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Accelerating Toward A Safer Future With Organ-Chips

Accelerating Toward A Safer Future With Organ-Chips

Jim Corbett is CEO of Emulate. His diverse global experience ranges from Fortune 100 companies to entrepreneurial start-ups.

On October 16, 1959, a 54-year-old woman lay recovering in the Cardiopulmonary Unit of San Francisco’s Presbyterian Medical Center. Days earlier she underwent surgery to address mitral stenosis. On the road to recovery, she began taking quinidine—an ion channel blocker intended to normalize her heartbeat. But that’s not how it played out. Cardiotoxicity appeared within four days and on October 24, she passed away of apparent heart failure.

In the following years, researchers recognized quinidine’s ability to block the human ether-a-go-go (hERG) potassium channel meant it could alter the heart’s electrical rhythm and elicit long-QT syndrome. Among other outcomes, long-QT syndrome increases a patient’s odds of experiencing sudden cardiac death. The problem wasn’t limited to quinidine. Any drug that alters hERG activity could potentially lead to long-QT syndrome.

Without a means to screen prospective compounds for hERG interactions, the threat of sudden cardiac death loomed large over drug development pipelines. In response, the hERG patch-clamp assay was developed, providing a sensitive in vitro tool for predicting cardiotoxicity. In 2005, parallel efforts from industry and governmental groups produced guidelines mandating the use of the hERG assay during preclinical drug development. There have since been no instances of new drugs inducing sudden cardiac death as a result of hERG blockage.

It took more than 40 years for technological, clinical and regulatory efforts to converge, but the end result is a safer drug development pipeline.

We are approaching a similar convergence with organ-on-a-chip (organ-chip) technology, one that has the potential to greatly improve drug development and patient safety. To do so, the drug development industry needs to incentivize organ-chip adoption through technological innovation and regulatory guidance.

The Urgent Need For Better Models

The popularity of organ-chips has risen thanks to their ability to emulate human tissue. Organ-chips are 3D structures in which heterogeneous cell populations cohabitate and are subject to mechanical stimuli. By using tissue-specific cell types and extracellular proteins, researchers can recreate functional units of organ tissue in an in vitro setting, enabling high resolution study of disease pathology and drug responses. Ample evidence shows organ-chips closely mimic in vivo counterparts and can serve as powerful tools for predictive toxicology, particularly when predicting drug-induced liver injury (DILI).

DILI is the leading cause of safety-related drug withdrawals in the U.S. and has exacted innumerable harm to patients. Just as long-QT syndrome did years prior, DILI is now the potentially lethal threat looming over drug development pipelines, with an estimated 13% of clinical trials failing due to hepatotoxicity.

Clearly, preclinical models are failing. For decades, animal models have served as last-line filters to prevent toxic compounds from reaching patients. Yet, mounting evidence indicates these models are significantly flawed and misclassify too many toxic compounds as safe. In relying on animal models to predict DILI, developers are playing a game of chance with every new drug, and patients will continue paying the price until better preclinical models are found.

This is where organ-chips can make a difference. One of the largest organ-chip studies to date found that each of the 22 hepatotoxic drugs used in the study had previously been found to be safe in animal studies, only to be reclassified as toxic once given to patients. This suggests that almost 90% of DILI cases in clinical trials could be prevented by supplementing animal studies with organ-chips. That means fewer failed trials, fewer liver transplants and fewer patient deaths. That’s just for DILI. Organ-chips are being developed for a multitude of applications in predictive toxicology.

Stepping Toward Integration

The hERG assay profoundly improved patient safety, and organ-chips may do the same. For this to happen, a community needs to be built around organ-chips to foster knowledge sharing, innovation and formulation of regulatory incentives.

Fortunately, recent trends indicate such a community is developing. The volume and scale of organ-chip research have grown in recent years, and we’ve seen an increase in data sharing through events like the MPS Summit and the launch of platforms like Moxi. This community has the opportunity to collaborate and drive large-scale studies needed to validate specific organ-chip applications.

Driven by this growing community, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) published guidelines that detail baseline characteristics that each new organ-chip must demonstrate to qualify as a valid model. Such guidelines help legitimize organ-chips and ease the path toward regulatory approval. To this end, the FDA’s newly created iSTAND initiative was launched to provide a path toward regulatory approval for devices like organ-chips.

If an organ-chip is demonstrated to be superior to animal models for predicting drug toxicities, legislation will be needed to incentivize its use. There is a growing movement to divest in the use of animals for predictive toxicology. In addition to statements of intent to decrease animal testing from the NIH and the EPA, legislative bodies have taken up the cause as well. This year, the U.S. congress is voting on the FDA Modernization Act—a landmark bill allowing researchers to replace animal models in preclinical drug screening with better model systems, including organ-chips. Similarly, the Humane Research and Testing Act of 2021 was put before congress. If passed, the bill would establish the National Center for Alternatives to Animals in Research under the NIH to fund the development of alternative research models (like organ-chips), to train scientists on applying these models, and to form collaborative research networks using these models.

Collectively, it’s clear organ-chips are on a path toward widespread adoption. But it’s not a sure thing.

In order for the organ-chip field to mature, we must expand the scale of research projects to qualify organ-chips, innovate technology to make it cheaper and higher throughput, and push for progressive regulations prioritizing patient safety over the status quo. These are not trivial hurdles, but they’re not insurmountable. The field has momentum, and if we lean into it, we may be able to build a safer, more productive future.


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