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Applied Biosystems and FDA s NCTR to Develop Gene Signatures for Toxic Anti-Diabetic Drugs

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Just two months after Applied Biosystems launched its rat whole-genome survey array, it has found a major clinical partner to explore the resourcefulness of its technology.

ABI, an Applera corporation, announced last week that it has partnered with the National Center for Toxicological Research, an arm of the US Food and Drug Administration that uses the rat array, to investigate liver toxicity associated with a class of diabetes drugs.

“This is really the first collaboration like this we’ve had in pharmacogenomics, so its pretty compelling,” said Sophie Patel, a spokesperson for ABI.

The study is being led by the division of systems toxicology at the NCTR’s facilities in Little Rock, Ark., and is focused on a class of anti-diabetic drugs based on glitazone. This drug family includes Rezulin, which was marketed by Pfizer until the FDA withdrew it from the market in 2000 due to severe liver toxicity.

According to ABI, other drugs from this class that are currently being marketed are Avandia, which is sold by GlaxoSmithKline, and Actos, which is sold by Takeda Chemical Industries.

The FDA’s website reports that these two drugs entered the market at the same time as Rezulin, and some patients using them have reported “hepatitis and elevated liver enzymes.”ABI said annual sales of the class of drugs amount to $3 billion.

Now, with the help of ABI’s rat-genome array, the FDA and ABI have been working on collecting data that the government can refer to in the future when assessing the safety risks as drugs from this class go through the approval process. The FDA also hopes this collaboration will enhance its understanding of the toxicity of some of these drugs.

Yvonne Dragan, the director of the division of systems toxicology at NCTR, told BioArray News this week that results of the study would be published in a peer-reviewed paper co-authored by ABI which may be available in a few months.

Dragan said that most of the major experiments had already been done, and that the investigation has moved into the data-analysis phase.

Dragan said that her center has a number of partnerships with different microarray companies, from Agilent to Illumina, but that ABI had been an attractive partner for the study because of the launch of the rat array in early 2005.

“Typically the models that are used in pre-clinical toxicology studies are the rat and dog,” explained Dragan, “so the availa-bility of the whole-rat-genome array is quite useful when you're trying to understand either the mechanism of toxicity of an agent, or if you are trying to get a handle on comparison within a drug class of relative difference and effect.”

She also said that the class of diabetes drugs were of interest to the FDA because it is still unclear why some drugs from the class pose few safety hazards to patients while others are hepatotoxic.

Dragan said that the results of the study would be used to supplement the knowledge of the professionals who are charged with evaluating the safety risks of new diabetes drugs derived from this class. They would use the toxicity signatures created by the study to assess the liver toxicity of an applicant’s drugs.

“This is a tool used to understand how to interpret array results in the context of multiple doses so that you can get a better handle on how to use that information for making those types of decisions,” Dragan said.

According to representatives from ABI, most of the actual investigation, which was announced March 10 at the Society of Toxic-ology Meeting in New Orleans, has already been completed.

NCTR has been providing the Foster City, Calif.-based company with samples, and ABI has been running the samples on its arrays and analyzing the information.

Gary Schroth, a group leader for ABI’s array development team who is working on the study, said that the investigation is truly a collaborative effort because ABI is not just acting as a tool vendor, but is actively involved in the study, which is being internally funded by ABI and NCTR.

“We have been involved in the design of the experiment, the execution of the experiment, the analysis of all the data, the design of the follow-up experiments,” Schroth said.

“So we’ve been involved in basically all aspects of it. They have the biological model system that they’re interested in — that’s the partnership there,” he said.

“They are providing us with the samples and we are doing the work in our lab.”

Schroth said that ABI and NCTR have been sharing data through a company server.

Schroth said that most of the samples have been run on its microarray platform, and that now ABI is “doing those TaqMan gene-expression experiments that kind of validate [the biomarkers that] we’ve seen in the microarrays.”

ABI said it hopes to potentially extend the results to other samples, and to study in more detail some of the pathways that popped up in the study that are believed to be critical for this toxicological effect.

Schroth wouldn’t speculate about the cost to ABI, but said the company had used 100 rat genome arrays in the study, and that the rat arrays have been available for $650 a chip since they were commercially released. Schroth commented that although the array was new, sales have been encouraging.

Schroth said that ABI had actively courted the NCTR to validate the utility of its array.

— JP

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