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A Test to Go With it

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Personalized medicine promises to tailor treatments to patients' diseases, so to determine whether a drug is suitable for a given patient, pharmaceutical companies are increasingly turning to companion diagnostic tests — tests that, by definition, are necessary to decide if a course of treatment is right for a particular patient. Many such companion tests are being used first in oncology.

"I think if you look at the history of companion diagnostics that have been brought to market, it's really in the targeted oncology space, and for most of these targeted therapies, it's very clear they work very well in specific populations," says Paul Beresford, the vice president of business development and strategic marketing at Biodesix. "Companion diagnostics are the tools to identify those populations."

While there is a lot of interest in companion diagnostic tests, only a handful have been approved by the US Food and Drug Administration, including two last year from Roche/Cobas and Abbott, and FDA is working to clarify its approval process through its latest draft guidance. The Cobas and Abbott tests are based on different technologies, and companion diagnostics in various companies' pipelines are also based on a number of methods. And while a number of companion diagnostics on the market and in development are for cancer drugs, other disease areas are also on the horizon.

"The appeal of a companion diagnostic depends on who you are appealing to because there are a number of stakeholders," says Stephen Little, the head of personalized healthcare at Qiagen. For a diagnostic company like Qiagen, this means a new market for its products, and, for a drug company, it's a way of targeting its therapies. For patients and doctors, Little adds, it's better treatment and a better value. "I think one of reasons that we're seeing quite a large increase in companion diagnostics is because all of these different stakeholders have figured out they can all benefit from the use of a companion diagnostic to target therapy," he says.

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Companion diagnostics appear to have caught on rapidly, especially in oncology. "That's something that has really been notable — the speed at which the world of cancer drug development has switched from the idea of a diagnostic being rare and unusual to you'd be surprised if you didn't have one," Little adds.

A number of tools

The first personalized medicine drug that arguably needed a diagnostic was Genentech's Herceptin (trastuzumab), which was approved by FDA as a therapy for Her2--positive breast cancer. There are a number of assays to detect Her2-positive breast cancer, including Dako's HercepTest, an immunohistochemistry assay as well as the company's fluorescence in situ hybridization test and its dual-color chromogenic assay — illustrating that a number of technologies can provide the same information.

There are a number of pieces to consider when choosing which technology is right for a companion diagnostic, Qiagen's Little says. First, "whatever it is you are trying to measure, the technology has to be able to measure," he says, adding that "once you've made the assumption that the technology will be able to generate the information, the next [considerations] are convenience, ease of use, and cost."

And companies are taking a variety of technological approaches in their companion diagnostic development — from FISH to real-time PCR to proteomics.

The Vysis ALK Break Apart FISH Probe Kit test from Abbott was approved alongside Pfizer's Xalkori (see sidebar) to detect non-small-cell lung cancer patients with ALK rearrangements, who would benefit from the treatment. "FISH is considered the gold standard for detecting gene rearrangements," says Kathryn Becker, director of Abbott Molecular. She adds that it is the only commercially available assay that can detect all ALK rearrangements with 100 percent specificity and 100 percent sensitivity.

Currently, Abbott is collaborating with Merck on a FISH-based companion diagnostic test for one of Merck's investigational cancer therapies. And Abbott's pipeline isn't limited to FISH — it also is developing tests based on real-time PCR, Becker says, and is considering other technologies, including sequencing.

The companion diagnostic approved alongside Roche's Zelboraf — the Cobas 4800 BRAF V600 Mutation Test — is a real-time PCR-based assay to detect BRAF mutations in melanoma patient samples. In development, the Cobas test was found to have 97.3 percent agreement with Sanger sequencing. Additionally, the Therascreen tests from Qiagen are real-time PCR-based diagnostics. One detects the presence or absence of EGFR mutations in tumors and another examines tumor samples for KRAS mutations to identify patients who may respond to EGFR inhibitor therapy like Erbitux (cetuximab).

