RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR RECEPTOR (P75) FC FUSION PROTEIN (TNFR-FC) IN RHEUMATOID-ARTHRITIS

BACKGROUND: Tumor necrosis factor (TNF) is the dominant mediator of th e cytokine cascade that causes inflammation and joint destruction in r heumatoid arthritis. A new class of agents under investigation, the bi ologic TNF inhibitors, inhibits the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR:Fc; Enbrel) blocks the activ ity of the cytokine TNF. The preclinical, Phase I, and Phase II data o f TNFR:Fc in rheumatoid arthritis are reviewed in this article. METHOD S: All available data on TNFR:Fc in rheumatoid arthritis were reviewed . These data included published literature and data on file at the man ufacturer.RESULTS: TNFR:Fc has been effective in many models of inflam mation, including animal models of rheumatoid arthritis and in clinica l rheumatoid arthritis trials. Conclusions from a study with TNFR ''kn ockout'' mice (genetically altered mice incapable of producing TNFR pr oteins) demonstrated that p75 TNFR is a natural antagonist of TNF-medi ated inflammation. A placebo-controlled, dose-escalation, Phase I tria l evaluated the safety and efficacy of TNFR:Fc in patients with rheuma toid arthritis. There were no serious adverse effects reported. A Phas e II, randomized, double blind, placebo-controlled trial evaluated 180 patients with active rheumatoid arthritis whose previous therapy had failed. A dose-response relationship was observed in the number of ten der and swollen joints; patients who received the highest dose (16 mg/ m(2)) of TNFR:Fc had the greatest improvement. Treatment was generally well tolerated. TNFR:Fc is nonimmunogenic; no antibodies to TNFR:Fc h ave been detected thus far in human studies.CONCLUSIONS: Preliminary d ata indicate that TNFR:Fc is an excellent candidate for future long-te rm studies in the treatment of rheumatoid arthritis.