The medical world took little notice earlier this month when Qiagen (NASDAQ: QGEN), a German maker of diagnostics equipment, asked the Food & Drug Administration to approve its test for a certain gene mutation associated with lung cancer. The mutation, involving the epidermal growth factor receptor (EGFR) found on the surface of cells, plays an important role in the rapid spread of tumor cells and is found in about 10 percent to 15 percent of Caucasians and 40 percent of Asians with non-small cell lung cancer.
This may all sound pretty esoteric, but Qiagen’s filing is in the vanguard of a major change in the way cancer drugs are being developed—and a critical step towards the long-awaited era of personalized medicine. Qiagen’s FDA application was made in tandem with a filing by Boehringer Ingelheim, another German company with a large U.S. operation in Ridgefield, CT, for its lung cancer drug afatinib, which targets the EGFR mutation. Indeed, the test and drug were developed in tandem, and Qiagen and Boehringer want the FDA to approve them both simultaneously.
The tests in these sorts of pairings are called companion diagnostics, and they are meant to determine if a patient should receive a particular drug, or how much of the drug should be administered. A number of diagnostic and pharma companies with a presence in the Northeast are, like Qiagen and Boehringer, forging partnerships to develop drugs and companion diagnostics simultaneously—more on this below. Qiagen, whose U.S. headquarters are in Gaithersburg, MD, has more than 15 projects underway to co–develop companion diagnostics, many of them with some of the biggest pharma companies, such as New York-based Pfizer (NYSE: PFE).
Such tests aren’t new, certainly. Roche’s Herceptin, prescribed for women with HER2-positive breast cancer, was the first cancer drug to be approved with a companion test, back in 1998. Progress has been slow since, however. According to a study published in July 2011 by Joshua Cohen at the Tufts Center for the Study of Drug Development in Boston, less than one percent of drugs available in the U.S.—most of them cancer drugs—have a companion diagnostic.
Part of the problem, Cohen determined, is that insurers are reluctant to reimburse for the tests because there is not enough proof to justify the cost that using them improves the efficacy of the drugs. But most of the existing tests were developed after the drugs they’re paired with were already on the market. Stephen Little, Qiagen’s vice president of personalized healthcare, told me in an interview that co-developing a test with a drug is a different story. “Once the FDA approves the drug and the test in tandem, based on clinical evidence, reimbursement is pretty straightforward,” he said.
The FDA has made it clear in numerous forums that it is keen to issue such joint approvals. In the summer of 2011 the agency issued draft guidelines for the development and regulatory approval of companion diagnostics in order to set up a clear pathway and speed such co-developments along.
Cancer is particularly suited to test/drug pairing, thanks to the discovery of more and more genetic mutations associated with cancer. The shift in oncology to targeted therapies over the last decade has made the search for diagnostics that can identify patients with those targets an obvious scientific, and business, strategy. “A successful diagnostic will clearly enhance the benefit to risk ratio,” said Andrew Dorner, vice president of translational medicine for Millennium: The Takeda Oncology Company in Cambridge, MA. “I think the general strategy for pharmaceutical development now is to understand how we can select those patients most likely to respond to a drug.” That both speeds up clinical trial enrollment and makes it easier to prescribe the drug to the correct patients if and when it’s approved, he said.
In fact, a companion diagnostic developed by Qiagen for AstraZeneca’s (NYSE: AZN) lung cancer drug gefitinib (Iressa) basically saved the drug. Gefitinib won FDA approval in 2003 for non-small cell lung cancer but its use was soon severely restricted after it turned out the drug did not help patients live longer than older therapies. A few years later AstraZeneca partnered with Qiagen to develop a test that would identify those patients with the specific mutation that the drug targets, and in 2009 the two companies won European approval for both the test and the drug, breathing new life into gefitinib.
The FDA sent a clear signal that it will look kindly on joint cancer drugs/test filings in August 2011, when it approved two such pairings in rapid succession: Roche’s vemurafenib (Zelbarof) for metastatic melanoma along with a test also developed by Roche; and crizotonib (Xalkori), made by New York-based Pfizer (NYSE: [[ticker: PFE]]) for non-small cell lung cancer, with a test by Abbott Laboratories (NYSE: [[Ticker:ABT]]) of Abbott Park, IL. Both the Roche and Pfizer drugs target mutations found only in a very small percentage of patients, and both companies said at the time that the parallel development of a companion diagnostic enabled them to speed up the timeline for their drugs.
Since then, deals between test makers and oncology drug companies have only accelerated.
• Syndax Pharmaceuticals of Waltham, MA, teamed up with Ventana Medical Systems, a Roche subsidiary, in January 2012 to develop a test to identify lung cancer patients most likely to respond to its experimental drug entinostat, for non-small cell lung cancer.
• In April 2012 Seattle Genetics (NASDAQ: SGEN), based in Bothell, WA, and Millennium announced a partnership withVentana to develop a companion diagnostic for brentuximab vedotin (Adcetris), a non-Hodgkins lymphoma drug approved in August 2011. Their goal is to be able to identify not only non-Hodgkins patients most likely to respond to the drug, but to identify other cancers with the same mutations.
• In October Qiagen inked a deal with Germany’s Bayer to develop diagnostics in conjunction with targeted therapies for solid tumors, starting at the very earliest stage of drug discovery. Qiagen already had a similar deal in place with Pfizer.
• This month Japan’s Astellas Pharma and Roche filed with the FDA for joint approval for an expanded use of Astellas’ erlotinib (Tarceva) in lung cancer using Roche’s companion diagnostic.
The dual development approach doesn’t always work, however. In September, MolecularMD of Portland, OR, pulled its FDA application for a companion diagnostic for Cambridge-based Ariad Pharmaceutical’s ponatinib, then also under review for treatment of two rare types of leukemia. The FDA had informed MolecularMD that its test didn’t qualify as a companion diagnostic because it didn’t “provide information that is essential for the safe and effective use” of the drug. The withdrawal didn’t harm the application from Ariad (NADSAQ: ARIA), however—ponatinib (Iclusig) was approved in December, three months ahead of schedule.
The Biotech Industry Organization (BIO) raised concerns about the FDA’s emphasis on parallel development of diagnostics and drugs in its comments to the draft guidance, worrying that the FDA guidelines don’t take into consideration the real-world stumbling blocks often in the way of such joint efforts. The trade association pointed out that it is not uncommon for development of the test and the companion drug to fall out of sync, or for a pertinent biomarker to not even be discovered until late in the development process, thus leaving the test’s development to late in the game.
William Goeckeler, head of oncology medical affairs at Boehringer, told me that certainly not all drugs, or all tumors, are amenable to companion diagnostics. The biology can be very tricky, and many tumors use multiple genetic pathways to grow and multiply. Nevertheless, he thinks in the future almost all cancer clinical trials will have a biomarker component that lends itself to a companion diagnostic. In fact, Boehringer started a major campaign in April, called “Let’s Test,” to educate oncologists and other health professionals about the value of testing their patients for biomarkers associated with their cancers.
“This is a very important area for us. We are really working on trying to incorporate diagnostics for biomarkers into the drugs we develop,” Goeckeler said. “This is transitioning into a commercial reality.”