NexDx Signs Exclusive Worldwide License Agreement with UC San Diego to Leverage Epigenetics Discoveries for Early Diagnosis of Rheumatoid Arthritis

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NexDx, Inc., a new molecular diagnostics company headquartered in San Diego, will leverage the epigenetics discoveries of an internationally renown UC San Diego rheumatologist to develop early diagnostic test for rheumatoid arthritis, which now is detected in most people after the disease has established and progressed. Rheumatoid arthritis disease progression is often characterized by painful, debilitating crippling of hands and feet.

NexDx, Inc. (http://www.nexdx.com), a new San Diego-based molecular diagnostics company headquartered in Sorrento Valley, has finalized an exclusive worldwide license agreement with the University of California, San Diego to develop and commercialize epigenetics discoveries in rheumatoid arthritis (RA). The original research was performed in the laboratory of Gary S. Firestein, M.D., Professor of Medicine at UC San Diego School of Medicine.

Epigenetics refers to the modifications to an individual’s unique DNA that influence the expression, or activity, of his/her genes without altering the order or sequence of the original DNA. These reversible modifications play an important role in determining disease susceptibility and severity, as well as response to therapeutic drugs, and help explain why a disease such as RA might strike one genetically identical twin but not the other.

“The epigenetics findings of Dr. Firestein’s UC San Diego lab will help fuel NexDx’s discovery of novel DNA methylation biomarkers, which are patterns or signatures that can be reliably measured in a blood sample and can serve as an objective indicator of whether or not a patient has RA,” said Jonathan Lim, M.D., NexDx’s Chairman, CEO and Co-Founder.

“NexDx’s first priority is to develop and commercialize such a diagnostic test for RA,” said Dr. Lim, also Managing Partner and Founder of City Hill Ventures, LLC (http://www.cityhillventures.com). Dr. Lim is the former President, CEO and Board Director of Halozyme Therapeutics, Inc.
During his leadership, from 2003 to 2010, Halozyme grew from five employees and a market value of $5 million to 140 employees and a peak market capitalization of nearly $1 billion.

Currently, most people with RA are diagnosed after the disease is already well established and has progressed. RA disease progression is characterized by swollen joints and crippling stiffness, particularly of the hands and feet, which can be painful and debilitating. RA can also damage the heart and lungs and can lead to accelerated atherosclerosis.

“With early diagnosis, physicians might be able to aggressively treat rheumatoid arthritis earlier than now possible and personalize therapy to minimize or halt disease progression,” said Dr. Firestein, an internationally recognized rheumatologist, as well as NexDx’s Scientific Advisor and Co-Founder. Dr. Firestein was Chief of the Division of Rheumatology, Allergy and Immunology at UC San Diego and is now Dean and Associate Vice Chancellor of Translational Medicine.

Early aggressive therapy helps preserve the RA patient’s physical function, quality of life and capacity to work, the American College of Rheumatology emphasized in its new RA treatment guidelines, issued in early April 2012.

The current tests used to differentiate RA from osteoarthritis, systemic lupus erythematosus, ankylosing spondylitis or other autoimmune conditions can lack specificity and/or sensitivity. Thus, RA remains primarily a clinical diagnosis rather than a disease diagnosed by molecular methods. As a result, many patients with early disease are not accurately identified and treated.

“Consequently, there is a clinical need for reliable, cost effective tests to correctly diagnose, predict outcome, and monitor therapeutic responses of RA and other autoimmune diseases with arthritic symptoms to reduce morbidity and mortality,” said Dr. Lim.

Dr. Firestein’s research revealed that the inflammation-producing cells lining the joints of RA patients are characterized by a striking pattern of DNA methylation, an epigenetic mechanism. The distinctive aberrant methylation pattern produces DNA signatures that may be the basis for diagnostic biomarkers for RA that can be easily identified in patient blood samples.

NexDx will evaluate the strength of these DNA signatures in blood samples of patients with RA in order to develop a blood-based test for the accurate diagnosis of early RA.
In addition, the aberrant DNA methylation signatures will be investigated by NexDx scientists to determine the optimal therapy and discover novel drug targets for biopharmaceutical company partners.

