An Unnoticed Event That May Symbolize the Future of Drug Testing

Today I'd like to hightlight a quite interesting (a symbolic even?) event that went relatively unnoticed by media and science commentators. Did you know that in 2020 the US FDA greenlighted the first drug candidate to enter clinical trials based solely on efficacy data derived from study in organoids, without the use of animal models? I didn't (thanks to Katya Tsaioun for sharing this article in her post, which popped up in my newsfeed and led me to the idea of writing about this topic now.

The drug candidate in question is Sanofi SA’s sutimlimab (SAR-445088; formerly BIVV-020), a humanized anti-C1s monoclonal antibody. In the study NCT04658472 I am discussing today, this antibody is tested in a new indication -- Chronic inflammatory demyelinating polyneuropathy (CIDP). So, it is a drug repurposing story.

The U.S. FDA OK'd the product under the brand name Enjaymo in February 2022 for the treatment of cold agglutin disease [CAD], in which activation of the complement cascade leads the immune system to destroy healthy red blood cells.

In the study I am highlighting today, Sanofi took that [CAD] safety data, combined it with efficacy data solely from microphysiological system-based study for CIDP, and that was the only data that was presented to FDA for a new indication.

“That’s the first time this has happened” according to James Hickman, CEO of Hesperos Inc. a company that developed the microphysiological system (human-on-a-chip) used in the study.

The study started recruiting just over two years ago, but the details were shared publicly only later, in 2022, following publication of a peer-reviewed paper Classical Complement Pathway Inhibition in a ‘Human-on-a-Chip’ Model of Autoimmune Demyelinating Neuropathies. The paper describes the use of a human-on-a-chip system to mimic disease mechanisms of rare autoimmune neuropathies that cannot be replicated in animal models.

This development offers a glimpse into the potential future of drug testing without traditional animal models (aka in vivo), especially for diseases that can't be simulated in animal models adequately.

Why care?

In fact, there exists over 10,000 rare diseases worldwide (there are varying numbers of rare diseases depending on the source) but only about 400 are being actively researched due to a lack of animal models. Chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy are rare, autoimmune neuropathies characterized by muscle weakness commonly resulting in difficulty ambulating and impaired hand function. Both are characterized by immune system hyperactivity through autoantibody production leading to peripheral nerve demyelination and reduction in nerve conduction velocity. While treatment with IVIG and steroids are available to patients, there is still a significant unmet need for novel, targeted treatments, which are lacking due in part to the absence of ideal animal models and of robust preclinical models that accurately mimic human disease.

Hesperos's organoid model revealed that a murine antibody could restore neuron function impaired by CIDP. Consequently, Sanofi SA’s sutimlimab was repurposed for CIDP treatment, combining prior safety data with the new efficacy findings. Remarkably, these combined data alone drove the FDA's approval decision, a solid milestone for the field of organ-on-a-chip systems.

Beyond CIDP, Hesperos is enthusiastic about leveraging microphysiological systems for other rare diseases. The long-term vision is to build enough confidence in these models for them to be accepted in studying more prevalent diseases.

The Broader Context

Biomedical Revolution: Thomas Hartung from Johns Hopkins University sees this development as a part of a larger revolution in bioengineering human organs. He highlighted how organoids were instrumental in understanding how the SARS-CoV-2 virus affected the human brain, a study which couldn't be conducted in animal models.

Addressing the Reproducibility Crisis: The emerging dominance of microphysiological systems indicates a potential solution to the "reproducibility crisis" in biomedical research. Traditional cell culture methods are laden with inconsistencies and inaccuracies. microphysiological systems provides a more standardized and accurate approach.

Moving Towards Standardization: Emphasizing the rapid progress in this field, the Good Cell and Tissue Culture Practice (GCCP) guidance underwent a revision in 2022, with the new GCCP 2.0 aiming to address the advancements and intricacies of cell models and to uphold the highest quality standards.

In Conclusion:

The embracing of organoids and MPS by regulators and the biomedical community heralds a transformative era in drug research and testing. While this is just the dawn, the potential implications for treating rare diseases and enhancing research quality are substantial. As well as the business potential of this sector.

Afterthought

I've been covering the area of organ-on-a-chip systems (and other emerging alternatives to animal testing) for quite some time now. Certainly, an important factor that is now playing in favor of many emerging companies in this space is a recent FDA Modernization Act 2.0 that became law on December 29, 2022.

Previously, it was a legal requirement for all drugs to be tested in animal models before first-in-man trials. The FDA Modernisation Act 2.0. has expanded the range of nonclinical models that can be used to progress drugs to clinical studies (including organ-on-a-chip systems, cell-based assays, computer modeling, and some other systems), but also recognizes that animal models are still needed in some cases.

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