Workshop Report

Abstract

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes

“…Cardiotoxicity remains one of the leading causes of drug development discontinuation and withdrawal of approved drugs ( Piccini et al , 2009 ). Challenges in translating preclinical cardiac safety data to humans has accelerated the search for developing novel human-relevant platforms to bridge translational gaps ( Abi-Gerges et al , 2020a ; Pang et al , 2019 ). Predictive adult human cardiac tissue- and cardiomyocyte-based models from healthy organ donors are now available for preclinical discovery studies ( Abi-Gerges et al , 2020b ; Britton et al , 2017 ; Nguyen et al , 2017 ; Otsomaa et al , 2020 ; Page et al , 2016 ; Qu et al , 2018 ; Trovato et al , 2020 ).…”

Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity

“…Therefore, there is a pressing need for predictable preclinical screening strategies for cardiovascular toxicities associated with emerging new drugs prior to clinical trials. The recent consideration of hiPSC-CMs for testing drug toxicity provided a partial solution for some contexts of use but did not solve the overall need in predicting effects in a diversity of functional cardiac modes of failure e.g., effects on endothelial cells, microvasculature or smooth muscle cells 15,16 . In addition to fetal-like properties, a single cell type does not replicate the complexity of a 3D heart tissue that contains multiple cell types and biological connections.…”

“…Animal models can fail in predicting drug adverse cardiac effects 10,11 , can be expensive and do not replicate many of the biochemical properties and hemodynamic aspects of the human heart and circulation [12][13][14] . Recently, human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) started being used to assess cardiotoxicity 15,16 . However, these cells have several fetal-like properties that can limit their usefulness in comprehensively predicting clinical cardiac drug side effects.…”

“…However, these cells have several fetal-like properties that can limit their usefulness in comprehensively predicting clinical cardiac drug side effects. The development of hiPSC-CMs microtissues is a promising effort to generate more mature phenotypes, but it is still a work in progress 15,16 ; because such microtissues still exhibit immature electrophysiology and lack cell-cell electrical coupling 17 . A less common approach has been the use of isolated primary human cardiomyocytes.…”

Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity

“…One representative iPSC technology at the forefront of transforming drug toxicology is the use of iPSC-derived cardiomyocytes ( Gintant et al, 2019 ; Pang et al, 2019 ). In particular, large-scale efforts exemplified by the CiPA initiative have been coordinated by academia, industry, and regulatory bodies to explore and validate iPSC-CMs as a viable option for predicting cardiac liabilities in a translational setting ( Colatsky et al, 2016 ; Blinova et al, 2017 ).…”