NEW ORLEANS Could a non-hepatic toxicogenomic profile have prevented the problems experienced by drugs such as Vioxx?
The use of toxicogenomic profiling in non-hepatic tissue is on the rise among drug makers in the United States, according to industry experts interviewed for this article. But few companies are willing to talk about the ways in which they are using these tools in their own R&D, and those that use them oftentimes do so narrowly.
For example, a cox-2 inhibitor such as Vioxx is "a very ready example" of how toxicogenomics using non-liver tissues might be put to use, said Pat Morgan, director of product management at Gene Logic. The company, which sells subscriptions to its database of toxicogenomic profiles, happens to have "a heart program under development, but it's not ready for prime time" for toxicogenomics applications, said Morgan.
Because the FDA requires the use of whole-body panels of toxicity testing for many drug studies, "fundamentally companies are going to want to go beyond liver," said Morgan. "There's always been that expectation that they'll look beyond liver, and it's getting there," she said. But those companies that do look beyond the liver generally big pharma finance their own programs and keep their results a secret, Morgan added.
Three main changes would speed the adoption of non-hepatic toxicogenomics cost, automation, and a better understanding of the genes involved in toxicity in each tissue, Kyle Kolaja, vice president of chemogenomics and toxicology at Iconix, told Pharmacogenomics Reporter this week. Kolaja chaired a symposium at the Society of Toxicology meeting, held here this week, entitled "Beyond Liver Toxicogenomics: Gene Expression Based Biomarkers in Non-hepatic Tissues." Iconix sells access to its toxicogenomics database.
To be sure, the use of toxicogenomic profiling in non-hepatic tissues is picking up speed, partly because the technology and knowledge have matured and the regulatory landscape such as the upcoming guidance for voluntary pharmacogenomic data submissions (see accompanying story here) has encouraged it, said Kolaja.
The request of an Iconix customer for one non-hepatic toxicogenomic profile over another depends on the mechanism of action of each compound, but the non-hepatic space is changing, he said. "Two-thirds of our [expression profiling] work has been on liver, and in the last year another third was heart tissue" and kidney, to a lesser extent, Kolaja said.
Of course, the databases are expensive. "The single most expensive thing is subscribing to large databases," which can run "between $3 million and $5 million" per year for a company "of Bristol-Myers Squibb's size," said Bruce Car, executive director of discovery technology, pharmaceutical candidate optimization, at Bristol-Myers. "You'd have to triple it for a company the size of GlaxoSmithKline and Pfizer." Car's estimation does not include the cost of labor or consumables, he added.
But among big drug makers, some in the industry said that this kind of profiling may already be fairly common internally. "I would say everybody is" doing some level of non-hepatic tox profiling, said Michael Lawton, associate research fellow at Pfizer. Lawton, a former Abbott staffer, said that company had "done work in all those areas" when he worked there. But still, the use of other organs is picking up, "because of success with things like liver," he said.
The adoption rate is a matter of contention, however. "Conservative companies are playing around a lot with the liver," according to Car. But as many as 25 percent of drug makers, he estimated, profile other tissues, or those tissues' primary cells in culture.
Gene Logic's Morgan estimated non-hepatic toxicogenomic profiling still makes up less than half of toxicogenomic profiling. Most of Gene Logic's customers feel they need to get into the practice because they feel it is inevitable, she said. Heart, kidney, bone marrow are "all things that eventually will be profiled," regularly, she added.
Other forces also encourage toxicogenomics, said Car. "We were requested by a regulatory authority to do transcriptomics if you're in a company that has no ability to do it, and a regulatory authority tells you to do it, you're so far behind the eight ball," he said. "Because of that, other companies must have been asked to do transcriptomics work as well." Car would not disclose the regulatory authority, except to say it was European and wanted information on a carcinogenic compound.
One reason Car sees toxicogenomic profiling picking up in other tissues is that liver profiling is good as a "reporter" of problems elsewhere in the body, but it is not so good for studying the liver. "Liver profiling for hepatotoxicity is very successful, but kind of redundant" since other methods are quicker and cheaper, Car said. Recognizing which tissue is likely to be affected toxically by a compound, such as ovaries for a reproductive problem, makes much more sense than focusing on the liver expression profiles as a proxy for toxic responses, said Car.