How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

Abstract

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: Fully characterize the incidence, prevalence and impact of drug‐induced cardiovascular issues at all stages of the drug development process. Ascertain the predictive value of existing non‐clinical models and assays towards the clinical outcome. Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…Cardiotoxicity is an important hurdle to drug discovery, with many compounds discarded during drug development because of potential toxic effects on the heart (Laverty et al , 2011; Hay et al , 2014) and difficulties in predicting how the human heart will respond. Cardiotoxicity is still a predominant cause of preclinical and clinical drug failure (McNaughton et al , 2014; Onakpoya et al , 2016; Siramshetty et al , 2016).…”

Chronic drug‐induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell‐derived cardiomyocytes

“…hERG inhibition) to detect liabilities that might translate into QT-prolongation and cardiac arrhythmias in humans. However, less attention is paid to the delayed cardiac liabilities that are currently identified in the more costly, late-phase toxicity studies using in vivo models, or in the worst cases within clinical development or on the market (Laverty et al, 2011;McNaughton et al, 2014). Furthermore, it is believed that one of the major factors contributing to the limited success of predicting clinical toxicities is the translatability across preclinical (animal) models into humans.…”

Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective

“…The cardiovascular, hepatic, renal, and gastrointestinal organ systems are frequently cited as those that drive a significant proportion of safety-related attrition. 7 Each of these organ systems has unique physiology, multiple cellular targets and manifestations of toxicity and biomarkers of those injuries to consider. In the case of the cardiovascular system, the myocardium, heart valves, and intra-and extra-cardiac arteries are all primary targets of both structural and functional toxicity.…”