FDA to Collaborate to Find Biomarker for Liver Toxicity

Pharmaceutical Executive

The Critical Path is alive and well, as demonstrated by an agreement between FDA and Massachusetts-based BG Medicine to identify molecules associated with liver toxicity in animal trials.

FDA will collaborate with Massachusetts-based BG Medicine to identify molecules that may indicate liver toxicity caused by drugs. If the two organizations can locate this type of molecule, it could be used as a biomarker to identify potential liver toxicity for drugs in development.

    In 2004, Janet Woodcock, FDA’s deputy commissioner for operations, identified liver toxicity as a problem that should be detected as part of the Critical Path initiative. By discovering adverse effects during the animal testing stage of development companies could potentially save a great deal of money, explained Pieter Muntendam, BG Medicine’s president.

    “Liver toxicity issues are said to be the number one reason for drug withdrawal and recall,” said Yvonne Dragan, director of the Division of Systems Toxicology at FDA’s National Center for Toxicological Research (NCTR) via email. She added that liver toxicity is a problem for one in six drugs in development.

    Liver toxicity can disrupt production of proteins that are manufactured in the liver, interfere with the liver’s role in detoxifying a poisonous chemical, or prevent chemicals from being eliminated from the body, according to Patricia Ganey, a professor of pharmacology and toxicology at Michigan State University. Drugs with toxic effects on the liver can cause people to feel ill, and even lead to transplants or death, she explained. 

    “Really the challenge is to identify which drugs will have the propensity to cause these types of reactions pre-clinically,” Ganey said.

    NCTR and BG Medicine plan to dose animals with drugs known to cause toxicity in humans that was not detected in animal studies. They will then use various types of spectroscopy to look for proteins, RNA, and other organic molecules that could potentially serve as biomarkers.

    Each organization will use different software to analyze the data they obtain. NCTR will use its public ArrayTrak software to correlate the genes and proteins expressed in the presence of the drug with known biological pathways, Dragan explained in an interview.

    By contrast, BG Medicine’s software looks at how different molecules in the cell – proteins, RNA, and metabolites – change in concert when exposed to drugs that are known to cause liver toxicity, explained Muntendam. The company’s software creates visual representations of these changes that will hopefully allow it to identify the molecules that orchestrate these changes, which they call “hubs.” These molecules could serve as markers for liver toxicity.

    “The data paint a picture completely untouched by humans,” Muntendam explained.

    The BG Medicine software looks for mathematical relationships between different components of the plasma, liver tissue, and urine such as: when molecule A is more concentrated, molecule B becomes less concentrated. According to Muntendam, each drug leaves a different “fingerprint” on the body that can be visualized.

    If the BG system identifies a molecule, the company’s researchers will search published studies and databases for information that could potentially correlate the molecule’s involvement with liver toxicity.

    Dragan said the two approaches could identify the same molecules or could offer different insights into liver toxicity.

    Five pharmaceutical companies were involved in designing the collaborative study. Dragan said no pharma companies have made a financial commitment to the project yet. If they do, according to Muntendam, they will have the right to use any data or biomarkers discovered by the collaboration.