Etanercept

Etanercept (Enbrel®), a soluble fusion protein that binds specifically to the cytokine human tumour necrosis factor (TNF), is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis and plaque psoriasis in the US, Italy, the rest of the EU and other countries worldwide.

Subcutaneous etanercept was efficacious and generally well tolerated in several large, well designed, clinical trials and in the clinical-practice setting in adult patients with rheumatoid arthritis, including methotrexate-naive patients with early disease and those with long-standing, treatment-resistant active disease. Etanercept plus methotrexate combination therapy was generally superior to either monotherapy in reducing disease activity and structural joint damage, as well as improving health-related quality of life (HR-QOL). Furthermore, etanercept monotherapy was superior to placebo and at least as effective as methotrexate therapy in reducing disease activity and improving HR-QOL in patients with early or refractory disease. The beneficial effects of etanercept monotherapy or combination therapy were sustained in the long term (≤9 years). Some pharmacoeconomic analyses suggest that etanercept is a cost-effective option in the treatment of patients with rheumatoid arthritis. Direct head-to-head comparisons with other biological agents would help to definitively position etanercept with respect to these agents. Nevertheless, extensive clinical experience indicates that etanercept is a valuable treatment option in adult patients with long-standing moderate to severe active rheumatoid arthritis and an emerging option in those with early disease.

Elevated serum and synovial fluid levels of TNF in patients with rheumatoid arthritis play a central role in the inflammatory process underlying this condition. Etanercept, a soluble fusion protein, binds to both TNFα and TNFβ (lymphotoxin), thereby blocking the interaction of TNF with receptors on the cell surface, preventing TNF-mediated inflammatory cellular responses and modulating the effects of other TNF-induced or -regulated molecules.

Subcutaneous etanercept is absorbed slowly and has a long elimination half-life, allowing once- or twice-weekly administration and resulting in a smooth steady-state concentration-time profile. It is distributed widely into tissues, including the synovium.

The efficacy of subcutaneous etanercept 25mg twice weekly in reducing disease activity and structural joint damage, as well as in improving the HR-QOL, has been shown in several well designed trials in patients with early or long-standing active rheumatoid arthritis, including those with treatment-refractory disease.

In methotrexate-naive patients with early (≤3 years from onset) rheumatoid arthritis, etanercept was at least as effective as methotrexate in reducing disease activity and radiographic disease progression during 12 months’ therapy, and showed a faster onset of action than methotrexate. The mean area under the curve for the American College of Rheumatology numeric index of overall response (AUC ACR-N) was significantly greater in etanercept than methotrexate recipients at 6 months (primary endpoint), although there was no significant difference between the two groups in terms of the total Sharp score at 12 months (primary radiographic endpoint). Etanercept recipients also experienced a more rapid improvement in HR-QOL than methotrexate recipients during the first 3 months of therapy, although thereafter there was no significant between-group difference until study end at 12 months. The beneficial effects of etanercept therapy achieved in the shorter term (≤12 months) were sustained during long-term therapy (≤8 years’ duration) in open-label extension trials.

In patients with treatment-refractory active rheumatoid arthritis, etanercept plus methotrexate therapy was generally superior to etanercept or methotrexate monotherapy in reducing disease activity and progression of joint destruction as well as improving HR-QOL in short- (≤6 months) or long-term trials (≤3 years). In the 3-year TEMPO trial, the AUC ACR-N at 6 months (primary endpoint) with etanercept combination therapy was greater than that achieved with etanercept or methotrexate monotherapy. The mean change from baseline in the total Sharp score at 12 months (primary radiographie endpoint) also favoured etanercept plus methotrexate recipients and was lower than that for methotrexate recipients, with a higher proportion of combination therapy recipients achieving remission of disease. The benefits of etanercept plus methotrexate combination were sustained at the 2- and 3-year timepoints in this trial. Etanercept monotherapy was more effective than placebo in two well designed trials (≤6 months’ duration) in treatment-experienced patients, with these benefits sustained in the long-term (≤9 years).

Fully published pharmacoeconomic analyses from a healthcare payer or societal perspective from several countries, despite inherent limitations, suggest that etanercept is a cost-effective option in the treatment of patients with rheumatoid arthritis.

Etanercept is generally well tolerated in adult patients with rheumatoid arthritis, with withdrawal rates due to treatment-emergent adverse events generally being similar to those observed in the comparator groups, including placebo, in clinical trials. Most adverse events were mild to moderate in intensity, with infections (35-67%) and injection-site reactions (10-37%) being the most frequently reported events in patients receiving etanercept monotherapy or combination therapy in shorter-term (≤12 months’ duration) trials. The long-term (≤9 years) tolerability profile of etanercept was generally similar to that seen during shorter-term therapy. The incidence of serious adverse events was generally similar in patients receiving etanercept plus methotrexate, etanercept, methotrexate or placebo therapy. Serious treatment-emergent adverse events associated with etanercept use in all approved indications include infections, malignancies, asthma and heart failure.

In patients with rheumatoid arthritis, the incidence of serious infections (including pneumonia, sinusitis and urinary tract infection) was ≈7.0% in etanercept or etanercept plus methotrexate recipients after up to 2 years’ therapy. Several cases of tuberculosis (6.4 cases/100 000 patient-years in the general US population and 6.2 cases/100 000 patient-years in patients with rheumatoid arthritis in the US) and rare incidents of CNS demyelinating disorders have also been reported in etanercept recipients in postmarketing studies, with these studies also suggesting that there may be pancytopenia, aplastic anaemia and worsening of congestive heart failure with etanercept treatment.