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Ventana's Growing Companion Dx Focus Mirrors Parent Roche's Investment in Personalized Rx


By Turna Ray

Ventana Medical Systems has been in a deal-making frenzy around companion diagnostics development.

In January alone, the instruments and reagents firm announced it was working with Aeterna Zentaris, Syndax Pharmaceuticals, Pfizer, and Bayer to develop tests that may be used to personalize a number of cancer treatments.

Tucson, Ariz.-based Ventana, which became a Roche subsidiary in 2008, markets one of the most widely used immunohistochemistry-based companion diagnostics for gauging best responders to Herceptin. The drug is marketed by another Roche subsidiary, Genentech, for breast cancer patients who overexpress the HER2 protein.

The recent flurry of companion diagnostic collaborations at Ventana is a result of Roche's drive to become a heavy hitter in the personalized medicine space, and Ventana's growing capabilities in the diagnostics industry.

"Companion diagnostics have always been a part of our strategy at Ventana," President Mara Aspinall told PGx Reporter this week. "But over the last few years … there has been tremendous enhancement of our technology, greater instrument placement and depth, and [development of] new assays. At the same time, Roche has become very focused and dedicated to personalized healthcare and on becoming the pharma partner of choice [in this space]. Those two things came together … and have enabled us to focus more on our companion diagnostics program."

Aspinall joined Ventana last August as the company's president and the head of Roche Tissue Diagnostics. Previously, Aspinall was CEO of On-Q-ity, a company developing diagnostics based on circulating tumor cell technology, and served as the president of Genzyme Genetics.

Although Ventana develops in vitro diagnostics, the bulk of its revenues comes from the sale of medical instruments and reagents. Aspinall's arrival at Ventana may coincide with the company's growing strategic focus on companion assays, but she said her charge isn't limited to increasing the company's presence just in this space, but to "advance Ventana as an important part of Roche Diagnostics."

Roche doesn't break out revenues for Ventana, but molecular diagnostics comprised only a single-digit percentage of its overall sales between 2003 and 2010. While Roche's overall diagnostics business netted 10.4 billion Swiss Francs ($11 billion) in 2010 sales — an 8 percent increase in local currencies over the prior year, molecular diagnostics posted revenues of 1.2 billion Swiss francs — a 4 percent increase in local currencies over the prior year.

Roche's tests and instruments are primarily sold in Europe, Middle East, Africa, and North America. The company launched 50 tests and instruments in various markets last year. Going forward, diagnostics stand to play a more integrated role in the company's personalized medicine efforts. Roche CEO Severin Schwan, who previously led the company's diagnostics unit, has said that as much as half of the company's portfolio will comprise molecularly targeted drugs over the next decade.

In step with this projection, Roche appears focused on becoming not just the go-to pharma partner in the personalized medicine space, but also the leading diagnostic partner for developing companion tests. Aspinall declined to provide a target for how much companion diagnostics might contribute to Roche's overall product sales going forward, however. "We don't think about [companion diagnostics] in terms of a revenue target," she reflected. "We think about it from a strategic point of view, or using our assays aggressively to enable personalized healthcare."

Focusing on CDx

The recent flurry of companion diagnostic deals for Ventana suggests that the company is not wasting any time in fulfilling this strategic goal.

Ventana opened 2012 by inking a companion diagnostics deal with the Canadian oncology drug development firm Aeterna Zentaris, under which Ventana will develop an IHC test that gauges the expression of the LHRH (luteinizing hormone-releasing hormone) receptor and identifies cancer patients who will respond best to Aeterna's investigational compound AEZS-108. Researchers believe that because AEZS-108 targets LHRH, the drug could be particularly effective in treating patients with LHRH-positive cancers.

The intravenous drug, which combines a synthetic peptide carrier and the chemotherapeutic doxorubicin, recently completed Phase II trials involving patients with endometrial and ovarian cancers, and is currently in Phase II studies for prostate and bladder cancer. Aeterna has filed an investigational new drug application with the US Food and Drug Administration for AEZS-108 in prostate, bladder, and triple-negative breast cancer. The drug has been granted orphan status as a treatment for ovarian cancer by US and European regulatory authorities.

Also earlier this month, Ventana and Waltham, Mass.-based Syndax announced they would work together to develop a companion diagnostic to select non-small cell lung cancer patients who will receive Syndax's lead investigational drug entinostat in combination with erlotinib (Genentech's Tarceva). Data from the trial ENCORE 401, presented at the World Conference on Lung Cancer this month, showed that NSCLC patients expressing high levels of the E-cadherin protein in their tumors lived four months longer than those treated with erlotinib plus placebo.

Based on the results of this randomized Phase II trial, Syndax plans to use a test developed by Ventana to select patients expressing high E-cadherin levels and assess their response to the entinostat/erlotinib regimen in a confirmatory study slated to launch in the second half of this year. Ventana last year developed and launched an IVD kit that measures E-cadherin levels in epithelial tissues. The company plans to validate this test in its CLIA-certified lab, so it can be used to select patients in the pivotal trial for the entinostat/erlotinib regimen.

Meanwhile, Pfizer has tapped Ventana to develop a second companion diagnostic for its NSCLC drug Xalkori, targeted to patients with ALK rearrangements in their tumors. The FDA approved the drug last summer alongside Abbott Molecular's Vysis ALK Break Apart Fluorescence In Situ Hybridization Probe Kit (PGx Reporter 9/7/2011).

