Validating and Using Cardiac NAMs for Toxicity Screening and Drug Development

Abstract

Technological advances and the desire to reduce dependence on animal models have brought human-relevant models to the forefront of drug development. This paradigm shift is leveraging the advances in in vitro systems and new approach methodologies (NAMs), which was the focus of a workshop convened by the Health and Environmental Sciences Institute (HESI) in May 2024. Highlights included discussions on predicting cardiac failure modes and the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), microfluidic systems like BioFlux™, and engineered heart tissues in enhancing early-stage drug safety assessments. Regulatory perspectives underscored the challenges and potential for integrating NAMs into submissions, advocating for standardized reporting and validation protocols. Case studies where NAMs offered superior predictivity compared to traditional methods are emerging and offer insights into a roadmap forward. However, there remains a need for collaboration among academia, industry, and regulatory bodies to ensure robust validation and adoption. These efforts aim to refine cardiovascular drug discovery, reduce attrition rates, and accelerate the transition toward more ethical and efficient preclinical testing paradigms.

Keywords: cardiac; cardiovascular; drug safety; new approach methodology; toxicology.