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Expert Insights: From animal to iPSC-derived models, a new era in preclinical evaluation

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By Radhika Menon

How has preclinical evaluation in drug discovery changed in the last decade?

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Expert Profile

Radhika Menon obtained her PhD in 2019 at the Johannes Gutenberg University in Germany. During her doctoral studies, she worked on the development of iPSC-derived brain organoids to model neurodevelopmental disorders. She has established iPSC differentiation protocols for neuronal, cardiac and hepatic cell lineages and has worked with 3D iPSC-derived spheroids, oligospheroids and organ-on-a-chip technology. Dr. Menon holds great expertise in cell differentiation and disease modeling in multiple therapeutic areas which is leveraged at Ncardia for manufacturing and cell development services.

Insights

Animal models have been vital to understanding disease mechanisms and clinical evaluation of drugs. Despite this, there is mounting evidence showing their lack of physiological relevance and inability to capture the complexity and functional context of human biology. Radhika discusses evidence to support the early introduction of iPSC-derived models in preclinical studies and encourage therapeutic developers to make the switch.

High attrition rates of clinical trials implicate high economic losses and, most important, lack of disease-modifying therapies for patients. As an example, 99.6% of drugs targeted for Alzheimer’s disease, which are successful in animal testing, are found ineffective in humans (Physicians Committee for Responsible Medicine). According to Radhika, these statistics are a major concern and highlight the urgent need for a change in preclinical evaluation.

Recently, the bill from FDA Modernization Act 2.0 has been passed by the Senate and House, removing the previously mandatory requirement of animal testing before clinical trials. This allows pharma and biotech companies to choose alternative models. The same vision is shared in Europe, where the EMA has announced measures to reduce animal testing and promote alternative approaches for scientific research. As stated by Radhika, this is a significant step forward for the modernization of drug discovery. It will not only reduce the use of animal models in preclinical testing, which has important ethical implications, but also encourage therapeutic developers to include more suitable models in their pipelines.

“I think this bill is, in part, a consequence of the increasing evidence supporting the value of alternative models for preclinical testing. Throughout the past decade, we have seen iPSC-cardiomyocytes derived from patients become key players for cardiotoxicity predictions and disease modeling (REF). Other models, like iPSC-neurons have shown their power for drug-repurposing screenings and are critical in target identification for neurodegenerative diseases.” 

From the perspective of an iPSC expert like Radhika, the new FDA regulations are great news too. It will enable further development of iPSC-based in vitro models, organ-on-a-chip models, tissue engineering, data science and AI-based analysis. 

These models are already advancing drug discovery with high reliability, but there is much more to be done to leverage the full potential of iPSC technology. I can think of, for example, clinical trials being supplemented and informed by data analysis of the drug’s effect on patient cohorts generated in vitro. Key steps such as patient selection and stratification would become much more accurate.

Despite the promising results obtained with iPSC-derived models, Radhika indicates that the high expertise required to apply this technology might be hampering its full expansion in the industry. Nonetheless, she underscores the value of Ncardia to facilitate the implementation of iPSC technology in drug discovery. 

I started my scientific career at the time iPSC discovery was awarded the Nobel Prize. It was an exciting time, and 10 years later, I find it equally exciting. At Ncardia, there is a unique combination of the wealth of knowledge built in the field of iPSC research with broad drug discovery services.

Are you wondering how iPSC technology could advance your therapeutic development programs? Contact our experts