This article has been clarified to note that Novartis discovered the gene marker linked to liver toxicities associated with lumiracoxib, not Novartis' diagnostics unit.
By Turna Ray
Cepheid and Novartis are collaborating on the development of a test for monitoring Bcr-Abl gene transcripts, which will help doctors more reliably manage Philadelphia chromosome-positive chronic myelogenous leukemia patients treated with Novartis' oncologic Gleevec.
Gleevec has been on the market for a decade for the treatment of Ph+ CML, and among oncologists it is already standard practice to molecularly monitor Bcr-Abl transcript levels to confirm patients have the disease and to ensure patients aren't relapsing or having a refractory response to treatment.
There is a lack of standardized procedures and reference materials in leukemia monitoring, however, which can make it difficult to compare results obtained from different labs.
In response, Novartis is hoping to reduce variability in Bcr-Abl transcript monitoring by developing and commercializing a test that reports results in line with a standard called the International Scale.
Published by the European LeukemiaNet consortium, the International Scale was developed with numerous stakeholders at the National Institutes of Health to serve as a global standard for detecting and reporting Bcr-Abl transcript levels.
"A standardized molecular monitoring Bcr-Abl test with greater reproducibility is expected to support optimal patient management decisions," Cepheid said in a statement. "By moving to a rigorously developed, regulatory-cleared/approved test which is also linked to the IS, the collaboration aims to reduce the variability that is currently inherent in Bcr-Abl testing."
Novartis has been working with others in the field to characterize the variability of Bcr-Abl testing. In 2007, Novartis, Qiagen, and several European agencies funded a trial to study the lack of comparability of Bcr-Abl mRNA quantification results generated by two quantitative reverse transcriptase PCR platforms ─ Roche's LightCycler platform and Life Technologies/Applied BioSystems TaqMan ─ at six laboratories.
As part of this study, led by Martin Muller of Heidelberg University, researchers concluded that standardization of quantitative PCR platforms is possible regardless of the PCR machine used; that the sensitivity of the test depends on the volume of peripheral blood used (with 2.5 mL considered to be "sufficient"); and that both ABL and G6PD can be used as control genes.
"The comparability of [quantitative RT-PCR] data does not depend on the use of identical platforms but on a common procedure to calculate results," the researchers concluded. "External standards may help to control the differences in performance between laboratories."
The researchers also called for international agreement on the use of PCR protocols for each platform, and recommended "the implementation of international control and calibrator materials, and the prospective use of these protocols within clinical trials."
European LeukemiaNet published the International Scale consensus after this study was published.
The test being developed by Cepheid and Novartis will be based on Cepheid's integrated PCR-based GeneXpert system, and will measure Bcr-Abl transcripts in peripheral blood specimens from patients diagnosed with Ph+ CML. This 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, the company said.
The companies plan to file for regulatory approval for the test through the FDA. If approved, Cepheid's GeneXpert system would be the first to receive FDA's stamp of approval for Bcr-Abl diagnosis and monitoring.
Even without FDA approval, the test will compete with others already on the market. Several companies, including Roche, Qiagen, and the Laboratory Corporation of America, market laboratory-developed tests to gauge Bcr-Abl transcripts for CML diagnosis and monitoring while on Gleevec.
Cepheid's Xpert Bcr-Abl has a CE Mark in Europe, and it has been available outside the US for four years. The deal with Novartis, under which Cepheid will receive up to $8 million in fees and milestone payments, will allow Cepheid to expand commercialization within the US. Under the terms of the agreement, Novartis will pay for clinical studies and other development expenses for the test.
Once the test is launched in the US, Novartis will retain exclusive global distribution rights for the Xpert Bcr-Abl test. Novartis's commercial team will work with Cepheid's sales group to market the test.
Novartis launched its own molecular diagnostics unit last year. The company so far has identified a marker that can help gauge which patients may be at risk for liver-related adverse events when treated with the Cox-2-inhibiting painkiller Prexige or lumiracoxib (PGx Reporter 02/10/10). The company is planning to submit lumiracoxib with a biomarker-based test to the US Food and Drug Administration but has not yet done so.
In inking the deal with Cepheid, the development and commercialization of a Bcr-Abl diagnostic can serve as a test case for Novartis' nascent diagnostic arm. Upon commercial launch of the Bcr-Abl test, Novartis and Cepheid may extend their collaboration for the development of other diagnostics in the area of personalized medicine.
Gleevec (imatinib mesylate) received FDA approval in 2001. The drug's label describes it as "a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML."
The drug's label reports data from several studies on the cytogenetic response of Ph+ CML patients as measured by their Bcr-Abl transcript levels.
For example, the label discusses one open-label randomized Phase III study involving more than 1,000 newly diagnosed Ph+ CML patients in chronic phase. This study reported that the probability of patients remaining progression-free at 60 months was 95 percent "for patients who were in complete cytogenetic response with major molecular response" — defined as a greater than 3-log reduction in Bcr-Abl transcripts as measured by quantitative RT-PCR at 12 months.
Comparatively, PFS was 89 percent for patients in complete cytogenetic response but without a major molecular response and 70 percent for patients who were not in complete cytogenetic response at this time point.
Although Bcr-Abl monitoring has been accepted as part of clinical practice for many years, Novartis has not until now invested in the development of an FDA-cleared commercial test for this purpose. Developing the test with Cepheid after a decade of clinical experience will likely mitigate any reimbursement hurdles that Novartis may have to face if the company was introducing a novel companion test that doctors aren't already comfortable with.
Bcr-Abl testing to diagnose and monitor Ph+ CML patients receiving Gleevec is one of the few pharmacogenomic strategies that the Centers for Medicare & Medicaid Services' Medicare Coverage and Evidence Development Advisory Committee has deemed clinically useful. During a meeting earlier this year, MEDCAC panelists expressed high confidence (4.27 average score from voting members) that BCR-ABL testing to diagnose and monitor CML improved outcomes (PGx Reporter 02/03/10).