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Recreating Life in the Lab: How Predictive Human Organ Models are Transforming the Efficiency of Drug Discovery

An often-underreported fact within the drug discovery and development industry is that around 90% of drug candidates reaching clinical trials ultimately fail, with an even greater number discarded before reaching the clinic at all. A recent market survey of mid-sized biotechs and large pharma companies highlighted efficacy and cost as the leading concerns during drug development, further demonstrating the impact that failed drugs can create. These failures are predominantly caused by a lack of efficacy, but unforeseen adverse effects in patients are also a factor for concern. Clearly, there is an urgent need for more translatable data between the preclinical and clinical phases of drug discovery and development to address the financial uncertainty caused by the high degree of drug candidate failure.

The NAM Revolution

Scientists now have access to a large range of preclinical tools for evaluating drug safety and efficacy, including simple in vitro 2D/3D cell culture assays and in vivo animal models. The former is convenient and scalable, enabling large numbers of candidates to be screened rapidly but these assays lack physiological relevance. The latter compensates by providing the complexity of a living system; however, animal models lack human relevance. A new wave of technologies, collectively called New Alternative Methods, or New Approach Methodologies (NAMs), aim to bridge this gap by modeling the physiological processes that occur in our organs and systems. NAMs are defined as any technology, methodology, approach, or combination that can provide information on drug hazard and risk assessment and avoid the use of animals. They include in silico, in chemico, in vitro, and ex vivo approaches. The complementary role of NAMs in drug discovery and development has become increasingly apparent following the FDA’s Modernization Act 2.0. The “Alternatives to Animal Testing” bill now allows the FDA to consider data generated from non-animal drug testing methods in IND submissions, where enhanced performance is proven.

An Introduction to Organ-on-a-chip

Organ-on-a-chip (OOC) technology has gained rapid traction within the NAM market over the past decade. OOCs, also referred to as microphysiological systems (MPS), were first described in 2010 with Harvard University’s lung-on-a-chip model, derived from microfluidic devices that assisted academics with cell culture.1 This has since paved the way for the commercial development of many additional organ models and technology providers.

OOC technologies generate 3D microtissues that recapitulate the microarchitecture, functions and physiological responses of human organs and tissues more accurately than conventional preclinical models. 3D microtissues are grown by co-culturing organ-specific primary human cells in the presence of microfluidic perfusion (to mimic the bloodstream), providing biomechanical stimuli, oxygen, nutrients and waste removal. Furthermore, OOC technology enables complex stimuli such as growth factors to activate cellular processes, interferons to trigger an immune response, fat loading to mimic western diets, and drugs to predict their human effects.