Innovating Drug Development: the Revolution of Organ-on-a-Chip Technology in Enhancing Safety and Efficacy Assessments

Abstract: In the evolving landscape of drug development, we propose integration of innovative preclinical in vitro models, such as Organ-on-a-Chip (OOC) technology to revolutionize predictive power for drug safety, toxicology, and efficacy assessments. This transformative approach ensures a more robust "fail early, fail fast" strategy, thereby increasing the likelihood of clinical success for candidate drugs.

Organ-on-a-Chip technology utilizes microfluidics to recreate tissue microenvironments in an organ-specific context. By reconstructing tissue-tissue interface via incorporating multiple cell types and extracellular matrix, by introducing mechanical forces and interactions with vascular and immune components, Organ-Chips offer a more reliable understanding of physiological responses, critical for predicting complications in humans, particularly for treatments focusing on human-specific targets. Our research explores the application of multiple biochemical and biomechanical cues within OOCs, emulating closely the cellular composition and cytoarchitecture of the tissue, gene expression and function that correlate with human responses in vivo.

We will present a comprehensive assessment of human Liver-Chips with a focus on drug-induced liver injury (DILI) prediction that showcases enhanced predictive validity compared to historical data from animal models and 3D spheroid cultures of primary human hepatocytes. This first of its kind study followed the pharma consortium Innovation and Quality (IQ) roadmap for developing in vitro liver models for the prediction of DILI. We will show the data obtained from 870 Liver-Chips across 3 donors testing a set of 27 small molecule drugs. Our results indicate that the Liver-Chip has an 87% sensitivity and 100% specificity, making this technology a superior predictive tool compared to animal models and prior preclinical in vitro models.

Furthermore, we will highlight how using a recently developed primary organoid-based human vascularized Colon Intestine-Chip, we recapitulated Immune Cell Recruitment into tissues, including attachment, extravasation, and effector immune responses, such as cytokine release and epithelial barrier disruption under inflamed conditions. Moreover, we validated the efficacy of several therapeutics that hinder inflammatory responses through various mechanisms of action. While traditional drug screening models fall short in capturing the intricate dynamics of immune responses within tissues, OOC technology provides a more realistic context for studying immune cell interactions, leading to a more accurate evaluation of therapeutic interventions efficacy.

In summary, integration of Organ-Chip technology into drug discovery and development pipeline offers a powerful approach for predictive modeling and better mechanistic understanding, enhancing the development of safer and more effective treatments while addressing industry challenges of costly drug attrition.