The soluble tumour necrosis factor (TNF) receptor, etanercept (TNFR-Fc, TNR 001, Enbrel®), is a fusion peptide consisting of 2 molecules of the p75 TNF&agr; receptor linked to the Fc portion of immunoglobulin G1. Etanercept antagonises the activity of TNF&agr; by binding to both the membrane-bound and soluble forms of TNF&agr;; it also binds to soluble TNF&agr;. Etanercept binds reversibly to TNF&agr;, unlike the Roche product lenercept, which binds irreversibly. Produced by various lymphoid cells in response to inflammatory stimuli, low concentrations of TNF&agr; increase macrophage and polymorphonuclear leucocyte cytotoxic effects, stimulate polymorphonuclear leucocyte cell surface receptors and regulate the production of other cytokines. TNF&agr; is thought to contribute to the pathogenesis of rheumatoid arthritis.Immunex (American Home Products) holds commercial rights to etanercept for North America and Wyeth-Ayerst (also American Home Products) has exclusive rights for territories outside North America. Immunex has an agreement with American Home Products for promotion of Enbrel® in North America. Wyeth-Ayerst will promote Enbrel® for all non-oncological indications. Immunex holds exclusive rights for the oncological indication and has an existing sales force. Boehringer Ingelheim in Germany is responsible for manufacturing the drug in commercial quantities.Etanercept is launched in the US for the treatment of moderate to severe rheumatoid arthritis in patients who have had an inadequate response to diseasemodifying antirheumatic drugs. Etanercept may be used in combination with methotrexate. Etanercept is undergoing phase III clinical trials in the US with Immunex for the treatment of Crohn's disease, and phase I trials for cachexia. In November 1998, Immunex filed a supplemental Biologics License Application for the use of etanercept as a treatment for moderate to severe, active, polyarticular juvenile rheumatoid arthritis. The FDA have informed Immunex that if this supplemental application is approved, the indication will qualify for Orphan Drug status.Phase III trials are in progress in Europe with Wyeth-Ayerst for the treatment of rheumatoid arthritis. Another phase III study is in progress to assess the diseasemodifying potential of etanercept in patients with early-stage rheumatoid arthritis.The compound has potential for the treatment of organ transplant rejection and inflammatory disorders. The potential of etanercept for use in organ transplant rejection indications is being investigated in preclinical studies in Canada and in phase I/II clinical trials in the US. Immunex is also conducting a phase II clinical trial in the US of etanercept in patients with advanced congestive heart failure.Immunex and the National Institute of Infectious and Allergic Diseases in the US have completed a phase I trial of etanercept for the treatment of advanced HIV-1 infection.It appears that Immunex was conducting clinical investigations on the suitability of etanercept for the treatment of Gram-negative sepsis. Animal data had shown that TNF&agr; was an important mediator of severe sepsis and etanercept bound and neutralised TNF&agr; and prevented death in animal models of bacteraemia and endotoxaemia. Immunex has since discontinued the development of etanercept for the sepsis indication because of poor clinical trial results.Immunex has initiated a phase IV study in the US to assess B-lymphocyte function in patients receiving pneumococcal vaccine who have been treated with etanercept. Since TNF is important for B cell regulation, there is a concern that immune processes might be affected by etanercept. The study is scheduled for completion during 1999.