Compound Name:AbataceptMolecular Target:B7-1 (CD80), B7-2 (CD86)Molecular Structure:CTLA4-Human IgG1 Fusion proteinLicensed Indication:Rheumatoid Arthritis, Juvenile Rheumatoid ArthritisManufacturer and/or Distributor:Bristol-Myers SquibbInitial FDA Approval:2005Summary:
Abatacept (Orencia) is a recombinant, fully human fusion protein consisting of the extracellular domain of CTLA-4 (cytotoxic T-lymphocyte antigen-4) and the Fc portion of human IgG1 that is engineered to prevent complement fixation. By binding to CD80 and CD86, the CTLA-4 (CD152) moiety prevents the “second signal” and thereby provides potent inhibition of co-stimulation required for full activation and production of T cells. Activated T cells are implicated in the pathogenesis of rheumatoid arthritis via stimulation of the inflammatory cascade, and therefore, joint inflammation and damage. Trials in adults with rheumatoid arthritis have demonstrated that abatacept treatment resulted in improvement in disease control, health-related quality of life and reduction in joint damage in patients who did not respond to other disease-modifying anti-rheumatic drugs (DMARDs). It also decreased serum levels of several cytokines and acute-phase reactants, particularly C-reactive protein, TNF-α, IL-6, and metalloproteinase-3. Studies in children, including long-term follow up studies, have suggested that Abatacept is effective, safe and on occasion, may be combined with methotrexate. Whether Abatcept is more effective than TNF inhibitors in children has not been established, but it seems to be as effective. Data from a European registry suggest that obesity does not impair response to abatacept in contrast to some studies indicating decreased response to TNF inhibitors.
Until recently, abatacept was only available as a monthly intravenous infusion. The intravenous dose for adults is: <60kg = 500mg; 60-100kg = 750mg; >100kg = 1000mg every 4 weeks. Children 6 – 17 years of age weighing less than 75kg are given a dose of 10mg/kg; those over 75kg are given doses based on adult weights. On July 29, 2011, the FDA approved the use of subcutaneous abatacept for the treatment of moderate to severe rheumatoid arthritis. The subcutaneous dose for adults is 125mg every week. However, efficacy and safety with the subcutaneous route in children 6 - 17 year old have not yet been established as of 2015.
Abatacept may be used as monotherapy or concomitantly with DMARDs. Abatacept is indicated for adult patients with moderately to severely active rheumatoid arthritis and for pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (polyJIA). Studies are underway evaluating the use of abatacept in giant cell arteritis, Sjogrens syndrome and systemic and cutaneous sclerosis.
Abatacept should not be combined with TNF antagonists, as this use has been shown to increase the risk of serious infections without showing an enhancement in treatment efficacy of RA. Patients treated with abatacept are at increased risk for infections. This is particularly true of patients with other predisposing factors. Before initiating therapy, all patients should be screened for latent tuberculosis infection, and if positive, they should receive appropriate therapy for TB prior to initiating abatacept. Similarly, screening for viral hepatitis should be performed. Live vaccines should be avoided in patients on abatacept. Pediatric patients should have their immunizations updated before initiating therapy. Subjects with chronic obstructive pulmonary disease (COPD) may develop more frequent respiratory complications. Hypersensitivity reactions, including anaphylactic shock (usually early in the initiation of therapy) have also been reported.
As with all biotherapeutics, the cost of therapy is substantial and is reviewed in a Dutch study comparing Abatacept, rituximab and TNF inhibitors.
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