pluricyte® Cardiomyocytes and integrated proprietary assay systems that are exceptionally well suited for implementation in various stages of drug discovery to improve decision-making, reduce attrition rates and provide an alternative for animal testing. Enabling market uptake and distribution of cell technology based innovations can be challenging, with large-scale production and development of regulatory compliant predictive models as main challenges. DeCISIoN will tackle these challenges and thus accelerate market uptake of Ncardia’s cardiac safety assays. In this project it will take the next steps and deliver
1) an up-scaled and more cost-effective manufacturing process;
2) novel, validated, predictive high-throughput cardiac assays for further improved cardiac toxicity and drug efficacy testing and
3) a fully developed marketing and commercialization strategy for the cardiac assays.
Safety issues remain a key problem in drug development. This is amongst others emphasised by the case of AstraZeneca where 82% of pre-clinical and 62% of phase I project closures where related to safety issues (Cook D., Nat Rev Drug Discov, 2014). Out of the safety related failures the cardiovascular system is involved in 17% of the preclinical failures and 24% of the clinical failures. Examples of cardiovascular effects, include arrhythmias, hypertrophy, hypertension and reduced ventricular function, which may lead to increased cardiac risk and possibly death. Additional reasons for the decline in success rates are related to the lack of predictive models for early drug efficacy screening. These high attrition rates contribute considerably to the total costs of drug development, and since these costs need to be compensated by the earnings of marketed drugs this impacts the prices of drugs.
Ncardia has developed Pluricyte® Cardiomyocytes and integrated proprietary assay systems that are exceptionally well suited for implementation in various stages of drug discovery to improve decision-making, reduce attrition rates and provide an alternative for animal testing. Enabling market uptake and distribution of cell technology based innovations can be challenging, with large-scale production and development of regulatory compliant predictive models as main challenges. DeCISIoN will tackle these challenges and thus accelerate market uptake of Ncardia’s cardiac safety assays. In this project it will take the next steps and deliver
1) an up-scaled and more cost-effective manufacturing process;
2) novel, validated, predictive high-throughput cardiac assays for further improved cardiac toxicity and drug efficacy testing and
3) a fully developed marketing and commercialization strategy for the cardiac assays.
Work Package 1: To develop an industrial manufacturing process for large-scale production of cardiovascular cell types.
For process development we have tested two approaches to scale-up cardiomyocyte production. Both adherent and suspension protocols for cardiomyocyte differentiation were tested. A suspension approach using small-scale bioreactors and subsequent scale-up in medium-scale bioreactors was successful in terms of cardiomyocyte differentiation efficiency and functionality. These suspension-bioreactor derived cardiomyocytes were functionally characterized after which process optimization was performed. The manufacturing process has been scaled up to >1L bioreactors with automated refreshments.
Work Package 2: To develop and validate Ncardia’s innovative high-throughput assays to screen for safety and disease modifying effects of compounds
Cardiac safety screening assays based on electrophysiology have been developed and optimized. A panel of drugs - of which clinical data is available - for validation has been generated. Data with these drugs in Pluricyte Cardiomyocytes have been generated in electrophysiology assays with several electrophysiology platforms. Furthermore we have developed novel assays such as for the clinically highly relevant biomarkers troponin and NT-proBNP, which are relevant for disease modelling, as well as for cardiotoxicity assessment. High-throughput compound screens have been performed as a demonstrator for both safety screening as well as drug discovery screening.
Work Package 3: To develop a commercialisation and marketing strategy for successful market introduction of the newly generated Pluricytes®, assays and services
Development of a marketing and commercialization strategy for the current and future products and services of Ncardia has been started. The merger of Pluriomics and Axiogenesis in September 2017 resulted in the rebranding of the merger entities under the name Ncardia, and a new business plan which is fully aligned with DeCISIoN goals and objectives. In order to support our new customers working with the current commercialized products, and to prepare the launch of our future products, the commercial team has been strengthened. In addition, various actions were taken: implementation of a CRM system, attending key international meetings, generation of new marketing materials and organization of workshops, user meetings and webinars.
For process development we have tested two approaches to scale-up cardiomyocyte production. Both adherent and suspension protocols for cardiomyocyte differentiation were tested. A suspension approach using small-scale bioreactors and subsequent scale-up in medium-scale bioreactors was successful in terms of cardiomyocyte differentiation efficiency and functionality. These suspension-bioreactor derived cardiomyocytes were functionally characterized after which process optimization was performed. The manufacturing process has been scaled up to >1L bioreactors with automated refreshments.
