When Genzyme Genetics last week launched its Flt3 mutation-analysis prognostic for acute myeloid leukemia mortality, it was also laying the groundwork for the eventual arrival of Flt3-inhibitor drugs that might require such a test to identify responders.
"I think that ultimately that is the goal — to use this as a driver of therapy," Celeste Chenet-Monte, marketing director at Genzyme Genetics, told Pharmacogenomics Reporter this week. But without a complementary drug on the market, the company will only offer the PCR-based test to help physicians better predict mortality in patients with AML. The company's interest in the test may signal that it believes that demand for a complementary test is significant even in the face of existing competitors in the area such as Quest, LabCorp, and academic centers.
A pharmaceutical company able to develop a promising AML therapeutic has a chance to stand alone in a market with an unmet clinical need. In fact, one company developing a Flt3 inhibitor, Cephalon, has been awarded orphan-drug designation for treatment of AML, according to a Cephalon spokesperson.
According to the American Cancer Society, there will be about 11,930 new cases of AML in the United States this year, and the 5-year survival rate of adults under 65 is about 33 percent. Currently available AML treatments are associated with treatment-induced mortality rates as high as 25 percent in poor-risk patients, according to the FDA. If Flt3 inhibitors continue to follow the pharmacogenomic route, and responders can be identified using a mutation test, the drugs are likely to be directed against the worst AML cases.
"Today, Flt3 is a very important negative prognostic marker, but ultimately, its future use is as a predictive marker in therapeutic selection of Flt3 inhibitors."
Currently, only Pfizer's Sutent inhibits the Flt3 receptor tyrosine kinase as part of its effects. But the drug is approved neither for that part of its activity, nor for AML. Flt3 is encoded by the gene that Genzyme's test exploits [see sidebar].
There are at least three Flt3 inhibitors wending their way through clinical trials as AML treatments, according to the US National Institutes of Health: MLN518, made by Millennium; PKC412, by Novartis; and CEP701, by Cephalon. None of them has progressed past phase II, and it remains unclear whether Flt3 mutation status will be a useful predictor of response, suggesting that Genzyme's test could remain a prognostic tool.
Genzyme offers the test as a CLIA lab service, and it does not intend to file the test for clearance as an in vitro device with the US Food and Drug Administration, Chenet-Monte said.
"Today, Flt3 is a very important negative prognostic marker, but ultimately, its future use is as a predictive marker in therapeutic selection of Flt3 inhibitors," she said. "We tried to cover the [pharmacogenomic markers] that already exist, and now we're looking out toward new ones — that's where the future is, and the key is to get in ahead of the drugs being approved, and that way the test is ready when the drugs come on the market."
Genzyme Genetics does not partner with drug makers, and Genzyme Analytical Services, the division that might collaborate with pharma to produce theranostics, was not able to reply before deadline.
An AML Link — or Not
The Flt3 assay, originally developed at Johns Hopkins University Hospital, tests bone marrow or blood samples for two different kinds of mutations associated with poor prognosis and a poor response to standard chemotherapy: internal tandem duplications, or ITDs, in the juxtamembrane region of the coding sequence; and SNP polymorphisms in the activation loop portion of the sequence.
Genzyme's assay can detect abnormal cells comprising 6 percent to 8 percent of the total cells in a sample, the company said last week in a statement.
Both types of mutations cause the final protein to remain constitutively active, with ITDs occurring in about 20 percent to 25 percent of AML cases, and activation-loop mutations in about 5 percent to 10 percent of cases, according to investigator Gary Gilliland, a tyrosine kinase specialist with experience working on Flt3 inhibitors at Brigham and Women's Hospital in Boston.
The Flt protein is a receptor tyrosine kinase in the same family as C-Kit and PDGFR. Although constitutive activation of Flt3 seems to confer a proliferative advantage to AML cells, the mutations are not sufficient to cause disease.
A Flt3 mutation test similar to Genzyme's product is offered by Quest and LabCorp, as well as by a number of academic centers, including Johns Hopkins, Stanford University Hospital, Sloan Kettering, Dana Farber, and Oregon Health and Sciences University.
In clinical trials of Flt3 inhibitors, investigators have identified a link between mutation status and response, although there is no clear indication that a diagnostic will be a useful guide for physicians.
"In phase I trials, people took all comers, but [investigators] looked at Flt3 mutational status," said Michael Heinrich, a professor of medicine at Oregon Health and Science University Cancer Institute in Portland who studies tyrosine kinases and the action of inhibitors in cancer. "In the phase II trials, [enrollment] was often restricted to patients only with the mutation."
