The right sequence makes the difference

Duke, SAEC lead effort to better understand the role of rare genetic variation in clozapine-induced agranulocytosis using whole genome sequencing

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DURHAM, N.C.—Duke University's Center for Human Genome Variation has announced a collaboration with the International Serious Adverse Events Consortium (SAEC) that will delve into the genetic sources of clozapine-induced agranulocytosis (CIA).

The benefit to patients who take clozapine will be to hone in on potential rare genetic variants that can predict the likelihood a patient will experience CIA, a serious drug-induced adverse event. CIA is a potentially fatal side effect in which patients experience a dramatic decrease in white blood cell counts, therefore making life-threatening infections a possibility.
Clozapine is highly regulated in the United States. It is only made available to patients through a special FDA-sanctioned special surveillance system. Under this program, patients must have a weekly white-cell count to receive their supply of the drug.
The SAEC is a nonprofit international research consortium formed in 2007 by the global pharmaceutical industry to better understand the role of genetics in drug safety.

Duke University's Center for Human Genome Variation, under the leadership of Dr. David Goldstein, professor of molecular genetics and microbiology, applies state-of-the-art genomic science to help understand how human genetic variation influences disease and drug response.

Dr. Anna Need of Duke's Department of Psychiatry will jointly manage the collaborative research.

Need says that clozapine currently is the best antipsychotic drug available to treat schizophrenia that is not responding well to other medications. She says it is used to treat psychotic disorders including schizophrenia, schizoaffective disorder and some cases of psychosis not otherwise specified.

Although only about 1 percent of patients are likely to develop CIA, all must be regularly screened for it as there is no way to identify that 1 percent until they start to show symptoms, Need explains.

"However," she adds, "because of the risk of agranulocytosis, physicians are reluctant to prescribe it. It is also an expensive drug to prescribe, because the patients must come in frequently for blood tests to check their counts.

"If there was a strongly predictive test, this could cut the costs of continual monitoring, saving Medicaid a lot of money and increase the number of patients taking clozapine," Need explains. "This would reduce the number of patients who have untreated schizophrenia, and thus reduce the costs to society of those patients."

Patients would benefit from having increased access to a drug that is proven to be effective in treatment-resistant schizophrenia, and proven to reduce the risk of suicide.  The commercial potential for better understanding the role of genetic variation would likely come in the enormous potential in heading off potentially fatal side effects before the arduous process of a patient becoming accustomed to a psychiatric medication takes place. Developing and marketing such a test would save patients, doctors and insurance and government programs time and money.

Last fall, the SAEC received a gift of research materials and data relating to the CIA cohort to be used in the collaboration from PGx Health, a division of Clinical Data Inc. The data corroborated the already published evidence for genetic associations in HLA region (Chromosome 6), consistent with a proposed immunological mechanism as an important causal factor associated with CIA.

Duke and the SAEC plan to expand on the data by conducting more extensive studies of CIA using state-of-the-art whole-genome sequencing techniques.

"Our genetic research on both drug-induced liver injury and serious skin rashes points to a strong role of the immune system in contributing to these adverse responses," says Arthur L. Holden, chairman of the SAEC, in a prepared statement. "By researching the genetics of drug-induced CIA, we hope to further our understanding into the genetics of immunologically mediated adverse drug responses. Our collaboration with Duke University's Center for Human Genome Variation represents our first pilot to use whole genome sequencing technology to better understand the role of rare genetic variation in such events."

"For many patients clozapine is the most effective drug available, but its use is constrained by the possibility of this serious adverse event requiring intrusive monitoring programs," says David Goldstein, professor of molecular genetics and microbiology at Duke University. "We hope that understanding the genetics of CIA will not only reduce its occurrence, but also allow wider use of clozapine."

Founded in Fall 2007, the SAEC is a private, nonprofit, global partnership of leading pharmaceutical companies, the U.S. Food and Drug Administration and academic institutions from around the world to identify and confirm genetic markers that may help predict which patients are at risk for drug-related serious adverse events. Through identifying and ultimately validating genetic markers associated with SAEs, the consortium hopes to reduce the patient and economic costs caused by drug-related SAEs. The SAEC also hopes to improve the flow of safe and effective medical therapies by better addressing idiosyncratic safety risks of new drugs before they reach the market. The SAEC provides free access to its study data and results to all qualified researchers.

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