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Genzyme Launches Gleevec-Resistance Dx, Hopes Replacement Tx Will Make it to Market

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Fulfilling a promise it made late last year, Genzyme Genetics last week launched a Bcr/Abl secondary-mutation diagnostic aimed at helping physicians identify patients with chronic myeloid leukemia that is in the process of becoming resistant to the Novartis drug Gleevec.

In addition to developing the Bcr/Abl mutation test, which is the first of its kind, the company also added two more common genetic tests to its product menu: an epidermal growth-factor receptor expression test based on FISH for identifying patients who may respond to tyrosine-kinase inhibitor therapies for non-small cell lung cancer, such as Iressa and Tarceva; and a Janus kinase 2, or Jak2, mutation test, which is used to confirm diagnoses of chronic myeloproliferative disorders.

Genzyme offers its testing services to clinicians and hospitals, and performs the tests in its own CLIA lab.

"It's been a busy quarter — they don't usually all hit that way," Celeste Chenet-Monte, Genzyme Genetics marketing director, told Pharmacogenomics Reporter last week. "We wanted to get them out as soon as we can, because they're ready in our lab."

Genzyme may be able to hit the ground running with the Bcr/Abl secondary-mutation test because the company has already established a market for its quantitative PCR Bcr/Abl diagnostic, which helps physicians monitor the status of a patient's CML.Genzyme performs "thousands" of monitoring tests every year, said Chenet-Monte.


"Potentially, [the Bcr/Abl mutation test's market] would be the entire Gleevec market, because somewhere upwards of 80 percent of patients now are on Gleevec, and of those about 5 percent a year will develop resistance."

The Bcr/Abl mutation test and its two companions are the next in a series that will include "about another half dozen" similar tests the company plans to release in 2006, and come soon after the company released two diagnostics for guiding treatment with separate cancer therapies.

In September, Genzyme launched an EGFR mutation test, which also is designed to help physicians identify people likely to respond to drugs such as Iressa and Tarceva; and in December, the firm launched a UGT1A1 test to help identify patients likely to experience adverse events in response to Pfizer's colorectal cancer drug Camptosar.

Most of these diagnostics can help suggest other courses of therapy, but the Bcr/Abl test cannot, despite the fact that Gleevec is viewed by some in the industry as a good example of therapy that can be guided using pharmacogenomics. At least three drug makers are currently developing therapies for Gleevec-resistant patients, but none has yet exited its pipeline. As such, results showing that a patient is becoming resistant to the drug will leave oncologists with few options.

Chenet-Monte said that the Bcr/Abl mutation test's market could "potentially … be the entire Gleevec market, because somewhere upwards of 80 percent of all CML patients now are on Gleevec, and of those about 5 percent a year will develop resistance." The chance of a patient developing a secondary, resistance-causing mutation appears to be associated with the length of time that the patient is exposed to the drug, and as many as 90 percent eventually become resistant to the drug due to a secondary mutation, she said.

Approximately 4,600 new CML cases were diagnosed in the United States in 2005, and about 25,000 CML patients are in remission on therapy in the US today, according to the American Cancer Society.

Gleevec targets the Bcr/Abl protein of cells that have developed a Philadelphia chromosome mutation, and 4 percent to 5 percent of patients each year become resistant to the drug as the result of a secondary Bcr/Abl mutation. Thus, Genzyme's test could be used to identify more than 1,000 newly resistant patients each year.Gleevec is a blockbuster. Last year, the drug generated $2.2 billion in sales for Novartis, an increase of 32 percent over 2004. In addition to greater market penetration, the company said contributing to the growth was an increase in the average daily dose for the drug.

The drug is indicated for all stages of chronic myeloid leukemia and some forms of gastrointestinal stromal tumors. Novartis submitted Gleevec to regulatory agencies in the United States, Japan, and the European Union for the treatment of acute lymphoblastic leukemia, but it is not yet approved for this indication.

The new Bcr/Abl test will catch on over time "as doctors start to see its value as an early predictor of resistance to the drug — hopefully in conjunction with monitoring," Chenet-Monte said. The company performs "thousands" of monitoring tests every year with the Bcr/Abl PCR test, she added.

Chenet-Monte said the company is marketing its new tests by sending experts to speak to clinicians individually, at grand rounds, tumor boards, and educational physicians' programs, as well as through brochures, mailings, and visits by sales representatives.

Building the Product

The Bcr/Abl secondary-mutation test is based on intellectual property that Cambridge, Mass.-based Genzyme obtained in an exclusive licensing agreement with the University of California at Los Angeles Jonsson Cancer Center in October. The test uses sequencing to detect all of the secondary mutations that confer Gleevec resistance to CML cells.

Many laboratories, including Genzyme, offer a quantitative RT-PCR test and an older FISH test for CML monitoring, which, like the mutation tests, uses blood or bone-marrow samples. When these diagnostics or other clinical factors reveal that the number of aberrant cells in a CML patient taking Gleevec is on the rise, patients can be tested with the Bcr/Abl secondary-mutation diagnostic to determine whether they are becoming resistant to the drug.

But there is not yet a drug to take Gleevec's place. "The [CML] drug that is furthest along is [Bristol-Myers Squibb's] dasatinib, and that may actually be FDA-approved within 2006, so it's quite far along," said Neil Shah, a researcher at the Jonsson Cancer Center and a member of its Hematopoietic Malignancies Program Area.

Shah cites Novartis' AMN107, which is "about six months behind," but in Phase II, as the next closest to the market. Wyeth's SKI-606 and Nippon Shinyaku's NS-187 are further behind still, said Shah.

Up to this point, doctors have simply been increasing the dose of Gleevec for resistant patients, which can hold CML at bay until resistant clone cells eventually prevail, said Chenet-Monte.

Pfizer's Sutent, which was approved late last month for GIST, may turn out to be a replacement for Gleevec in resistant GIST patients.

— Chris Womack ([email protected])

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