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Crescendo Publishes Validation Study Supporting Use of Vectra DA for Assessing RA Activity

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The journal Arthritis Care & Research has published a 371-patient validation study supporting use of Crescendo Bioscience's protein biomarker-based Vectra DA test as a tool for assessing rheumatoid arthritis activity.

The study, published online last week, found that Vectra DA provided an effective measure of RA disease activity, tracking significantly with the current gold standard for measuring RA activity, the Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) metric. It also found that the test tracked disease progression over time and could be useful for early identification of responders and non-responders to methotrexate and anti-tumor necrosis factor therapies like Abbott's Humira (adalimumab), Amgen/Pfizer's Enbrel (etanercept), and Janssen Biotech's Remicade (infliximab).

The paper is part of an ongoing effort by Crescendo to establish and promote Vectra DA for use in a variety of RA treatment applications, Bill Hagstrom, Crescendo president and CEO, told ProteoMonitor this week. The company, he said, published a verification study on the test in the May edition of Annals of the Rheumatic Diseases and currently has eight additional manuscripts "making their way through the pipeline."

Vectra DA is an immunoassay-based laboratory-developed test that measures levels of 12 proteins in blood to assess RA activity. Crescendo released the test in November 2010, and it is currently available in 49 states through the company's CLIA laboratory. New York state is the exception, and, said Hagstrom, the company has filed an application with the state's department of health and hopes to begin offering the test there soon.

Hagstrom didn't provide the number of tests the company had sold since its launch, but he said that the company had evaluated samples from more than 20,000 patients. He added that more than 400 rheumatologists have ordered the test since its launch – just over 10 percent of the roughly 3,500 rheumatologists operating in the US.

Traditionally, physicians have diagnosed and monitored RA using the DAS28-CRP test, a measurement that analyzes patient levels of painful or swollen joints as well as blood levels of C-reactive protein, a measure of inflammation. Due to factors like differences in patients' pain thresholds, however, the test is inherently subjective, making a more objective, quantitative test desirable.

In the ARD study, Vectra DA classified patients as exhibiting low versus moderate versus high disease activity with AUROC (area under receiver operating curve) performance of .77 and .70 in seropositive and seronegative patients, respectively. The test followed patient DAS28-CRP scores with correlation of .56 and .43 in seropositive and seronegative patients, respectively.

These numbers demonstrate that Vectra DA tracks with DAS28-CRP said rheumatologist Jeffery Curtis, an associate professor of medicine at University of Alabama, Birmingham, as well as an author on the study and a consultant for Crescendo. But, he added, they don't indicate an extremely tight correlation between the two. The hope, he said, is that this means additional information is being picked up by Vectra DA compared to the DAS28-CRP test.

"This paper showed that [Vectra DA] is correlated [with DAS28-CRP]," he said. "But if it was too well correlated, we would say 'If it's only as good but no better than the [existing method of] clinical assessment and we know that that is somewhat flawed, then where is the extra information?'"

The data demonstrate "the validity of [the test] in large numbers of rheumatoid arthritis patients," Curtis told ProteoMonitor.

Now, he said, studies are needed to further demonstrate that Vectra DA not only correlates with patient DAS28-CRP scores but that it can, in fact, enable doctors to better optimize their clinical care.

"We need [studies that] show that having this information is truly better for achieving better patient outcomes than not having it," he said.

Curtis suggested a number of potential clinical uses for the test – all of which, he noted, Crescendo is investigating in studies that are currently underway.

One key application, he said, could be using the test to determine if patients have truly gone into remission – something currently difficult to do without expensive and complicated procedures like ultrasounds or MRIs.

Other uses, Curtis said, include predicting disease flare-ups to enable more rational dosing of drugs; detecting joint damage occurring at levels undetectable by other methods; and distinguishing RA symptoms from those caused by other chronic pain diseases like fibromyalgia.

Curtis said that based on his own practice and his discussions with other rheumatologists, physicians are currently using Vectra DA primarily for tracking disease activity over time and for helping to make treatment decisions in borderline cases.

"I see some of my colleagues and myself as using this blood test to sort of break the tie about whether to escalate care and add drugs or to switch drugs," he said. "If a patient has occurring arthritis, 20 joints are swollen and tender, they can barely move, and you know you want to use drug X, you may not need this test. But it can be useful to break a tie about whether to make a change [in therapy], and that's often how I use it."

The ARD study also suggested that Vectra DA might prove useful in identifying responders to a given drug early in treatment, Curtis said. It found that the test identified significant changes in clinical responders to methotrexate and anti-TNF therapies as early as two weeks after the start of treatment – significantly before changes in DAS28-CRP scores could be observed.

Hagstrom said the company is working with several pharma companies with RA drugs in their pipelines on using Vectra DA in their development process. He added that there are currently nine RA drugs on the market and more than 50 in development across the pharma industry.

"Each company is trying to determine the subtleties and nuances of their drugs in a highly competitive market … so understanding exactly how the new drug performs and seeing shifts or differences can be very important as they think about their program," he said.

Last month at the European League Against Rheumatism's Annual European Congress of Rheumatology, Crescendo presented posters indicating that Vectra DA tracks RA patient response to anti-TNF therapy and that it tracks patient response to treatment with the Jak inhibitor TOFACITINIB.

The company also presented data at last year's American College of Rheumatology and Association of Rheumatology Health Professionals’ annual meeting demonstrating that the test could identify patients responding to anti-TNF drugs (PGx Reporter 11/9/2011).

Vectra DA's potential usefulness in early assessment of drug response could also help the company in its efforts to obtain reimbursement for the test, Hagstrom said.

He declined to give specifics regarding current payor coverage of Vectra DA, saying that "we're still fairly early days on the reimbursement side of things," but noted that RA had emerged as a significant area of interest for insurers due to the "significant escalation of overall drug spending" related to the disease.

Insurers "have seen a significant escalation of [RA-related] drug spend such that about 23 to 27 percent of the overall specialty pharmaceutical budget for most plans is consumed by drugs for inflammatory conditions, which is largely rheumatoid arthritis," Hagstrom said. "That's second only to drugs for oncology."

There's reason to think this spending could be made considerably more efficient, he added, noting that roughly two-thirds of RA patients have either no response or only a moderate response to initial anti-TNF treatments.

"So, [insurers] would like to see a capability in the market [for predicting drug response] that is more objective, quantitative, or reproducible" than conventional measures, Hagstrom said.

Crescendo plans to continue offering Vectra DA through its CLIA laboratory, but, Hagstrom said, "we are carefully monitoring [US Food & Drug Administration] activities" and "are prepared to respond" in the event that the agency tightens its regulation of laboratory-developed tests.

Last September, Myriad Genetics made a $25 million debt investment in Crescendo, securing a three-year option to purchase the firm (GWDN 9/9/2011). The deal provided the company funding "to help us accelerate our overall growth," Hagstrom said, and potentially gives it access to Myriad's molecular diagnostic expertise as it continues to push Vectra DA into the market. He noted, however, that Crescendo continues to operate independently, with Myriad playing no oversight or operating role.

Moving forward, Hagstrom said, the company aims eventually to develop additional tests in rheumatology broadly. However, he noted, in the near future it will focus on expanding into areas specific to RA.

"In that context we've identified three additional areas for expansion in [RA]," he said. "Looking at structural damage in patients at given points in time; selecting an optimal therapy for a patient once they've decided to move onto a biologic; and determining cardiovascular risk in an RA population."

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