New Test May Help Patients With RA Avoid Useless Treatment

Janis C. Kelly

November 16, 2010

November 16, 2010 — A network of rheumatology practitioners is teaming up with several pharmaceutical companies to evaluate a new biomarker screening test that might help identify patients with rheumatoid arthritis (RA) who are unlikely to benefit from treatment with antitumor necrosis factor-alpha (anti-TNF) agents. This could help clinicians avoid exposing individual patients to adverse effects from drugs unlikely to be effective, reduce healthcare costs, and quickly identify patients who would be candidates for other regimens or for clinical trials of new agents.

The Biomarkers of Anti-TNF Treatment Efficacy in Rheumatoid Arthritis–Unresponsive Populations (BATTER-UP) Consortium will undertake a prospective study to investigate predictive biomarkers in about 1000 patients with RA with moderate to severe disease who have unsatisfactory response to conventional disease-modifying antirheumatic drugs and are about to start treatment with an anti-TNF agent, or who have had inadequate response to an initial anti-TNF agent and are about to switch to a different one. Exclusion criteria include prior exposure to 2 or more anti-TNF agents, to abatacept (Orencia; Bristol-Myers Squibb), to rituximab (Rituxan; Genentech and Biogen Idec), or to any other biologic therapy for any disease.

The investigators in this observational study will attempt to validate an 8-gene biomarker set based on work by Biogen Idec researchers as likely to predict anti-TNF responsiveness in patients with RA. In preliminary results, the 8-gene biomarker set predicted with 89% accuracy individuals who did not reach EULAR DAS-28 "good" response after 14 weeks of treatment.

The leaders of the BATTER-UP Consortium are Michael E. Weinblatt, MD, the John R. and Eileen K. Riedman Professor of Medicine at Brigham and Women's Hospital in Boston, Massachusetts, and Peter K. Gregersen, MD, director of the Center for Genomics and Human Genetics at North Shore-Long Island Jewish Hospital's the Feinstein Institute for Medical Research in New York City. Dr. Gregersen was one of the researchers who developed the Biogen Idec test.

The 8 genes included in the screen are CLTB, MXRA7, CXorf52, COL4A3BP, YIPF6, FAM44A, SFRS2, and PGK1.

Interestingly, Antonio Julia, MD, and colleagues from Hospital Universitari Vali d'Hebron in Barcelona, Spain, have reported similar accuracy from a different 8-gene set for predicting response to infliximab (PloS ONE. 2009;4:e7556). The Julia set includes HLA-DRB3, SH2D18, GNLY, CAMP, SLC2A3, IL2RB, MXD4, and TLR5. It was tested using whole-blood RNA samples from 44 patients with RA.

"In the long run, a screening tool is possible and desirable. The BATTER-UP trial is designed to provide the statistical power to replicate the 8-gene signature or to identify an alternative signature that could be used as a screening tool," John Carulli, PhD, told Medscape Medical News. "However, at this point in time the published signature should be regarded as the result of a pilot study and suitable only for research purposes." Dr. Carulli is director of genetics and genomics in the Department of Drug Discovery at Biogen Idec, in Cambridge, Massachusetts.

Eric L. Matteson, MD, director of rheumatology at the Mayo Clinic, in Rochester, Minnesota, told Medscape Medical News: "This study represents an important step in the right direction for rheumatology therapeutics. This ability to predict treatment response is where we need to go in our efforts to provide tailored care to our patients. A corollary is whether we can develop similar tests to determine if there will be side effects. It will be useful to gain more experience with this assay in routine practice to confirm its utility. A formal registry with patients from multiple areas could be useful in this regard."

Dr. Matteson also noted that the ability to predict who would not benefit from anti-TNF therapy might be expected to result in significant savings by enabling clinicians to avoid the use of treatment that is unlikely to be effective.

S. Louis Bridges, Jr., MD, PhD, director of the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham, said: "If this study shows that the 8-gene biomarker set can with reasonable accuracy predict who will or will not respond to TNF inhibitors, further validating studies will almost certainly be needed."

He continued, "The test would ideally be highly accurate (>90%), reliable across patients with different clinical situations (disease duration, autoantibody positivity, different race/ethnicity, etc), but this study may not have the statistical power to show this. If it is reproducible, reliable, generalizable, etc, it may result in significant savings by avoiding the use of treatment unlikely to be effective. It may also affect the design of future clinical trials in that patients unlikely to respond to anti-TNF agents may be selected for studies of investigational new drugs."

This study is being funded by and coordinated by Biogen Idec. Dr. Matteson and Dr. Bridges have disclosed no relevant financial relationships. Dr. Gregersen and Dr. Weinblatt direct consortium scientific activities through a scientific advisory board and publication team. Funding and operational support for BATTER-UP are from Biogen Idec, Bristol-Myers Squibb, Centocor Research & Development, Crescendo Bioscience (whose Vectra DA disease activity biomarker test has just been launched in the United States), Genentech, pharmacy benefit manager Medco Health Solutions, Regeneron Pharmaceuticals, and Sanofi-Aventis.


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