One reason mutation status is not a sure-fire way to predict Flt3 inhibitor response is that mutation status can identify two of possibly many mechanisms that can force Flt3 to remain active. Other factors that might complicate the ability of a Flt3 test to identify responders include inhibitors that may be active on a combination of kinases that together have more of an effect than Flt3 inhibition. Moreover, researchers may find that overexpression of Flt3 is a better gauge of response than mutational status.
"The feeling is that there will be a better response in the Flt3 mutant population, and if the studies are designed that way — and positive — then the FDA label's indication is going to be for Flt3-mutant leukemia," Heinrich said.
One reason to think that it may be difficult to predict response to Flt3 inhibitors is that the compounds generally arose from drug programs seeking to inhibit a related kinase, such as C-Kit, said Heinrich. "So far it hasn't been possible to make a single inhibitor against [one of] those family members," he said. "Flt3 inhibitors always inhibit Kit or PDGFR to some extent."
The Rx Challengers
Cephalon's CEP701 has been involved in one completed phase II trial in patients with refractory AML who have Flt3 mutations. A second phase II trial is underway to examine the drug's effect on the proportion of relapsed AML patients with a Flt3 mutation who achieve a second remission.
Cephalon hasn't explored what sort of activity CEP701 might have in patients without a Flt3 mutation, said Peter Brown, the company's vice president of clinical oncology. "Our early research suggests that the drug will be most active in patients who have the mutation," he said. The company has not collaborated with any diagnostic companies for a Flt3 theranostic, he added.
Should CEP701 be approved on the basis of its trial involving Flt3-mutated patients, the FDA will probably "want assurance that a validated assay is commercially available for doctors, it should want to put patients on this drug," said Brown. Genzyme's and other companies' Flt3 assays could help reassure the FDA that Flt3 mutational status is becoming established as a part of AML treatment.
Millennium's AML compound, MLN518, is currently involved in two phase I clinical trials, one of which examines safety and tolerability in patients with ITD Flt3 mutations, while the other is investigating it in combination with standard chemotherapy, enrolling patients with and without Flt3 mutations.
"It's too early to tell" whether patients with Flt3 mutations respond better to MLN518, said Phil Trepicchio, director of Millennium's clinical research and pharmacogenomics program. The compound is directed at activated Flt3, regardless of the mechanism of activation, he said.
Meantime, Novartis' compound, PKC412, is involved in a phase I/II study examining the responses of patients with AML and patients with myelodysplastic syndrome. These patients are stratified according to Flt3 mutational status to receive the compound alone or in combination with the chemotherapeutic itraconazole.
Another PKC412 study in AML and myelodysplastic syndrome is examining its efficacy in patients with wild-type or mutated Flt3 as a phase II trial. Two other trials involving the compound, a phase I and a phase II, make no mention of Flt3.
Novartis was not able to respond to questions before deadline.
— Chris Womack ([email protected])
The First Flt3 Inhibitor — Sort of
Pfizer's drug Sutent, which inhibits Flt3 as part of its action, is not being studied for use in AML. The drug was approved in January for renal cell cancer and gastrointestinal stromal tumors after failure with Gleevec therapy.
"The period of drug washout or drug holiday was the problem because the leukemia would come roaring back too quickly, whereas in solid tumors, it would probably grow more slowly … so a period of being off the drug is OK," as minor tumor regrowth would occur between dosing cycles, said Michael Heinrich, a professor of medicine at Oregon Health and Science University Cancer Institute in Portland who studies tyrosine kinases and the action of inhibitors in cancer.
The drug is mentioned in 32 phase II and phase III clinical trials, many of which are related to its approved indications, and none of which are in AML.
Because Flt3 inhibitors have not been active enough as stand-alone AML treatments, sponsors are testing their drugs as complements to chemotherapy for that indication, said Heinrich. Both Novartis' PKC412 and Millennium's MLN518 are being studied in trials involving chemotherapy. Sutent is also involved in several trials in combination with a chemotherapeutic, none of them in AML.
Interestingly, the two-part nature of Flt3 activating mutations might introduce an opportunity for choosing between inhibitors of the kinase. "Depending on what the mutation is, the drug might be more or less active," said Heinrich. Thus, a physician's choice of drugs might be informed by which specific Flt3 mutation a patient's disease carries.