Deliver the liver

FOSTER CITY, Calif.—In an effort that plays into the Critical Path Initiative of the U.S. Food and Drug Administration (FDA), life sciences company Entelos is partnering with the Hamner Institutes for Health Sciences in Research Triangle Park, N.C. to shed light on how pharmaceutical drugs and chemical agents can sometimes damage the liver.

The two-year project will bring Hamner's more than 30 years of experience in environmental health sciences, chemical risk assessment, liver injury and systems biology together with Entelos' Physiolab technology, a large-scale computer model that simulates disease in a virtual patient. Their aim is to create an in silico model that can help identify patient types who are at risk for developing liver injury in response to drug exposure.

Creating organ or disease models for predictive biosimulation is nothing new for Entelos, which has enjoyed multiple successes in such work, but this is the first time the California-based company will be focusing so much on patient safety.

"We made a commitment to move into the area of patient safety and adverse events a few years ago, but really, our work has continued to focus on efficacy," notes Mikhail Gishizky, chief scientific officer for Entelos. "The first question our pharma partners have generally wanted to know is how effective a drug will be against a given indication. Now, as we've established our capabilities in the area of efficacy, we're seeing more interest in the area of creating in silico models that address safety, and we see a lot of our future being in that area given how big a problem safety can be for getting drugs to market."

Understanding liver toxicity is the major issue in drug safety studies and arguably the biggest issue nowadays in drug development in general, notes Dr. Paul Watkins, director of the Center for Drug Safety Sciences in Research Triangle Park, a joint collaboration between the Hamner and the medical and pharmacy schools at the University of North Carolina, Chapel Hill.

"Drug safety has really become the bottleneck to drug development, and that will continue going forward," Watkins says. "Drug companies have come up with more effective drugs and are finding success by tying clinical trials to genetic studies and creating adaptive trials, so it should be easier to make drug discovery and development more efficient. But there has been too little development in understanding drug toxicity, particularly with the liver, which is the chief reason the drugs are stopped mid-trial or taken off the market."

Along with Entelos and Watkins' team, two FDA scientists will work on the scientific advisory board for the project. The project is born originally out of interest from the FDA for its Critical Path Initiative, which aims to reduce the time it takes to develop and approve safe and effective medical products to serve patients in need.

An important aspect of the liver toxicity model being created is that it will be a dual-species platform, representing a virtual population of humans and a virtual population of rats, Gishizky stresses, "which will really allow the translational research piece of this project to occur."

By the end of the project's two-year run, there will be a version 1 of the liver toxicity platform, which will be used by the FDA in its assessment of potential liver toxicity for drug candidates, and the platform also will be made available to academic and pharma company researchers under an as-yet-to-be-determined model. Entelos expects to begin taking on custom projects for companies or academic interests after version 1 is available, and will create modules for specific drug discovery and development applications. Many, if not most, of those modules will be proprietary in nature.

"Version 1 of the model won't be perfect," Watkins notes, "but the FDA feels it will be a great improvement on how it is doing things now, and I think that's true as well."