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Allele and Antigen-Specific Treatment of Rheumatoid Arthritis: A Double Blind, Placebo Controlled
Phase 1 Trial
ARTHUR KAVANAUGH, MARK GENOVESE, JAN BAUGHMAN, ALAN KIVITZ, KEN BULPITT, NANCY OLSEN, MICHAEL WEISMAN, ERIC MATTESON, DANIEL FURST, RONALD van VOLLENHOVEN, JAMES ANDERSON, STANLEY COHEN, NATHAN WEI, JAN MEIJERINK, CINDY JACOBS, and SIMONETTA MOCCI
ABSTRACT. Methods. Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 µg/kg was escalated in subsequent cohorts to a maximum of 150 µg/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria. Results. Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263. Conclusion. AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA. (J Rheumatol 2003;30:449-54) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Division of Rheumatology, Allergy and Immunology, University of California, San Diego, San Diego, CA; Division of Rheumatology, Stanford University, Stanford, CA; Altoona Center for Clinical Research, Duncansville, PA; Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA; Division of Rheumatology and Immunology, Vanderbilt University, Nashville, TN; Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA; Division of Rheumatology, Mayo Clinic, Rochester, MN; Department of Rheumatology, Karolinska Institute, Stockholm, Sweden; Professional Research Network of Kansas, Wichita, KS; Metroplex Clinical Research Center, Dallas, TX; Arthritis and Osteoporosis Center of Maryland, Frederick, MD; NV Organon, Oss, The Netherlands; and Corixa Corporation, Seattle, WA, USA. Supported by NV Organon and Corixa Corporation. A. Kavanaugh, MD, Division of Rheumatology, Allergy and Immunology, University of California, San Diego; M. Genovese, MD, Division of Rheumatology, Stanford University Medical Center; A. Kivitz, MD, Altoona Center for Clinical Research; K. Bulpitt, MD, Division of Rheumatology, University of California, Los Angeles; N. Olsen, MD, Division of Rheumatology and Immunology, Vanderbilt University; M. Weisman, MD, Division of Rheumatology, Cedars-Sinai Medical Center; E. Matteson, MD, Division of Rheumatology, Mayo Clinic; D. Furst, MD, Division of Rheumatology, University of California, Los Angeles; R. van Vollenhoven, MD, PhD, Department of Rheumatology, Karolinska Institute; J. Anderson, MD, Wichita, KS; S. Cohen, MD, Metroplex Clinical Research Center; N. Wei, MD, Arthritis and Osteoporosis Center of Maryland; J. Meijerink, PhD, NV Organon; J. Baughman, MPH; C. Jacobs, MD, PhD; S. Mocci, MD, PhD, Corixa Corporation. Address reprint requests to Dr. A. Kavanaugh, Center for Innovative Therapy, Division of Rheumatology, Allergy and Immunology, UCSD, 9310 Campus Point Drive, Suite A111, La Jolla, CA 92037-0943, USA. E-mail: akavanaugh@ucsd.edu Submitted March 18, 2002; revision accepted September 10, 2002. |