Abstract
With the emergence of a wide array of new therapies for the management of rheumatoid arthritis, not only has treatment improved markedly over the past two decades, it has also grown increasingly complex. With 10 approved biologic therapies in the United States comes a growing need for tools that can turn complex biological data into actionable insights for physicians and patients to make informed and personalized treatment decisions.
A progressive and debilitating autoimmune disease, rheumatoid arthritis (RA) causes pain and stifiness and over time leads to joint damage and disability. It occurs when a person's immune system goes awry, causing inflammation in healthy joints. About 2.4 million people in the United States have RA; of those, more than 1 million have moderate to severe disease.
There is no cure. Treatments focus on controlling the inflammation or dampening the immune attack to prevent joint damage and slow the progression of the disease. Upon diagnosis, patients are typically treated with a combination of standard anti-inflammatories, including aspirin. Patients with moderate-to-severe disease are put on disease-modifying antirheumatic drugs, or DMARDs, such as methotrexate a biologic, to slow the disease. The biologics block key inflammatory pathways—including TNF, IL6, JAK, CD20, CTLA4, and IL1—to shut down the immune response in a targeted fashion.
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From a disease-management perspective, these treatments pose challenges due to wide variation in patient response. Response rates for biologics to treat RA range from 30 to 70%, and it typically takes more than three months to ascertain if a patient is responding to a particular therapy. This lack of clarity contributes to poor outcomes, with only 40% of patients achieving remission in one year from the flare-ups that are the hallmark of RA, and results in approximately $5 billion in spending on treatments that don't provide benefit.
In light of these issues, the molecular diagnostic specialists at Selventa have been focused on addressing the central question of how they can both monitor disease activity, and also provide physicians and patients with clinically relevant information to make optimal treatment decisions.
Overcoming Disease Complexity
In contrast to targeted therapeutic approaches that focus on the identification of a single genetic mutation like HER2 in breast cancer or the Philadelphia chromosome in chronic myelogenous leukemia, diagnostic tools for RA treatment require an approach that can synthesize a multi-factorial web of biological information.
RA is mediated by complex, systemic and local biology that differs from patient to patient. While a few inflammatory-related proteins are measured as part of the diagnostic and disease-monitoring process, there is no single protein, DNA, or RNA factor that can diagnose, monitor, or effectively provide information about a patient's disease to a physician making treatment decisions. With the large number of different biologics available to the treating physician, currently there is no way to discern which one would be best for a patient at a given time.
The solution in RA, therefore, requires more complex individualized diagnostic decision-making tools—based on advances in “omics” technologies that allow the seamless integration of thousands of molecular data points and the exploration of complicated disease biology from patient to patient. An omics approach harnesses a comprehensive range of complex, biological information (genomic, epigenomic, transcriptomic, proteomic, metabolomic, electronic medical records), thereby enabling a clinically relevant dashboard of relevant patient-specific data that physicians, patients, and researchers can use to make optimal treatment decisions.
The clinical contributions made by an effective omics tool would be many. Such a tool could, for example, help identify in advance which therapy is most likely to be beneficial (a particularly important contribution, given how many biologic options are available); monitor whether the therapy is working; and indicate when the therapy can be safely stopped.
ClarifyRA Progress
The Selventa vision is to exploit omics technology and provide RA patients with a holistic RA management system to deliver information to the physician to aid in treatment decision. To realize this vision, Selventa is developing ClarifyRA, a blood-based, predictive decision tool for rheumatologists.
The company's first clinical validation study was heralded in a paper that appeared June 2015 in the journal BMC Medical Genomics. This paper—“Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis”—described the creation of a gene-expression classifier to predict, before treatment, which RA patients would be unlikely to respond to the commonly administered first-line biologic, the anti-TNF therapy infliximab.
Using data from a meta-study of patients treated with infliximab, Selventa investigators examined whole blood samples and detected the activity of 18 signaling pathways, applying an algorithm together with prior knowledge to characterize the activity of TNF in the blood.
This method made it possible to identify 30% of non-responders in advance, with high accuracy.
With these clinical validation results in hand, the company is pursuing multiple avenues to further enhance the clinical utility of ClarifyRA, while also exploring the development of other classifiers in other disease areas. In RA, Selventa intends to establish a molecular correlate to disease activity, which can also be monitored with a simple blood test—providing new insights into disease activity in response to treatment to further inform disease management strategies.
Selventa also plans to expand the test to include information about the biologic targets outside of infliximab/TNF, and to validate the findings through a large clinical study. With wider use of complex biologics, increasing attention being paid to improved disease management, and an emphasis on tighter cost control, the company believes the omics revolution in clinical decision making in autoimmune diseases has just begun.