Biodesix, however, is aiming to bring proteomics to the diagnostic realm. The company has developed VeriStrat, a MALDI-TOF mass spectrometry--based test to identify advanced non-small-cell lung cancer patients who may benefit from EGFR inhibitor therapy. The test, Beresford says, appears to be picking up host response to the tumor. Indeed, he adds, they have been getting encouraging results that the test will also work for other cancers, including breast cancer and colorectal cancer. "Because of the fact that host responses to the tumor can be seen in serum, we feel we are essentially detecting a disease state beyond the specific tumor that therefore applies to multiple cancer types," Beresford says.

In it together

To bring companion diagnostics to market, diagnostic companies often partner with the pharmaceutical companies developing the companion drug. Qiagen has partnered with half a dozen drug companies — from AstraZeneca to Lilly to Pfizer — to develop diagnostics for drugs, and Abbott, which worked with Pfizer to bring Xalkori and the ALK test to market, is currently working with Merck, among others. Biodesix is also collaborating with drug companies to develop tests for their drugs. Part of the challenge there is coordinating the timelines and goals of both companies, and the various regulatory systems.

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"It is a challenge. Is it difficult? Well, yes it is," Qiagen's Little says. "You are dealing with two different companies, and two different regulatory systems, and two different development time-scales. So it's not an easy thing to do. It's not straightforward."

The companies have to communicate and understand what it is that the other does. "The key to be successful [is] we have to understand not only our diagnostic world, but also the world that pharmaceutical companies live in, and vice versa," he adds. "And they've got to understand how diagnostics work and the world that we live in."

Abbott's Becker says that companies working together will be important in bringing personalized treatments to market. "What we've learned from our work with Pfizer and other companies is that successful partnerships and collaborations will be the key in adapting successfully to this shift toward more personalized treatments: No one company or entity has all the answers — a variety of expertise and experience is required," she adds.

Draft regulations

FDA is encouraging the co-development of drugs and diagnostics. The agency issued a draft guidance on in vitro companion diagnostic devices shortly before the approvals of Zelboraf and Xalkori last summer that emphasized such tightly knit development.

The draft guidance states that a companion diagnostic is a device that "provides information that is essential for the safe and effective use of a corresponding therapeutic product." Ideally, such tests and therapies would be developed and go through the regulatory process at the same time, especially if they are new.

"The goal of the draft guidance that was issued last July was to put out our policy position that if a drug depended on a diagnostic test result to be used safely and effectively we would want to approve the diagnostic that went with that drug," says Elizabeth Mansfield, director of Personalized Medicine at FDA's Center for Devices and Radiological Health's Office of In Vitro Diagnostic Device Evaluation. She adds that "the goal there was to tell people that, 'Look if your drug really depends on this test, then we need to approve the test.'"

Mansfield says that the guidance is in the process of being finalized, and that it could be out as early as the end of 2012. She adds that FDA is working on a co-development guidance that discusses the process of developing drugs and diagnostics together.

Other areas

While many of the companion diagnostics on the market and in development are for determining which patients should receive certain cancer drugs, companies are also looking to other disease areas.

Qiagen's Little says that neurological and autoimmune diseases may be the next big areas for companion diagnostics, though oncology will continue to have a large share of the tests.

"Oncology was a beachhead, and then autoimmune diseases are a big area with neurodegenerative diseases following close behind," Biodesix's Beresford adds.


[Sidebar] Recently approved

Two drugs and their companion diagnostics were approved back-to-back last summer. FDA approved Roche's Zelboraf and the Cobas BRAF mutation test simultaneously in mid-August to treat melanoma, and Pfizer's Xalkori and an ALK fusion test from Abbott at the beginning of September for the treatment of non-small-cell lung cancer.

"I think that these processes went pretty well. We worked pretty closely with all the companies involved from very early on, and so they knew what we wanted and where we were going with our policy," says FDA's Elizabeth Mansfield. "Everything aligned and we were able to approve them early — both the drug and the diagnostic — and I think that everybody, FDA and the sponsors, think that those went pretty well."

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