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LGC s Clozapine Efficacy Dx Could Support Clinical Data s Biomarker Research of Drug

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Psychiatry retains its position as an early proving ground for pharmacogenomic applications with LGC's launch last week of a SNP service to predict response to the schizophrenia drug clozapine.

And whereas the London-based company is hoping its service and a possible test will identify responders, Clinical Data has identified genetic markers related to adverse reaction associated with the medication. Both developments may work toward making clozapine less expensive, and could help make the drug a first-line therapy, though the two firms haven't linked efforts so far.

Clozapine, a generic drug, can be a very helpful drug for those who respond. Of the drugs indicated for schizophrenia, it's the most effective for the disease's worst manifestations, but it remains a third-line treatment.

Clinicians generally run schizophrenia patients through the gamut of other therapies before prescribing clozapine, partly because non-responders are common — around half of patients respond to the drug — and partly because some patients can suffer its one lethal side effect: agranulocytosis, a potentially fatal inability to produce white blood cells.

Still, "I can certainly tell you that in the discussions we've had with psychiatrists, it's almost universally held, still, to be the most effective drug for schizophrenia," Carol Reed, Clinical Data's chief medical officer, told Pharmacogenomics Reporter this week.


"It is the second most expensive medical-care field after heart disease, just [due to] the cost of the drug, the hospitalization, and the fact that there's no cure for this — it's ongoing through the lives of the patients."

LGC licensed its new test from King's College of London, whose Institute of Psychiatry developed it, and the company plans to begin offering the service in January, Paul Debenham, director of life sciences at LGC, told Pharmacogenomics Reporter this week. Following a stint as purely a service offering, the test may become a product based on LGC's HyBeacons technology that the company initially will roll out to reference laboratories, he said. Alternatively, LGC may decide to issue laboratory service licenses, but either way, the firm hopes to "start discussions with interested parties by the second quarter of next year," he added.

Eventually, LGC would like to produce a version of the test to send to clinics, since the company's technology allows a device to be built that is small and simple enough for desktop work, Debenham said.

Within Europe, the test can be self-certified for a CE Mark, and the firm hopes that it or a partner will apply for clearance with the US Food and Drug Administration as a precondition for distributing a test in the United States, said Debenham. He declined to estimate when LGC might take this step, although he hinted that the company has been in discussions with several potential partners for a US rollout.

"The test will be appropriate for all [schizophrenia] patients eventually, because often patients have incidences of [the disease] where the treatment comes under control, then they come off treatment and it recurs," often resulting in a new treatment, said Debenham.

Schizophrenia occurs on average in about 0.55 percent of the population throughout the world, but the number varies from country to country, according to a review article in the November 2002 issue of the Canadian Journal of Psychiatry. Schizophrenics number about 300,000 in the United Kingdom, or about 0.5 percent of the population, while there are about 2.2 million in the United States, or more than 0.7 percent of the population, Debenham said.

In identifying responders, LGC's clozapine SNP test has the potential to reduce the cost of treatment, said Debenham. Clinicians can take as long as five years to find an appropriate drug for a particular patient through essentially hit-and-miss means, he said. During that time, patients often quit or discontinue treatment with an average of four drugs having experienced adverse reactions or incomplete effects, he said.

Approximately 50 percent of patients respond to clozapine, and "if one could say that we do know the backstop [drug] is probably going to work for these patients, then that might well bring that forward as a treatment, rather than going through this rather protracted progression through the first-[line] drugs and so on," Debenham said.

Other Clozapine PGx

There do not seem to be any other commercial entities working on the pharmacogenomics of clozapine outside of Newton, Mass-based Clinical Data, which acquired the research efforts of Genaissance in October. In December, Genaissance said it had discovered genetic markers that could be used to help predict which patients would develop agranulocytosis.

At the time, Richard Judson, then Genaissance's CSO, estimated that it might produce a diagnostic for determining risk of the condition, which affects approximately 0.8 percent of patients taking clozapine, by 2007.

"We're in the process of validating those findings and moving forward with a test," said Clinical Data's Reed. However, she said the company was not willing to disclose how much progress it had made in developing the test, other than mentioning that it might be available "some time next year."

Is There Overlap?

Despite the fact that the two products seem to complement one another, Clinical Data and LGC have no plans to collaborate around diagnostics for the drug, said Reed and Debenham separately.

But just as LGC's test for response to the drug could save time and money by targeting which patients might receive it, so too could Clinical Data's test for adverse reactions. Although clozapine is available as a generic, "it's not pennies a day yet, it's still a fairly expensive generic, and a lot of that is because of this blood monitoring that has to be done" to prevent agranulocytosis, said Reed.

And it seems that given schizophrenia's considerable treatment costs, such tests would be welcomed. For example, the Schizophrenia Society of Canada estimates that it costs around CA$2.35 billion, or about US$2 billion to treat the country's approximately 300,000 schizophrenics each year.

A rough estimate of the cost of clozapine treatment per patient is £300 month, or $515 per month, said Debenham. Citing other estimates, he said the amount expended on schizophrenia treatment worldwide amounts to as much as $65 billion a year, $12 billion of which are accounted for by drug sales. "At least in the UK, and I think that translates internationally, it is the second most expensive medical-care field after heart disease, just [due to] the cost of the drug, the hospitalization, and the fact that there's no cure for this — it's ongoing through the lives of the patients," he said.

Also like LGC, Clinical Data scientists have also considered the possibility that an effective test could change clozapine's third-line-treatment status. "I think one would certainly hope that if it can be shown that it could be safe in some subgroup of patients, that it could reach second-line status, at least for those patients," said Reed.

LGC's Clozapine Test Details

LGC's test is based on the work of Robert Kerwin and Maria Arranz at King's College, which accurately predicts response or non-response in about 80 percent of patients using 11 different SNPs, said Debenham. "The prediction for efficacy of a treatment in psychiatrics is difficult, because although there's good evidence to say that there's a strong genetic component, nonetheless there are a whole lot of psychosocial factors that can affect the well-being and improvement of the patient," he said. The researchers based their measure of response on the traditional measure of overall function in a schizophrenic patient, the Global Assessment Scale.

The SNPs assessed by LGC's test "are associated with the classic neurotransmitter receptor targets, and what-have-you. Clozapine, like a number of these drugs, [doesn't] act on one single neurotransmitter receptor," but a family of them, Debenham said.

— Chris Womack ([email protected])

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