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BI's Gilotrif Latest Success for Companion Diagnostics Space


By Jennifer Boggs
Managing Editor

Qiagen NV's Therascreen EGFR RGQ PCR Kit gained FDA approval alongside Boehringer Ingelheim GmbH's lung cancer drug Gilotrif (afatinib), putting another notch in the win column for the growing companion diagnostics space, though there are still challenges to overcome before the use of companion diagnostics becomes routine in the marketplace.

Gilotrif was approved specifically for advanced non-small-cell lung cancer (NSCLC) patients whose tumors express the EGFR exon 19 deletions or exon 21 L858R substitution gene mutations. EGFR gene mutations are estimated to be found in about 10 percent of NSCLC cases, with the majority of those expressing the EGFR exon 19 deletions or exon 21 L858R substitution.

Qiagen's diagnostic is designed to identify patients with those mutations, who will be likely responders to the tyrosine kinase inhibitor. The kit runs on the company's Rotor-Gene Q MDx molecular detection instrument, which uses real-time PCR technology and is "widely placed" throughout laboratories in the U.S., so patients presenting with signs and symptoms of NSCLC can be tested to see whether they are likely to respond to Gilotrif, said Tadd S. Lazarus, Qiagen's chief medical officer.

"The whole aim of companion diagnostics is to get it right the first time, with minimal adverse events and side effects and to get as close to remission as possible," he said.

Therascreen EGFR RGQ PCR Kit marks the third approval for Qiagen in the companion diagnostic space and the second to run on the Rotor-Gene platform. The firm previously gained approval for a Therascreen KRAS test for use in colorectal cancer patients.

"It's really exciting because we've gone from a world of the microscrope, looking at staining, to getting to the genetic level of cancer," Lazarus added. The idea of a personalized approach to health care – getting the right drug to the right patient – is something that has been bandied about the industry for a while. "But now the pace is really snowballing," he said.

The FDA continues to express a preference for companion diagnostics for use in tandem with targeted therapies and has rewarded firms that opt for that development route.

In 2011 , both Pfizer Inc.'s Xalkori (crizotinib) and Roche AG's Zelboraf (vemurafenib) won earlier-than-expected approval. Xalkori, indicated for late-stage NSCLC patients with abnormalities in the anaplastic lymphoma kinase (ALK) gene and paired with Abbott Molecular's Vysis ALK fluorescence in situ hybridization(FISH) probe kit, was cleared a month ahead of schedule, while Zelboraf and its companion 4800 BRAF V600 mutation test won FDA clearance for metastatic melanoma patients with the BRAF V600E mutation more than two months before its PDUFA date. (See BioWorld Today, Aug. 18, 2011.)

Boehringer's Gilotrif, which has been developed alongside the companion diagnostic since 2009, received similar treatment from regulators. The Ingelheim, Germany-based firm's new drug application was accepted in January by the FDA, with the agency granting it a six-month priority review. Boehringer had not publicly disclosed a specific PDUFA date, but told investors that a decision was expected in the third quarter. Gilotrif is the second drug approved this year for patients with NSCLC who have the EGFR mutations. The FDA approved in May to extend the use of kinase inhibitor Tarceva (erlotinib, Roche and Astellas Pharma Inc.) concurrently with the cobas EGFR Mutation Test from Roche's diagnostic unit.

Gap in the 'Ecosystem'

Despite the obvious benefits of having companion diagnostic and therapeutic combos hit the market – in addition to accelerated drug development timelines, being able to identify patients most likely to respond to a drug should cut down on the number of ineffective treatment regimens, thereby reducing overall health care costs – there are still some hurdles to overcome.

In some cases, the delay is a technical one; sometimes the mechanism of action of a compound is not clearly elucidated until later in the development timeline or there is not a convenient way of testing for a specific mutation or tumor subtype.

"Some cancers are stubborn and very difficult," Lazarus said, such as pancreatic and ovarian cancers. But even in those instances, "great headway is being made."

