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Clinical Data to Launch Clozapine Dx Later in 06 As CLIA Test, Plans to Discuss Test With FDA

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Clinical Data plans to launch its first molecular diagnostic later this year, a product designed to identify patients at risk for developing severe adverse events to the third-line schizophrenia drug clozapine, Carol Reed, the company's chief medical officer, told Pharmacogenomics Reporter this week.

Clinical Data will offer the test before the end of the year through its CLIA lab, but the company is not discounting plans to talk about the test with US regulators. "We certainly have plans to discuss the implications of this with" the US Food and Drug Administration, Reed said. "Some of the groups at FDA are already aware of what we've been doing, and we look forward to continuing those relationships, as well as cultivating some other groups within FDA who need to know, but might not be as familiar with it."

"I think the need to seek FDA approval for [the test] will depend on the life-cycle management issues … as well as discussions with FDA and where they might like to see it go," she added.

Approximately 0.8 percent of patients taking clozapine develop agranulocytosis, which is an inability to create white blood cells that can quickly lead to infections and death. Patients prescribed clozapine must have failed at least two other treatments, and they are required to undergo weekly blood testing to detect white blood-cell depletion.


"I think the need to seek FDA approval for [the test] will depend on the life-cycle management issues … as well as discussions with FDA and where they might like to see it go."

Sales for clozapine amount to approximately $200 million per year. The drug is available from Novartis under the name Clozaril, and generic versions are sold by Teva Pharmaceuticals and Mylan Pharmaceuticals. Between 80,000 and 90,000 people in the United States take the drug, with "at least that many" in Europe, Reed estimated. "It gets about 4 percent of the antipsychotic market," she said.

It seems clear that upgrading clozapine's status from third-line to first-line treatment would increase the drug's sales and bolster sales of Clinical Data's test. The maximum number of patients who might be given the test, assuming clozapine is approved as a first-line therapy, probably equals the incidence of schizophrenia, which is about 1.4 per 1,000 people per year, according to a May review article in the online journal Public Library of Science Medicine.

The company also said it hopes the test will encourage US regulators to consider upgrading clozapine to a first-line, and thus more widely prescribed, treatment. Until then, Clinical Data plans to sell its test to clinicians involved in the tedious monitoring process that currently accompanies clozapine treatment. However, the firm has not begun discussing with the FDA whether its test can play a role in the agency's decision to make the drug a first-line therapy.

Asked if this test can remove a large number of poor responders, the FDA said it would be interested in exploring Clinical Data's evidence. And if the data are "confirmed predictive, [it] could [hypothetically] result in further discussions with the sponsors of clozapine regarding how to reflect this in labeling," an FDA spokesperson said this week. She said discussion of what drug label changes might take place was "too speculative."

In addition, the test may not have reached its final form. Clinical Data is continuing to research the genetic nature of clozapine adverse events, and it may add further genes and "other markers" to the test, said Reed. She declined to estimate when the company might develop an improved version of the test. "I think you'll see continued improvements over the next 10 years — not only as we continue our research efforts, but also as the test actually gets launched and we see some real-world use."

In addition to typical psychiatrists, the company is considering advertising the test to psychiatrists who operate clozapine clinics that monitor patients on the drug for signs of agranulocytosis. The company also hopes to market the test to hematologists, "who are very frequently consulted for patients who are on clozapine," said Reed.

Reed said the company is still formulating its strategy about approaching professional organizations representing these specialties.

— Chris Womack ([email protected])

Clinical Data's test may not only be effective for identifying adverse responders for clozapine. To some degree, agranulocytosis, the adverse event associated with the schizophrenia drug, happens to be linked to a large number of therapeutics, and Clinical Data believes some of the genomic markers it has identified for clozapine may be more broadly applicable.

"I think knowing that our marker is in the HLA complex points you in the direction of a mechanism of action that you [might be able to apply to] other drugs that cause this problem, and whether you might expect the same mechanism of action," Clinical Data CMO Carol Reed said. She declined to specify which other drugs might be appropriate for the test.

Because there are several different causes of drug-induced agranulocytosis, and the mechanism of clozapine-induced agranulocytosis remains unclear, the applicability of Clinical Data's test to other therapeutic agents is unclear, too.

There are several therapies associated with the most common cases of drug-induced agranulocytosis and neutropenia, which is an abnormally low number of neutrophils, another kind of white blood cell: dipyrone, mianserin, sulfasalazine, phenothiazine, semi-synthetic penicillin, NSAIDs, aminopyrine derivatives, benzodiazepines, barbiturates, gold compounds, sulfonamides, and anti-thyroid drugs, according to Medicine World, an industry online publication.

— CW

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