About NexDx, Inc. (http://www.nexdx.com)

NexDx, Inc. is a scientifically driven molecular diagnostics company providing next generation products and services for personalized medicine in autoimmune diseases. Our goals are to revolutionize the quality of biomarkers and tests available to rheumatologists and patients to help them make better informed, more individualized treatment decisions for rheumatoid arthritis (RA) and other autoimmune diseases; and to discover truly novel and validate existing autoimmune disease targets for biopharmaceutical companies to enable the development of innovative targeted therapies for rheumatology patients.

The company, founded in August 2011 by Jonathan E. Lim, M.D., and Gary S. Firestein, M.D., is a pioneer in the application of epigenomics and other next generation molecular approaches to the discovery, development, and commercialization of novel biomarkers and tests for diagnostic and therapeutic applications in autoimmune diseases.

Leveraging the company’s proprietary Methylome Discovery™ platform consisting of bioinformatics, mathematical algorithms, pattern recognition, and pathway mapping, NexDx scientists are identifying the DNA methylation patterns that are the most predictive of RA and other autoimmune diseases. The company will then develop and commercialize objective, highly accurate and biologically relevant diagnostic tests for early RA and other autoimmune diseases. Their analysis of these methylation patterns may reveal new information about the pathogenesis of the disease, as well as novel drug targets that biopharmaceutical company partners can evaluate for the development of more personalized medical treatments for people with RA and other autoimmune diseases.

For more information about NexDx’s progress since its founding in August 2011, please visit: http://www.nexdx.com/nexdx_history.html.

About the UC San Diego epigenetics discoveries in RA

At the American College of Rheumatology Annual Scientific Meeting in Nov. 2011, Dr. Kazuhisa Nakano presented research (http://bit.ly/xGPdfD) from the Firestein lab, about the first systematic genome-wide evaluation of DNA methylation in fibroblast-like synoviocytes (FLS), central mediators of joint damage that are found in the synovium, the connective tissue membrane lining the cavities of joints. FLS are the aggressive immune effector cells that release cytokines and other factors responsible for inflammation inside the cavities of joints.

In the study, FLS were isolated from diseased joints in patients with RA and osteoarthritis (OA). A striking pattern of DNA methylation characterized FLS from RA patients, but not OA patients. The group also determined that the genes abnormally methylated in RA are involved in immune response, cell trafficking and inflammation. Dr. Firestein and his colleagues said their results indicate that DNA methylation of critical genes and regulatory pathways in primary synoviocytes is a novel method to determine non-DNA encoding contributions to RA and identify new therapeutic targets.

About rheumatoid arthritis (RA)

RA, which typically strikes between the ages of 30 and 50 years but also can afflict children, is the most common chronic inflammatory joint disease with an estimated incidence of about 1 to 2% of the U.S. population, and a 2 to 3 times higher prevalence in women than in men. The overall costs associated with RA are estimated to exceed $30 billion annually in the U.S.

Unlike osteoarthritis, RA is a systemic disease in which the body's immune defense system attacks the thin layer of cells called the synovium that lines each joint. This abnormal immune response generates proteins that inflame body tissues and further damages cartilage and bone. The swollen joints and crippling stiffness, particularly of the hands and feet, can be painful as well as debilitating. In RA, the immune system can also damage the heart, lungs and membranes that surround these organs.

Even though the exact cause is unknown, RA is thought to be triggered by a combination of a genetic predisposition, an enhanced immune response and environmental influences.

Treatment with disease-modifying anti-rheumatic drugs (DMARDs) can often decrease a RA patient’s pain and discomfort and limit joint damage that can result from RA. Treating RA patients early in the disease process can prevent or minimize joint damage, and result in disease remission in about 40% of patients and clinical improvement in 80% of patients.

When patients with symptoms of joint pain and stiffness are first evaluated by physicians, one of the most common diagnoses is undifferentiated arthritis (UA). Only about 33% of patients diagnosed with UA develop RA, and 40 to 50% of patients with this diagnosis experience spontaneous remission.

The blood tests currently used as part of the differential diagnosis of RA measure autoantibodies, the antibodies produced by the RA patients’ own immune systems, which include rheumatoid factors and anti-citrullinated protein antibodies. In addition to assisting in diagnosis, these tests can help identify patients who are likely to benefit from DMARD therapy and can often correlate with disease severity. However, the specificity of these tests is variable (70-98%). Their sensitivity also is limited (30-88%). As a result, the tests produce many false negative results, and thus often do not detect early disease.

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Cathy Yarbrough
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