Under its deal with Pfizer, Ventana will develop an ALK rearrangement test based on its OptiView DAB detection and Cell Signaling Technology's D5F3 antibody. The test, Ventana believes, will allow doctors to gauge patients whose tumors express ALK at very low levels.

Ventana's IHC-based ALK test, if it passes muster through the necessary regulatory bodies, could offer another testing option for patients receiving Xalkori. Additionally, the test may be used in the development program for other drugs in Pfizer's pipeline.

"We really see the IHC test as an additional testing option for NSCLC patients who have the ALK rearrangement," Aspinall said. "IHC has clear well-known use in [ALK testing]."

In 2010, Yung-Jue Bang, a professor at the Seoul National University College of Medicine and a Pfizer collaborator on Xalkori's development program, said that the Abbott FISH test had nearly 100 percent concordance with IHC tests conducted in his laboratory (PGx Reporter 6/9/2010).

According to Ventana, the specific design of validation trials required for FDA approval of its IHC ALK test is confidential. As such, Aspinall said it is too early to speculate how the IHC test may be used in the clinical setting — whether as an alternative to FISH testing or in addition to FISH testing to gauge best responders to Xalkori.

In its fourth companion diagnostics deal announced this month, Ventana this week said it would develop a molecular diagnostic that Bayer Pharma will use to identify patients most likely to benefit from an investigational antibody-drug conjugate. The IHC-based test will analyze "the expression level of certain tumor targets serving as biomarkers in clinical studies for patient selection," Ventana said in a statement.

Under the terms of its agreement with Bayer, Ventana will be responsible for developing, manufacturing, and commercializing a companion diagnostic test for the unnamed Bayer ADC. Over the next five years, both partners have the option to develop other companion tests alongside the targeted cancer drug. Ventana and Bayer did not disclose the financial terms of the agreement.

Although Ventana wouldn't discuss a specific timeline for the launch of its companion diagnostic products, the company identified its work with Clovis Oncology to develop a hENT-1 assay as a "near-term opportunity." The test under development will predict the percentage of hENT1-low pancreatic cancer patients who may not derive benefit from treatment with a lipid-conjugated gemcitabine drug candidate, CO-101.

Previously published studies suggest that pancreatic cancer patients whose tumor cells express low levels of hENT1 may be resistant to gemcitabine therapy. CO-101 is in late-stage development at Clovis for first- and second-line treatment of pancreatic cancer.

Finally, Ventana and Advanced Cell Diagnostics are co-promoting the first RNA in situ hybridization assay system, called the RNAscope Formalin-fixed Paraffin-embedded Reagent System, which drug developers can use to discover and validate biomarkers. Ventana claims the RNA ISH technology can analyze gene expression in the context of tissue architecture and gauge around 5,000 genes and 15,000 non-coding RNAs that other tests can't interrogate. Researchers will also be able to perform retrospective studies by using RNAscope to analyze 400 million clinically annotated, archived FFPE tissue samples.

"The ACD collaboration was specifically designed to support our Discovery XT [platform] line. It enables pharma to do their own companion diagnostic discovery work on their instruments… in a more efficient way," Aspinall said. "If [these] pharmas find something through their discovery work, then the process starts to take [the technology] from a research-use only product to an IVD test."

Ventana and ACD are automating RNAscope on Ventana's Discovery Ultra and Discovery XT slide-staining platforms. The partners expect to launch the test in the first quarter of this year as a research-use-only test.

Working with Other Pharmas

When it comes to personalized medicine development, Roche has traditionally preferred to apply its diagnostics capabilities to its internal drug development programs, rather than encourage its diagnostics divisions to work with competing drug firms.

Herceptin, a drug for HER2-positive breast cancer developed by Roche subsidiary Genentech, was initially approved with Dako's Herceptest as its companion diagnostic. However, over the years, Roche has applied its internal diagnostics capabilities to launch new companion diagnostics supporting that blockbuster treatment. Last year, Ventana garnered FDA approval for its Inform HER2 Dual in situ hybridization DNA Probe Cocktail, which is a test that uses color-forming dyes rather than fluorescence to assess whether a patient's tumor sample has too many copies of the HER2 gene and should be treated with Herceptin.

More recently, Roche internally developed the BRAF companion test for its personalized melanoma drug Zelboraf. The company is also developing a companion EGFR-mutation test for its non-small cell lung cancer drug Tarceva in the first-line setting, and a test to gauge super-responders to the investigational asthma drug lebrikizumab being developed by Genentech.

The fact that Ventana is ramping up companion diagnostics efforts with third-party drug developers suggests that Roche sees a significant revenue opportunity in making its diagnostics capabilities broadly available to other pharmas and biotechs. However, because it is developing these companion tests for potential Roche competitors, Ventana has adopted strict firewall procedures isolating the work it performs for each partner.

Each project "is an individual companion diagnostics [deal] in and of itself," Aspinall explained. "So, it doesn't matter if [the partner is] Roche pharma or another pharma. Each of those [programs] is walled off, so one collaborator doesn't know about the other collaborator."

She added that Ventana uses separate IT systems so that the data from each diagnostic project is saved in different locations, and uses separate teams and alliance managers for external work versus internal work.

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