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New Studies Suggest Crescendo's Vectra DA Can Track Rheumatoid Arthritis in Variety of Settings


Originally published on Dec. 11.

Crescendo Bioscience recently presented data from several studies that add to a growing body of knowledge supporting the use of its Vectra DA molecular diagnostic as a tool that physicians can use to assess disease progression and track treatment response in rheumatoid arthritis patients in different settings.

At the American College of Rheumatology's annual meeting last month, Crescendo presented data from studies investigating how well its multi-marker test assesses disease progression in rheumatoid arthritis patients treated with methotrexate plus prednisone, the monoclonal antibody tocilizumab, and the JAK inhibitor tofacitinib. A fourth study investigated whether Vectra DA could be used to assess which rheumatoid arthritis patients would respond to early treatment.

Vectra DA measures serum concentrations of 12 protein biomarkers related to the pathophysiology of rheumatoid arthritis. After analyzing these markers in a patient, the test uses a proprietary algorithm to yield a score between 1 and 100 that correlates to a measure of disease activity. A patient receiving a score between 45 and 100 according to Vectra DA has high disease activity; a score between 30 and 44 suggests moderate disease activity; and a score between 1 and 29 means low disease activity.

"Published studies and ACR presentations show that Vectra DA can be used in different types of patients with rheumatoid arthritis: early and late, seropositive and seronegative, patients with comorbidities, different types of therapies, different categories of disease activity based on clinical and imaging data," Oscar Segurado, chief medical officer at Crescendo, told PGx Reporter.

For example, in a retrospective analysis of serum samples for patients previously enrolled in the prospective, randomized CAMERA II study, researchers from Crescendo and the University Medical Center Utrecht in the Netherlands compared how 92 patients responded to either a regimen containing methotrexate plus prednisone or methotrexate plus placebo when assessed by Vectra DA, by looking at individual markers in the Vectra DA test, and by DAS 28. The standard disease-measuring method DAS 28 factors in tenderness of joints, patient self-assessment, C-reactive protein, and the rate at which red blood cells sediment.

The study showed that both the DAS28 score and the Vectra DA score fell more rapidly and in greater amounts when patients were treated with the methotrexate plus prednisone regimen versus just methotrexate alone. Analysis by the molecular diagnostic and DAS 28 yielded "similar response profiles" for these patients, the researchers said in the abstract.

However, when patient response was analyzed by the individual biomarkers gauged by Vectra DA, patients with certain sets of biomarkers appeared to have a more pronounced response to the methotrexate/prednisone combination. For example, patients harboring, MMP-1, TNFR-1, VCAM-1, YKL-40, leptin, CRP, IL-6, and VEGF and treated with the prednisone-containing regimen had a more rapid and pronounced response than those who received just methotrexate. Meanwhile, for patients with the marker SAA, the addition of prednisone made no difference in their response profiles.

Based on this and other previously published studies, Crescendo currently sells Vectra DA as a test that doctors should use in conjunction with other tools to measure rheumatoid arthritis progression in patients over time. However, Crescendo believes that Vectra DA is an improvement over DAS 28 and other standard tools for measuring disease activity.

"Several publications and presentations demonstrate that Vectra DA is superior to other clinical measures for detecting joint inflammation and predicting joint damage, as well as resolving discordant cases and assessing rapid response to drug therapies," Segurado said, noting that the company is engaged in reimbursement discussions with payors about Vectra DA.

Although currently Crescendo markets Vectra DA as a tool that doctors should use alongside other measures, the company is testing the feasibility of using Vectra DA as a standalone measure of disease. "We are now focused on conducting research to obtain additional evidence of the independent value Vectra DA brings to assessments with acute phase reactants and other clinical tools," Segurado noted.

In addition to producing a disease activity score, Crescendo also reports concentration levels of individual markers associated with disease activity or treatment response. "Because of the subjectivity of current clinical measures, there is a need for an objective quantitative measure of disease activity," Segurado said. "The complexity of RA, and the differences in the rate of change of individual biomarkers following therapy, point to the need for a quantitative laboratory test that measures multiple biomarkers."

Several studies reported at ACR explored whether tracking concentration levels of specific biomarkers by Vectra DA could provide a snapshot of how well patients were responding to different types of treatments.


According to the company-sponsored Vectra DA website, the diagnostic can be performed throughout a patient's treatment continuum. For example, Crescendo notes that the test can be used after a patient is diagnosed with rheumatoid arthritis to garner a baseline measure of disease activity; after the patient is started on a new treatment to gauge whether the drug is impacting disease activity levels; and then periodically during subsequent doctor visits to track whether the treatment dose needs to be altered or an entirely new drug needs to be prescribed.

Rheumatoid arthritis is treated with a variety of drugs, including non-steroidal anti-inflammatory drugs, steroids, disease-modifying antirheumatic drugs (such as methotrexate), immunosuppressants, tumor necrosis factor-alpha inhibitors, and other drugs targeting inflammatory processes in the body. In order to support the claim that Vectra DA can be used to track whether patients are responding to these treatments, Crescendo must test how well the disease activity score and concentration levels of the specific markers tested reflect disease activity in patients treated with a particular type of therapeutic.

