Counseling Points - December 2008 - (Page 7)

BLyS and a proliferation-inducing ligand (APRIL), another cytokine in the TNF family.10 Atacicept has been shown to affect several stages of B-cell development and may inhibit the survival of cells responsible for making antibodies.10 A recent small, multicenter, phase-Ib, double-blind, placebo-controlled study involving 73 patients investigated the tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous atacicept.10 Patients received the active study drug in single 70-mg, 210-mg, or 630-mg injections or placebo injections or repeated atacicept injections given 2 weeks apart (three doses of 70 mg, three doses of 210 mg, or seven doses of 420 mg.) Preliminary results demonstrated that atacicept penetrated synovial fluid and reduced immunoglobulin rheumatoid factor (RF) levels from 40% to 45%. Additionally, decreases in anti-citrullinated protein antibodies (ACPA), which are serological markers for RA, were observed in the patient group that received seven doses of 420 mg atacicept. However, atacicept treatment was not associated with decreases in erythrocyte sedimentation rate (ESR) nor C-reactive protein (CRP) levels. Overall, 44% of patients treated with the active agent reported adverse events, which included non-serious injection-site reactions and urticaria. Three events (arthralgia, RA exacerbation, and rheumatoid nodule) were considered serious, but no serious infections occurred. Atacicept is being studied in two additional RA clinical trials in combination with other biologic DMARDs (adalimumab and rituximab).11 The compound is also being investigated as a potential therapy for SLE, lupus nephritis (LN), MS, and optic neuritis, a disease that is strongly associated with MS, as well as B-cell malignancies.1,3 Belimumab Belimumab (LymphoStat-B®), which is being developed by Human Genome Sciences, is an investigational BLyS inhibitor that is currently being evaluated as a treatment for SLE and RA.1-4 This infusional compound is a fully human monoclonal antibody that targets and inhibits the biological activity of soluable BLyS.1-4 Belimumab binds three different receptors that are expressed on B cells and restores the potential for autoantibody-producing B cells to undergo apoptosis (programmed cell death).12 A recently completed phase-2, multicenter, double-blind, placebocontrolled study evaluated the safety, tolerability, and efficacy of three infusional doses of belimumab compared with placebo.13 ACR20 response rates were significantly higher in all groups taking the active study drug than in the placebo group (20% versus 16%, respectively, P=0.021).13 Results also demonstrated that belimumab 7 patients had reduced B-cell and RF levels compared with placebo patients. Additionally, belimumab was safe and well tolerated at all doses and the incidence of adverse events, serious adverse events, and laboratory abnormalities was similar for belimumab- and placebo-treated subjects. The most frequently reported adverse events associated with belimumab therapy were arthralgia, headache, and upper respiratory tract infection.13 IL-6 Receptor Antagonists In autoimmune diseases, the body is not able to discern its own cells and tissues from foreign pathogens; thus, an immune response is initiated and the body attacks itself.4 IL-6 is one of a number of pro-inflammatory proteins activated when the body perceives pathogenic invasion.4 Consequently, this protein is overexpressed and found in abnormally high amounts in the synovial tissue of RA patients. IL-6 is a pleiotropic cytokine, meaning that it influences a number of critical cells and signaling pathways involved in autoimmune disorders.14,15 It is thought to activate T cells, macrophages, and osteoclasts as well as induce antibody production by B cells.14,15 IL-6 is also an important activator of the hepatic acute-phase response, which is responsible for increases in ESR and CRP levels that are correlated with the degree of RA disease activity and joint destruction seen in patients.14,15 IL-6 is one of a number of pro-inflammatory proteins activated when the body perceives pathogenic invasion. Tocilizumab Tocilizumab (Actemra®), manufactured by Roche, is the first humanized monoclonal antibody that binds to the IL6 receptor and neutralizes IL-6 function.1 It is currently being evaluated for RA and juvenile idiopathic arthritis in late-stage clinical trials.1,3-4 Recently published findings from the Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders (OPTION) study demonstrated that RA patients treated with the agent experienced a rapid and significant reduction in disease signs and symptoms.16 This double-blind, randomized, placebo-controlled, parallelgroup, phase-3 trial enrolled 622 subjects with moderate to severe RA. Patients were assigned to receive infusional doses of either tocilizumab 4 mg/kg or 8 mg/kg or placebo every 4 weeks with background methotrexate.16 Results revealed that at 24 weeks, significantly more patients who DECEMBER 2008

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Counseling Points - December 2008

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