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Novartis to Fund US Commercialization of CML Companion Dx on Cepheid's GeneXpert System

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By Ben Butkus

Cepheid said this week that it has entered into an exclusive collaboration with Novartis to commercialize a test to monitor BCR-ABL gene transcripts in peripheral blood from patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

The deal is expected to aid physicians in managing Ph+ CML patients treated with Novartis' Gleevec by creating a standardized molecular monitoring test that can be used by many labs with greater reproducibility, the companies said.

The agreement is also Cepheid's first with a major pharmaceutical company for the development of a companion diagnostic test, and is expected to benefit the Sunnyvale, Calif.-based molecular diagnostics company by expanding the test menu for its GeneXpert platform and driving additional sales of the system, David Persing, Cepheid's chief medical officer, told PCR Insider this week.

"The obvious advantage to us is that we have yet another test that is going to be widely promoted with the assistance of a major pharma partner, which will be used in the context of patient management for [Ph+ CML]," Persing said. "[Novartis is] essentially underwriting the R&D and clinical trial costs, so the net effect for us is that we get one more product to run on the same GeneXpert platform that already exists in more than 700 hospitals in the US."

Under the agreement, scientists from Cepheid and Novartis will develop a PCR-based test on GeneXpert to measure BCR-ABL transcripts in peripheral blood specimens from Ph+ CML patients, with the intent of seeking regulatory approval from the US Food and Drug Administration. It would be the first such test to receive FDA clearance.

As part of the deal, Cepheid will receive an upfront fee of $5 million from Novartis, with an additional $3 million in milestone payments over the next year. Once the test is commercialized in the US, Novartis will have exclusive global distribution rights to the Xpert BCR-ABL test under a combined Cepheid-Novartis label and working in concert with Cepheid's commercial operations team, Cepheid said.

The companies said that the test, used in conjunction with other lab tests, will help doctors monitor levels of BCR-ABL transcripts in Ph+ CML patients and aid in their management. Further, a key aspect of the test will be that its results will be linked to the International Scale, an internationally vetted and accepted standard for monitoring BCR-ABL transcript levels in Ph+ CML patients.

"Results linked to the International Scale are important to determine whether a patient has achieved the important therapy milestone of 'Major Molecular Response,'" a Novartis spokesperson wrote in an e-mail to PCR Insider. "By moving to a standardized molecular monitoring test that can be used by many labs with greater reproducibility, we aim to improve patient care by reducing the variability that is currently inherent in BCR-ABL testing, and increasing confidence of patient management decisions."

The spokesperson added that Novartis conducted "an extensive evaluation of potential collaborators" before settling on Cepheid's GeneXpert system for the test, bud did not provide details on the criteria the company used to select the platform.

Cepheid has marketed a BCR-ABL monitoring test for GeneXpert in countries recognizing the CE Mark since 2006 and, according to Persing, was already planning to submit its test to the FDA for approval before it struck its agreement with Novartis.

"First, we gained a partnership with the world leader of therapeutics for this particular condition," Persing said. "Second, we gained their strength and promotional capabilities worldwide. And third, they are covering the costs of a program that we were already planning on spending money on anyway."

Persing also noted that an important reason for the collaboration was that Novartis has access to "unprecedented quantities of specimens from clinical trials that we will have access to, to verify performance of the test. As a result of that specimen collection, we will have sufficient numbers to make a very compelling case for regulatory approval."

Cepheid's CE-Marked Xpert BCR-ABL test is based on a nested PCR method whose worth has already been demonstrated: Persing said that a similar method is used in Cepheid's Xpert MTB/RIF test for diagnosing tuberculosis and rifampin- and multi-drug-resistant TB. That test received a clinical vote of confidence for its performance in remote and resource-poor regions of the world in a New England Journal of Medicine research paper published in early September (PCR Insider, 9/2/10).

"That approach has had such extraordinary success in improving sensitivity that we have opted to use that approach in other settings where we want to get maximum sensitivity," Persing said.

In order to make the BCR-ABL test easy to use, "we couldn't expect a laboratory to have to manipulate multiple milliliters, maybe 10 or 20, of whole blood in a nucleic acid extraction protocol, Persing said. "Many laboratories were used to doing this to obtain good sensitivity for their BCR-ABL assays."

The Xpert test, on the other hand, maintains a similar level of sensitivity to other laboratory-developed tests but uses much less blood — about 200 μL — "because it is so sensitive it can detect just a few cells," Persing added.

For Cepheid, the US availability of an Xpert BCR-ABL test would likely expand the market for Cepheid's GeneXpert system because it will expand the menu of molecular tests that can run on the platform.

Persing noted that for certain labs, the BCR-ABL test alone might be "a very compelling reason to get the system." This might be especially true for laboratories that currently send their BCR-ABL tests out to reference labs, which is the "dominant strategy for this particular test," he said.

"A send-out test is … very expensive, takes a long time, and is not standardized," Persing said. "Novartis quickly recognized that. They realized that you couldn't rely on BCR-ABL tests from laboratory to laboratory, or even time point to time point within the same lab. They recognized the need … to develop a test that conforms to international standards; and that's reproducible, accurate, quantitative, and highly sensitive."

Another interesting aspect about the deal is the nature of Ph+ CML disease progression. Whereas once the condition was almost certainly fatal, it has been rendered chronic by the success of treatment with Gleevec.

"If you look at the natural history of [Ph+ CML] before Gleevec, there were only 10,000 or 15,000 patients existing in any given year, because the disease would occur and rapidly take its course and the patients would die," Persing said. "Since Gleevec, the number of patients has grown steadily year over year, about 5,000 to 10,000 patients added per year, because they're all surviving.

"So the interest is in developing a test to identify patients … whose management is appropriate based on the quantitative measurement of BCR-ABL transcript," he added.

The BCR-ABL test development agreement may also be a gateway to further companion diagnostic collaborations between Cepheid and Novartis. In a statement, Cepheid said that the companies "will explore further collaboration to develop other diagnostics which will help physicians better manage patient treatment."

Both Persing and Cepheid's spokesperson declined to provide additional details about potential further collaborations. However, in general, Persing said that Cepheid views GeneXpert as an ideal platform for companion diagnostic testing because of its quick turnaround time and conduciveness to use in a near-patient setting.

"The last thing a drug company wants is for a prescribing decision to be held hostage by a diagnostic test that may take days or weeks to happen," Persing said. "They'd much rather have results available quickly so all that info can be integrated into a patient management decision quickly."

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