The bigger sticking point to date has been reimbursement. The Centers for Medicare & Medicaid Services (CMS) "hasn't been the easiest" to work with, Lazarus noted, a fact he said threatens to harm the innovation and investment in the companion diagnostic space, which "should be a fundamental element of cancer treatment.

"There is an ecosystem of quality and compliance," he told BioWorld Today. Qiagen begins work early on with the FDA and goes through the process of obtaining a pre-market approval, "the most difficult diagnostic submission," which involves "expensive and wide-ranging clinical studies."

In the case of its Therascreen EGFR RGQ PCR Kit, the company was rewarded for its efforts with an FDA approval. But it's the next step that has proved troublesome.

"Laboratories want to participate, but when CMS does not give appropriate reimbursement," the ecosystem breaks down, he said.

It likely will take industry continuing its efforts to reach out to lawmakers to provoke a sea change in the reimbursement environment, a push that will gain momentum as more companion diagnostics win FDA approval. Then they will not view it as a one-off, but part of an exciting continuum at the forefront of cancer care," Lazarus said.

Plenty in the Pipeline

Qiagen is doing its part in that regard. The company, headquartered in Venlo, the Netherlands, had a well-established reputation in scientific research and drug development circles before it began in recent years to build a molecular diagnostics portfolio. In 2009, it acquired companion diagnostics pioneer Dxs Ltd., of Manchester, UK, in a deal valued at up to $130 million. That acquisition brought Qiagen rights to the Therascreen technology, which, at the time, was generating buzz for its KRAS kit. (See BioWorld International, Sept. 30, 2009.)

The company since has signed a number of companion diagnostic collaborations, including 2011 agreements with Eli Lilly and Co. involving a JAK2 inhibitor in development for blood cancers and with Pfizer involving an HER-1 inhibitor and other tyrosine kinases in development for NSCLC. Lazarus said there are 13 cancer partership programs in the works.

"This is not just a trend, but a rapidly growing field," he said.

And Qiagen isn't alone. Abbott Molecular, for instance, also has been busy. It has inked a deal with Epizyme Inc. to develop a companion diagnostic test for use with the biotech's EPZ-5656, an early stage drug targeting DOT1L, a misregulated enzyme believed to activate genes causing mixed lineage leukemia. The Abbott Park, Ill.-based firm also has an agreement with Janssen Biotech Inc. and Pharmacyclics Inc. to explore the benefits of its FISH-based test to identify patients with a genetic subtype of chronic lymphocytic leukemia who may respond best to recently submitted Bruton's kinase inhibitor ibrutinib.

Other players include Roche's diagnostics unit, which was responsible for the Zelboraf diagnostic through a partnership with Plexxikon Inc., later acquired by Basel, Switzerland-based Roche. There's also Novartis AG unit Genoptix Medical Laboratory, which, according to a disclosure by newly public Ambit Biosciences Corp., is developing a companion diagnostic for the biotech's FLT3 inhibitor quizartinib in acute myeloid leukemia. (See BioWorld Today, Feb. 22, 2013.)

And last year French diagnostics firm Skuldtech SAS emerged as the developer of a predictive test to identify patients most likely to benefit from AB Science SA's tyroskine kinase inhibitor masitinib in pancreatic cancer. Skuldtech's test is based on the expression profiles of five undisclosed genes and was able to identify patients with aggressive courses of the disease. (See BioWorld Today, Nov. 7, 2012.)

Rather than partnering with a diagnostics firm, some emerging biotechs are opting to develop both drugs and diagnostics in-house. Endocyte Inc., for one, is developing imaging agent etarfolatide (EC20) in tandem with its folate receptor-targeting cancer drug vintafolide (EC145). That program is in Phase III testing in platinum-resistant ovarian cancer and in Phase IIb testing in NSCLC.

And recent start-up Vitruvian Biomedical is taking aim at the personalized medicine field by balancing work on both diagnostics and therapeutics. Among its programs include a heat-shock protein inhibitor and companion test. (See BioWorld Today, Sept. 22, 2012.)