Previously, Crescendo presented data suggesting that the markers gauged by Vectra DA can measure the change in disease activity after a rheumatoid arthritis patient has received anti-TNF therapies (PGx Reporter 11/9/2011).

At the ACR meeting, researchers from Crescendo and the University of Occupational and Environmental Health in Japan presented data from a retrospective analysis of 52 patients who had received the IL6 receptor-blocking, monoclonal antibody Actemra (Genentech's tocilizumab) for at least one year. The drug works by normalizing levels of C-reactive protein and serum amyloid A proteins that rise in response to inflammation. However, past studies have also shown that Actemra can increase serum levels of IL6, cytokines linked to inflammatory and immune response.

In the latest study, testing by Vectra DA indicated that in the patient cohort, CRP and SAA exhibited the greatest percentage decrease compared to all other component markers after treatment with Actemra from baseline to 24 weeks and from baseline to 52 weeks. Of the 12 biomarkers gauged by Vectra DA, "IL6 was the only biomarker whose median serum concentration increased."

According to Segurado, further study is needed to establish the specific association between IL6 levels, disease activity, and response to Actemra. "We are working to determine whether this IL6 effect can explain the reduction of the median percentage of change in the Vectra DA score in patients treated with tocilizumab or more accurately reflects the patient’s disease activity," he said. "We are collaborating with companies with IL6 pathway antagonists to investigate this phenomenon in larger cohorts."

In the same study, researchers found that Vectra DA was able to differentiate between patients experiencing clinical remission and non-remission as defined by other criteria. Additionally, although disease activity scores by clinical measures such as DAS 28-ESR, the Clinical Disease Activity Index, and Vectra DA improved after treatment with Actemra at 24 and 52 weeks, "DAS 28-ESR and CDAI scores showed proportionally greater improvements than the [Vectra DA] score," the study authors reported in the abstract.

Based on these findings, the study authors believe that Vectra DA "may be superior" to DAS28 for "predicting good outcomes in radiographic progression and physical function" in rheumatoid arthritis patients treated with Actemra. However, more research is needed to validate this finding, the researchers noted.


In another collaborative effort between Crescendo and Japan's University of Occupational and Environmental Health, researchers looked at whether Vectra DA could track patients' response to the JAK inhibitor Xeljanz (tofacitinib). The US Food and Drug Administration in November approved Pfizer's Xeljanz as a second-line treatment for moderate to severe rheumatoid arthritis.

In this study, researchers used Vectra DA to test serum samples from 37 patients treated with Xeljanz at baseline, after 48 weeks of treatment, and after 52 weeks of treatment. The study authors found that after one year, mean levels of disease activity measured by Vectra DA and by conventional measures "markedly" decreased, but changes in disease activity scores during the same period didn't correlate with radiographic progression. However, the researchers pointed out that mean levels of IL6 and MMP-3 were decreased "markedly" at one year and correlated with changes in radiographic progression.

"Tofacitinib[-related] improvements in clinical disease activity is reflected in the changes in molecular biomarkers," the study authors concluded. "Association between serum IL6 levels at one year and change … [in radiographic progression] suggests that tofacitinib effects on joint damage might in part [be] mediated via IL6."

Segurado noted that this exploratory study showed that Vectra DA scores change "significantly" in Xeljanz-treated patients. "We believe that further research is necessary to assess the value of profiling individual biomarkers, such as IL-6," he said.

Predicting Early Response

Lastly, at ACR, researchers from Crescendo and the Karolinska Institute presented a study investigating whether Vectra DA could be used to predict which rheumatoid arthritis patients were having an early response to treatment with methotrexate. The trial analyzed blood samples from a subgroup of 186 patients in the Swedish Epidemiological Investigation of Rheumatoid Arthritis who had had the disease for less than one year and had received methotrexate.

The researchers analyzed samples at baseline and three months by DAS 28 and, for the same period, assessed concentration levels of the 12 protein biomarkers in Vectra DA as well as five additional markers. "At baseline, none of the biomarkers or disease activity scores could discriminate good responders from moderate/non-responders at three months," the researchers reported in the abstract. The study authors also noted there was "no improved prediction of response at three months by any combination of the tested biomarkers" after adjusting for baseline DAS 28 and anti-cyclic citrullinated peptide status.

However, concentrations of several biomarkers and the Vectra DA score were significantly associated with disease activity measurements by DAS 28 at baseline and at three months. Additionally, changes in biomarker concentrations and Vectra DA scores were able to differentiate between good responders and moderate/non-responders to methotrexate at three months, according to the abstract presented at ACR.

"Currently disease activity measures at baseline, including DAS 28, are not good predictors of future response to any particular therapy," Segurado said. "However, this study also analyzed the change in Vectra DA score between baseline and three months, and found that changes of Vectra DA score correlated with clinical response by the [European League Against Rheumatoid Arthritis] Response categories."

The study authors concluded based on the findings that the Vectra DA score might be a good surrogate marker for measuring disease activity and differentiating between clinical responders from non-responders newly started on methotrexate.

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