Bristol-Myers Squibb Company (PRINCETON, New Jersey) announced that the US FDA has approved an update to the product labeling for OrenciaR (abatacept) regarding the progression of structural joint damage in rheumatoid arthritis (RA) patients. The indication was strengthened from "slowing" to "inhibiting" the progression of structural damage in adult patients with moderately-to-severely active RA, who have had an inadequate response to one or more disease-modifying, antirheumatic drugs (DMARDs), such as methotrexate (MTX) or tumor necrosis factor (TNF) antagonists.

Orencia is indicated for reducing the signs and symptoms of RA and inducing major clinical response in patients with the disease, and it may be used as monotherapy or concomitantly with DMARDs. However, Orencia should not be administered concomitantly with TNF antagonists or with anakinra. Orencia is administered as a 30-minute intravenous infusion at a fixed-dose based on body weight.

The labeling change is supported by 2-year radiographic data from the Phase III AIM (Abatacept in Inadequate responders to MTX) trial, which met the coprimary endpoints of ACR 20 scores at 6 months and both the Health Assessment Questionnaire Disability Index (HAQ-DI) scores and the joint Erosion Scores (ES) at 1 year. Fifty-six percent of Orencia/MTX-treated patients had no progression during the first year compared with 45% of placebo/MTX-treated patients. In the open-label extension period of the study, 75% of patients initially randomized to Orencia and MTX and 65% of patients initially randomized to placebo and MTX were evaluated radiographically at year 2. The progression of structural damage in Orencia/MTX-treated patients was further reduced in the second year of treatment, following which 51% of patients had no progression of structural damage as defined by a change in the Genant-Modified Total Sharp Score (TSS) of zero or less compared with baseline. More than half of patients on Orencia had no radiographic progression in either year 1 or 2 (56% and 65%, respectively). This radiographic impact was consistent with benefits seen in clinical measures of disease activity.

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), is a selective costimulation modulator of T-cell activation and works in a fundamentally different way than cytokine antagonists. Costimulatory molecules are essential for effective T-cell activation and differentiation. CD28 on T-cells, together with 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 T-helper 1(TH1)/T-helper 2 (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. In a collagen-induced rat arthritis model, Orencia suppressed inflammation, decreased anticollagen antibody production, and reduced antigen-specific production of interferon-gamma.

—A. Techman

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