In research that may eventually upgrade clozapine from a third-line schizophrenia treatment to a second-choice option, Genaissance Pharmaceuticals said this week it had discovered genetic markers capable of identifying patients at risk for clozapine-induced agranulocytosis.
Taking into account the amount of time required for validation studies and a product launch, a diagnostic may be released within two years, said Richard Judson, Genaissance CSO.
The study, known as clozapine and Agranulocytosis Relationship Investigated by Genetics, is a small one, involving 33 cases and 57 controls, and so must undergo stringent validation.
The third-line anti-psychotic clozapine is highly valued among psychiatrists, but approximately 0.8 percent of patients develop agranulocytosis, an inability to produce white blood cells, said Judson. Infections and death can quickly follow agranulocytosis.
“It takes about two weeks for this condition to set in fully, so if you blood test every week, you can catch it before it gets out of hand,” said Judson. In addition to the danger of agranulocytosis, psychiatrists often find it difficult to subject schizophrenic patients to weekly pinpricks, “so as a consequence, the drug is not used as widely as psychiatrists would like,” he added.
Because patients must have failed at least two other treatments before using clozapine, only “hundreds” of people are affected by the danger of agranulocytosis. However, a test sensitive enough to move the drug further up the treatment hierarchy would be used by many more patients per year than the pinprick.
The agranulocytosis rate does not have to be “cut down to zero,” but “far enough” that the risk-benefit ratio of the drug is “net positive,” said Judson. Suicide is a major risk factor affecting schizophrenic patients who discontinue antipsychotics, he added.
For its cases and controls, the company recruited patients who had previously taken clozapine and developed — or not developed — agranulocytosis.
In all, Genaissance identified 75 candidate genes, including genes involved in drug metabolism, drug transport, and schizophrenia etiology, then resequenced each gene in study participants, Judson said. “We came up with four candidate markers that each individually identifies a pretty good set of the cases,” he said.
“The things we are finding are pretty big effects, with odds ratios of 10 or 12” to one, Judson said.
From this point, the company hopes to develop a diagnostic test, but Judson declined to disclose whether the company would undertake product development alone, or seek collaboration. The company currently manufactures one test, the Familion test for Long-Qt, and it owns the intellectual property of the thiopurine methyltransferase test produced by Prometheus Laboratories.
The research was funded by Genaissance and conducted in a joint effort with John Kane, chairman of the Department of Psychiatry at the Zucker Hillside Hospital.