Bristol-Myers Squibb Co (RUEIL-MALMAISON, France) announced that the European Commission has granted approval for Orencia® (abatacept), the first and only selective costimulation modulator of T-cell activation, for the treatment of rheumatoid arthritis (RA). Costimulatory molecules are essential for effective T-cell activation and differentiation.

Orencia, in combination with methotrexate (MTX), is indicated for the treatment of moderate-to-severe active RA in adult patients who have had an insufficient response or an intolerance to other disease-modifying antirheumatic drugs (DMARDs), including at least one TNF inhibitor. Reduced progression of joint damage and improvement of physical function have been demonstrated with a combination treatment of Orencia and MTX. Orencia will be available in several countries in the European Union beginning June 2007.

Efficacy and safety data of Orencia were generated from a clinical trial with placebo-controlled and open-label extension periods that included more than 2600 patients. When the disease-modifying effect was assessed radiographically, Orencia in combination with MTX reduced the rate of progression of structural joint damage compared with placebo and MTX after 12 months; further reduction in X-ray progression was seen after 2 years. Orencia is initially administered, without need for premedication, in a 30-minute intravenous injection on the 1st, 15th, and 30th day of treatment, then once every 4 weeks thereafter.

Activated T-cells are implicated in the pathogenesis of RA and are found in the synovium of patients with RA. Orencia, a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1) works in a fundamentally different way than cytokine antagonists. CD28 on T-cells, as well as its ligands CD80/CD86 on antigen-presenting cells, is a pivotal costimulatory molecule for the induction of functional T-cell responses. Stimulation of T-cells in the absence of CD28-CD80/CD86-mediated costimulation results in impaired proliferation, reduced cytokine production, and altered Th1/Th2 balance. Orencia inhibits T-cell activation by binding to CD80/CD86, thereby blocking interaction with CD28. In vitro, Orencia decreases T-cell proliferation and inhibits the production of the cytokines TNF-α, interferon-gamma, and interleukin-2 (IL-2). In a rat collagen-induced arthritis model, Orencia suppressed inflammation, decreased anticollagen antibody production, and reduced antigen-specific production of interferon-gamma.

—A. Techman

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