Work Package 2: To develop and validate Ncardia’s innovative high-throughput assays to screen for safety and disease modifying effects of compounds
Cardiac safety screening assays based on electrophysiology have been developed and optimized. A panel of drugs - of which clinical data is available - for validation has been generated. Data with these drugs in Pluricyte Cardiomyocytes have been generated in electrophysiology assays with several electrophysiology platforms. Furthermore we have developed novel assays such as for the clinically highly relevant biomarkers troponin and NT-proBNP, which are relevant for disease modelling, as well as for cardiotoxicity assessment. High-throughput compound screens have been performed as a demonstrator for both safety screening as well as drug discovery screening.
Work Package 3: To develop a commercialisation and marketing strategy for successful market introduction of the newly generated Pluricytes®, assays and services
Development of a marketing and commercialization strategy for the current and future products and services of Ncardia has been started. The merger of Pluriomics and Axiogenesis in September 2017 resulted in the rebranding of the merger entities under the name Ncardia, and a new business plan which is fully aligned with DeCISIoN goals and objectives. In order to support our new customers working with the current commercialized products, and to prepare the launch of our future products, the commercial team has been strengthened. In addition, various actions were taken: implementation of a CRM system, attending key international meetings, generation of new marketing materials and organization of workshops, user meetings and webinars.
The current state-of-the art models for testing drug safety or efficacy have many well-recognised shortcomings. Overall three types of models can be distinguished: in vivo, ex vivo and in vitro model. The first two of these models are only available with animals or animal tissue, limiting its predictive value for drug efficacy testing due to the significant differences between animal and human hearts. In vitro models for safety and efficacy testing generally rely on single cell type systems, such as immortalised cell lines overexpressing a specific target protein. These types of in vitro models do not capitulate the complex physiological situation in which a human heart cell in vivo is present.
The use of Pluricyte® Cardiomyocytes test systems allows researchers to overcome the many well-recognised problems with current model systems, when investigating effects on the human heart. Pluricyte® Cardiomyocytes are functionally characterized, contain no transgenes, are produced in large quantities, are quality controlled and the use of maturation-inducing media ensures consistent cell quality and minimal batch-to-batch variation.These properties make them exceptionally well suited for implementation in pharmaceutical drug discovery and development.
Impact
*Increased success rates in drug development. Current drug research and development programs are inefficient and drug failure rates at a late-stage are still very high (66% in clinical phase I; 30% in phase II). Ncardia aims to improve the efficiency by implementing stem cell based solutions in R&D.
*Reduced cardiac toxicity in marketed drugs. 50% of the drugs withdrawn from the market in the period 1994-2006 were related to cardiac toxicity. Ncardia’s toxicity testing systems will substantially increase the chances to establish cardiac toxicity risks in an early stage of drug discovery.
*More human based drug efficacy screening. The inadequate clinical prediction of safety and efficacy of compounds for human heart tissue can have serious impact on patient health. Ncardia will be able to create highly accurate patient-derived disease-in-a-dish models that will substantially increase the predictive value of preclinical drug discovery and development.
The use of Pluricyte® Cardiomyocytes test systems allows researchers to overcome the many well-recognised problems with current model systems, when investigating effects on the human heart. Pluricyte® Cardiomyocytes are functionally characterized, contain no transgenes, are produced in large quantities, are quality controlled and the use of maturation-inducing media ensures consistent cell quality and minimal batch-to-batch variation.These properties make them exceptionally well suited for implementation in pharmaceutical drug discovery and development.
Impact
*Increased success rates in drug development. Current drug research and development programs are inefficient and drug failure rates at a late-stage are still very high (66% in clinical phase I; 30% in phase II). Ncardia aims to improve the efficiency by implementing stem cell based solutions in R&D.
*Reduced cardiac toxicity in marketed drugs. 50% of the drugs withdrawn from the market in the period 1994-2006 were related to cardiac toxicity. Ncardia’s toxicity testing systems will substantially increase the chances to establish cardiac toxicity risks in an early stage of drug discovery.
*More human based drug efficacy screening. The inadequate clinical prediction of safety and efficacy of compounds for human heart tissue can have serious impact on patient health. Ncardia will be able to create highly accurate patient-derived disease-in-a-dish models that will substantially increase the predictive value of preclinical drug discovery and development.