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Compugen, Roche Deal to ID Response Markers for RA Drugs May Lead to Dx

Compugen’s GeneVa technology will serve as the platform for Roche’s efforts to discover genetic variations linked to patient response to certain rheumatoid arthritis treatments.
Compugen, based in Tel Aviv, Israel, announced the co-discovery and license agreement on Dec. 20, saying the companies aim to develop an FDA-approved and CE Marked genetic test for best-responders.
It is not immediately clear Roche plans to genetically differentiate the patient population for existing RA drugs or to better define a population for an investigational agent.
Roche currently markets the RA drug Rituxan and has an investigational drug, Actemra, in Phase III trials. However, the company was unable to respond to queries about the deal prior to deadline.
“It can often take months of usage to determine whether or not [certain treatments] are appropriate in individual cases” of rheumatoid arthritis, Compugen said in a statement. “This collaboration aims to address the difficult and important clinical challenge of selecting the right drug for the right patient.”
Separately, Roche has been studying biomarkers linked to the risk of developing the disease. Recently, Roche Centralized Diagnostics in Penzberg, Germany, identified a biomarker that may enable clinicians to detect the disease early in its development. The company plans to create a diagnostic test based on this finding.
“Detecting the disease as early as possible – even before clinical symptoms occur – could help physicians to intervene at an earlier stage and prevent damage and disabilities,” Roche states on its website. “New diagnostic markers could therefore improve existing methods of diagnosing RA.”
Compugen’s Role
RA is an autoimmune disease affecting 21 million people worldwide. There are an array of available treatments, including over-the-counter nonsteroidal anti-inflammatory drugs, such as ibuprofen and naproxen sodium; corticosteroid medications, such as prednisone and methylprednisolone; disease-modifying antirheumatic drugs such as hydroxychloroquine, sulfasalazine, minocycline, and methotrexate, immunosuppressants such azathioprine and cyclosporine; TNF inhibitors such as etanercept, infliximab, and adalimumab; and the T-cell inactivating agent abatacept. However, many of these treatments are hampered by serious side effects and lack of efficacy.
Compugen’s role is to “select around a few hundred variations from its proprietary genetic atlas … and check their frequency in the populations of responders and non-responders using samples by Roche,” a Compugen spokesperson told Pharmacogenomics Reporter late last month. “Compugen will be doing the experiment and that analysis.”
The analysis will be done on Compugen’s GeneVa platform. The technology, which the company claims employs a technique that can shorten the SNP-discovery process, can genotype genomic insertions and deletions from between 15 bases and 50,000 bases.
According to Compugen, GeneVa can scan selected genomic regions or whole genomes to discover variations related to a particular phenotype, and then sequence those genes to find the causative variation.

When a marker is found, the plan is to develop a test kit that will be submitted to the US Food and Drug Administration and other international regulatory bodies for approval, according to Compugen.

“The GeneVa platform, which allows fine scale indel genetic studies, completes this research scheme by directing the efforts toward variations which are larger than SNPs,” Compugen states in literature about the platform. “These variations are believed to have a more direct influence on genes and be the final causative variations rather than intermediate correlated SNPs. Thus, a fine scale INDEL-based study opens a new route which can ease and shorten the way to the final marker discovery.”
According to the company, the GeneVa platform has been used to conduct genetic predisposition studies for type II diabetes and Parkinson’s disease, for which more than 200 fine-scale variations were tested.
Whether Compugen’s collaboration with Roche will focus on finding genetic variations of response to currently marketed drugs or to investigational products will be decided “based on Roche’s needs and the availability of appropriate samples,” the Compugen spokesperson said.
When a marker is found, the firms plan to develop a test kit that will be submitted to the US Food and Drug Administration and other international regulatory bodies for approval, according to Compugen.
The spokesperson added that Compugen expects to begin its analysis at the start of the year, and initial results are slated for release in the third quarter.
Drug Candidates
Although it is not yet clear for which drugs Compugen and Roche plan to develop a diagnostic, Roche’s rheumatoid arthritis pipeline offers some possibilities. On its website, the company notes that both the monoclonal antibodies Rituxan and Actemra have “a novel mechanism of action [that] provides benefits to patients who do not respond adequately to current therapeutic options, or for whom these therapies may be a best first choice in the future.”
Roche is touting Rituxan as the first and only drug for rheumatoid arthritis that targets B cells, which are the components of the immune system believed to contribute to RA. Actemra, meantime, has been shown in clinical trials to be superior over conventional disease modifying anti-rheumatic drugs and has shown to decrease pain and other symptoms in a study of Japanese patients.
Roche also has two RA drugs in early-stage clinical trials. One, R1594, generally called ocrelizumab, is a humanized anti-CD20 monoclonal antibody that targets B cells but may be less immunotoxic and have fewer side effects than other available treatments. In clinical trials, ocrelizumab has also shown that it might be effective against other autoimmune diseases, such as systemic lupus erythematosus and multiple sclerosis.
The other candidate, R1503, inhibits a protein called p38 MAP kinase, which regulates the production of autoimmune disease-related cytokines such as tumor necrosis factor and interleukin 1 and IL-6.
Importance of Biomarkers
Among the most common autoimmune diseases, RA is characterized by inflammation of the membrane lining the joints, leading to cartilage loss and bone degradation. As a result, joints can become misaligned, causing pain, redness, stiffness, and swelling. Left untreated, patients can become disabled.
However, diagnosing RA is challenging because the onset of the disease manifests with symptoms that are hard to gauge. According to the American College of Rheumatology, RA symptoms include morning stiffness, arthritis of more than three defined joints, arthritis of hand and finger joints, symmetrical arthritis, rheumatoid nodules, rheumatoid factor, and radiographic changes.
When at least four out of the seven symptoms are fulfilled over a period of six weeks, RA can be diagnosed. Though not definitive, clinical tests for the C-reactive protein and the rheumatoid factor also help guide diagnosis and early detection, which the ACR said is critical.
According to the ACR, identifying biomarkers and developing diagnostics can help guide treatment. To those ends, researchers at Roche Centralized Diagnostics have assessed 54 biomarkers using blood samples collected from RA patients treated at six European centers. This research has helped identify antibodies against cyclic citrullinated peptides as biomarkers that can enable early detection.
In clinical trials, the anti-CCPs showed more than 75 percent sensitivity and over 95 percent specificity in detecting RA early in patients. Based on this research, Roche is currently developing a diagnostic using its own Elecsys platform, the company has said.

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