, Volume 67, Issue 17, pp 2609-2633
Date: 14 Sep 2012

Etanercept

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Summary

Abstract

Etanercept (Enbrel®), a recombinant, dimeric, soluble tumour necrosis factor (TNF) receptor protein, is approved in various countries for the treatment of adult patients with ankylosing spondylitis or psoriatic arthritis.

Monotherapy with subcutaneous etanercept 25mg twice weekly or 50mg once weekly was effective and generally well tolerated in patients with ankylosing spondylitis or psoriatic arthritis participating in several large, well designed clinical studies. Treatment with etanercept was more effective than placebo in reducing disease activity and improving health-related quality of life (HR-QOL) in both patient populations, and in delaying structural disease progression in patients with psoriatic arthritis. The beneficial response to etanercept achieved with shorter-term treatment was sustained in studies of up to 4 years’ total duration. Randomised, well designed, head-to-head comparisons, including pharmacoeconomic analyses, with other anti-TNF biological modulators are required to accurately position etanercept and fully establish its cost effectiveness. In the meantime, etanercept is a valuable treatment option for patients with ankylosing spondylitis or psoriatic arthritis who are suitable candidates for therapy.

Pharmacological Properties

Etanercept is a recombinant, dimeric, soluble TNF receptor protein. By competitively inhibiting the binding of two pro-inflammatory cytokines — TNFα and TNFβ (lymphotoxin) — to membrane-bound receptors, etanercept renders them biologically inactive and thus modulates the biological responses they induce or regulate.

Subcutaneous etanercept therapy generally had beneficial effects on biological markers of cartilage degradation/turnover in patients with ankylosing spondylitis or psoriatic arthritis. In patients with ankylosing spondylitis, etanercept treatment significantly reduced levels of serum matrix metalloproteinase-3, human cartilage glycoprotein-39 (both markers of cartilage degradation/turnover) and C2C (a marker of type II collagen degradation), and elevated levels of serum 846 epitope (a marker of proteoglycan aggrecan turnover). It also significantly increased the proportion of interferon-γ- and TNFα-producing CD4+ and CD8+ T cells. In patients with psoriatic arthritis, etanercept therapy reduced the expression of circulating osteoclast precursor levels and had a significant effect on the activation of a number of intracellular pathways associated with the signalling of cytokines such as TNFα or interleukin-1.

Etanercept is slowly absorbed from the site of subcutaneous injection and appears to be widely distributed throughout the body, including bone, kidney, liver, spleen and synovial fluid. After binding to TNFα, etanercept is believed to be metabolised by proteolytic processes in the body in the same way as other proteins; the by-products are then either recycled or eliminated in the urine and/or bile. Etanercept is slowly cleared from the body and has a long half-life, thereby allowing once- (50mg dose) or twice- (25mg dose) weekly administration.

Therapeutic Efficacy

Subcutaneous etanercept, at the recommended dosages, effectively improved clinical outcomes in patients with ankylosing spondylitis or psoriatic arthritis, and delayed radiographic disease progression in patients with psoriatic arthritis. Shorter-term (≤24 weeks) therapy with etanercept 25mg twice weekly or 50mg once weekly was better than placebo in reducing disease activity, according to the primary endpoints (Assessments in Ankylosing Spondylitis [ASAS] 20% improvement response rates in patients with ankylosing spondylitis; American College of Rheumatology [ACR] 20% improvement criteria and Psoriatic Arthritis Response Criteria [PsARC] in patients with psoriatic arthritis). Placebo-adjusted response rates were 31–37% in patients with ankylosing spondylitis (ASAS20), and 44% (ACR20) and 64% (PsARC) in patients with psoriatic arthritis. Noninferiority between the two etanercept dosages was established in a 12-week double-blind study in patients with ankylosing spondylitis. Furthermore, in general, etanercept therapy was significantly more effective than placebo treatment in terms of secondary endpoints, including ASAS 20%, 40%, 50% and 70% improvement response rates in patients with ankylosing spondylitis, and PsARC and ACR 20%, 50% and 70% improvement response rates in patients with psoriatic arthritis.

The shorter-term benefits of etanercept 25mg twice weekly were sustained during longer-term treatment in patients with ankylosing spondylitis (≤212 weeks’ total duration) and those with psoriatic arthritis (≤96 weeks’ total duration). Moreover, etanercept 25mg twice weekly delayed radiographic disease progression in a longer-term study in patients with psoriatic arthritis. In those with ankylosing spondylitis, longer-term etanercept therapy improved spinal mobility measures and reduced active spinal inflammation.

Recommended dosages of etanercept significantly improved the shorter- and longer-term HR-QOL of patients with ankylosing spondylitis or psoriatic arthritis versus placebo.

Pharmacoeconomic Considerations

A fully published modelled pharmacoeconomic analysis, conducted from a UK National Health Service perspective, predicted subcutaneous etanercept to be dominant (i.e. more effective and less costly), regardless of gender, time horizon or ‘rebound scenario’, over infliximab 5 mg/kg in patients with psoriatic arthritis. Furthermore, modelled analyses generally estimated etanercept to be more costeffective than infliximab or standard care in the treatment of ankylosing spondylitis or psoriatic arthritis.

Tolerability

Recommended dosages of subcutaneous etanercept were generally well tolerated during the shorter- (≤24 weeks) and longer- (≤96 weeks’ total duration) term treatment of patients with ankylosing spondylitis or psoriatic arthritis. The nature and incidence of treatment-emergent adverse events were generally similar to those in the placebo groups. Injection-site reactions, however, were consistently reported in significantly more etanercept 25mg twice weekly than placebo recipients. The majority of treatment-emergent adverse events and laboratory abnormalities were mild to moderate in severity.