Drug-induced liver injury is the leading cause of acute liver failure. It is also the single greatest reason the U.S. Food and Drug Administration refuses to approve a drug, pulls a drug from market, restricts its use, or issues warnings to physicians.

 

Foster City, California-based Entelos thinks it could help reduce these risks using computer modeling to predict if a drug would have liver toxicity problems. Through the use of its so-called "virtual patients" system, the determination would be made early in the drug development process. The FDA seems to agree on the potential.

 

The agency's Center for Drug Evaluation and Research has entered into a Cooperative Research and Development Agreement with Entelos to build predictive computer models, which could identify liver toxicity problems before a pharmaceutical company has made a significant investment to bring a drug to market.

 

Janet Woodcock, deputy commissioner with the FDA and its chief medical officer, said that early detection of potential drug safety problems is one of the objectives of the agency's Critical Path Initiative, an effort to modernize the drug-development process. Under the initiative, the FDA is pursuing collaborations such as the one with Entelos to find innovative ways to reduce the time it takes to bring new and important medical products to the market.

 

"The FDA has identified modeling and simulation and quantitative disease models as one of the important new methods to help bring a systems-level, mechanistic understanding of human biology that can lead to trial designs and early prediction of efficacy and safety," Woodcock said.

 

Computer-Simulated Disease Models
The ten-year-old company was founded by a team that consisted largely of aerospace and defense industry veterans who had the idea of applying modeling and simulations common in aerospace design to pharmaceutical research and development. The company takes human biology and reduces it to mathematical formulations in an effort to predict how a given compound will act in the body. Already, pharmaceutical companies such as Johnson & Johnson and Pfizer have worked with Entelos in the hopes that its modeling would cut the cost and accelerate the process of drug development.

 

The company has developed computer-simulated disease models to help select and develop compounds, assess safety, optimize clinical trials and combination therapies, evaluate in-licensing candidates, and help pharmaceutical companies better position products. In addition to internal drug programs in rheumatoid arthritis and women's health, Entelos partners with global pharmaceutical companies and provides customized technology and research services in cardiovascular diseases, asthma, obesity, diabetes, rheumatoid arthritis, anemia, cholesterol metabolism, and skin sensitization.

 

Computer simulations provide answers faster and cheaper than could be had in the wet lab or in the clinic, wrote Evolution Securities Analyst Jonathan Senior in a report on Entelos earlier this year. "Its predictive ability has the potential to prevent programs that would end up as a 'dead end' before even starting," he said. "By developing drugs faster and not spending money on 'hopeless' programs, the pharmaceutical industry could save cash and improve its productivity."

 

Understanding Liver Injury
It is that same promise that the FDA hopes to capitalize on through its agreement with Entelos. Under the terms of the two-year agreement, Entelos will work with the agency to develop a computer model of drug-induced liver injury. Entelos and the FDA have designed a platform development plan with input from an expert scientific panel and a number of pharmaceutical companies. The goal is to use this platform to guide the development of clinical biomarkers and preclinical assays to identify patient types and drug combinations that increase the risk of developing liver injury.

 

James Karis, president and CEO of Entelos, said the liver appears to be the most common target organ for toxicity during the course of drug development, and animal studies appear to be limited at best in predicting human liver toxicity.

 

"There is clearly a need to better understand the mechanisms of liver injury in man so that molecular or cellular screening assays and biomarkers can be developed to identify problems earlier," said Karis. "Such information will help patients, physicians, the FDA, and pharmaceutical companies avoid costly clinical failures and withdrawal of life-saving drugs from the market."