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Novartis, Invivoscribe to Develop Companion Test for Acute Myeloid Leukemia Rx Midostaurin

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Originally published Feb. 22.

By Turna Ray

Invivoscribe, a firm that has exclusive access to intellectual property for FLT3 mutation testing, will be developing a companion test for Novartis' investigational acute myeloid leukemia drug midostaurin.

Novartis' midostaurin is currently in Phase III studies as a treatment for newly diagnosed AML patients with FLT3 mutations. The FLT3 tyrosine kinase inhibitor is being investigated in a double-blind trial where newly diagnosed AML patients are being randomized to receive daunorubicin and cytarabine with or without midostaurin followed by high-dose cytarabine and midostaurin. The study is current recruiting patients, and one of the requirements for participating in the trial is that newly diagnosed AML patients must have FLT3 mutations.

Last week, Invivoscribe and Novartis announced that they would together develop a test that gauges which patients have FLT3 mutations and therefore are more likely to benefit from combination treatment with midostaurin and chemotherapy. Invivoscribe plans to work with its subsidiary Laboratory for Personalized Molecular Medicine, or LabPMM, to develop the test, and then collaborate with Novartis Molecular Diagnostics to clear it with the US Food and Drug Administration.

Invivoscribe CEO Jeffrey Miller could not reveal the timing for regulatory filing for the drug and the test. A Novartis spokesperson told PGx Reporter that the company would be unable to respond to questions ahead of press time.

Novartis and Invivoscribe plan to commercialize the Rx/Dx combination product simultaneously worldwide. As such, Invivoscribe is in the process of building its global laboratory infrastructure.

LabPMM, located in San Diego, is CLIA and CAP-accredited and provides testing services for FLT3 and NPM1 mutations, two markers that have been linked to AML prognosis. Additionally, Invivoscribe recently opened another lab in Planegg-Martinsried, Germany, which will expand the company's European reach. The German facility will be accredited and accepting samples later this year, Invivoscribe stated.

Miller told PGx Reporter that Invivoscribe is planning to expand its lab facilities to Asia and South America, as well. The company aims to standardize and harmonize testing for FLT3 mutations across all its sites to ensure that customers are getting concurrent results.

The financial details of Invivoscribe and Novartis' collaboration have not been made public. Miller said that under the terms of the deal, Novartis has no reach-through rights to Invivoscribe's patents to the FLT3 mutation.

Molecular Testing Strategy

Midostaurin works by blocking certain enzymes' kinases that facilitate cancer cell growth. Specifically, the drug inhibits the FLT3 cell receptor, which is overactivated in AML patients with mutated FLT3. According to published data, FLT3 is mutated in approximately 30 percent of AML patients.

Treatment guidelines and IP considerations linked to FLT3 mutation testing suggest that the partnership between Novartis and Invivoscribe to develop a companion test for midostaurin was inevitable. As such, it is unclear why Novartis and Invivoscribe didn't ink an Rx/Dx partnership earlier in the drug-development process.

The National Comprehensive Cancer Network updated its AML treatment guidelines last year to recommend testing for certain FLT3 mutations, as well as NPM1, CEBPα, and c-KIT in all patients diagnosed with AML.

Additionally, Invivoscribe, which plans to garner regulatory approval for the test from the FDA, said in a statement that LabPMM "is currently the only clinical laboratory with an exclusive license to the patents required to generate a FLT3 result that can be used toward a regulatory approval of a companion diagnostic."

There is already a substantial body of knowledge suggesting that patients with certain FLT3 mutations, such as FLT3-ITD, have a high risk of disease relapse and poor overall survival. However, studies have also shown that AML patients have varying outcomes when different FLT3 mutations are combined with other molecular markers. For example, AML patients with wild-type FLT3 and NPM1 molecular markers have had better survival in studies than those harboring FLT3 mutations and NPM1.

LabPMM claims on its website that it is the only reference lab "licensed to perform testing to determine FLT3 and NPM1 mutation status." Miller noted that through LabPMM, Invivoscribe holds exclusive licenses to patents for FLT3 mutation testing, and non-exclusive licenses to IP for NPM1 mutations testing.

Although there may be other markers that gauge best responders to midostaurin, so far Novartis and Invivoscribe have only announced developing a test that gauges FLT3 mutations." On its website, Novartis notes that midostaurin also inhibits several other molecular targets including c-KIT, VEGFR-2, PDGFR, and the Pgp-mediated multidrug resistance gene MDR. The drug also inhibits isoforms of the serine/ threonine protein kinase C.

Miller said that it "remains to be seen" whether downstream Novartis and Invivoscribe develop companion diagnostics for mutations other than FLT3. He added that physicians treating AML patients routinely request testing from LabPMM for both FLT3 and NPMI mutations.

Improving Options

Past studies looking at midostaurin's activity in combination with chemotherapy in FLT3-mutated AML patients have considered using pharmacogenomics to reduce the need in AML patients for stem cell transplantation, which requires matched donors.

Since AML patients with FLT3 mutations have decreased survival, there are few options available to this subset of patients beyond palliative care, chemotherapy, and stem cell transplantation. However, when receiving an infusion of donor stem cells, AML patients first receive high doses of chemotherapy, which may kill blood cells and increase the risk of life-threatening infections.

In December 2009, researchers from the Dana-Farber Cancer Institute reported results from a Phase I study involving 40 newly diagnosed AML patients who were first given daunorubicin and cytarabine to induce remission, and then treated with cytarabine and midostaurin twice daily at high and low doses. In this study, 32 of the patients, or 80 percent, experienced a complete response, meaning that circulating AML cells in their bodies decreased to undetectable levels.

Among those with complete responses, 74 percent had normal FLT3 and 92 percent had mutated FLT3. "Eighty-five percent of the group with mutated FLT3 were alive one year after treatment, and 62 percent were alive two years after," the researchers said in a statement reporting the results of the study, which was presented two years ago at the American Society of Hematology's annual meeting. "These results were comparable to those of the normal FLT3 group (81 percent one-year survival, and 62 percent two-year survival)." Additionally, the study showed that patients receiving higher doses of midostaurin experience nausea and vomiting, but patients at lower doses "tolerated the therapy well."

According to the researchers, results of this early study funded by Novartis and several other drug developers, "suggest[ed] that a combination of an FLT3 inhibitor and chemotherapy might be effective enough to reduce the need for donor stem cell transplantation in AML patients with mutated FLT3 who have entered first remission."

In addition to AML, Novartis is studying midostaurin in a Phase II trial as a treatment for aggressive systemic mastocytosis.


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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