Recombinant Human Tumor Necrosis Factor Receptor (P75) Fc Fusion Protein (Tnfr: Fc) in Rheumatoid Arthritis

Author:

Murray Kim M,Dahl Stephen L

Abstract

BACKGROUND: Tumor necrosis factor (TNF) is the dominant mediator of the cytokine cascade that causes inflammation and joint destruction in rheumatoid arthritis. A new class of agents under investigation, the biologic TNF inhibitors, inhibits the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR: Fc; Enbrel) blocks the activity of the cytokine TNF. The preclinical, Phase I, and Phase II data of TNFR: Fc in rheumatoid arthritis are reviewed in this article. METHODS: All available data on TNFR: Fc in rheumatoid arthritis were reviewed. These data included published literature and data on file at the manufacturer. RESULTS: TNFR: Fc has been effective in many models of inflammation, including animal models of rheumatoid arthritis and in clinical rheumatoid arthritis trials. Conclusions from a study with TNFR “knockout” mice (genetically altered mice incapable of producing TNFR proteins) demonstrated that p75 TNFR is a natural antagonist of TNF-mediated inflammation. A placebo-controlled, dose-escalation, Phase I trial evaluated the safety and efficacy of TNFR: Fc in patients with rheumatoid arthritis. There were no serious adverse effects reported. A Phase 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 tender and swollen joints; patients who received the highest dose (16 mg/m2) of TNFR: Fc had the greatest improvement. Treatment was generally well tolerated. TNFR: Fc is nonimmunogenic; no antibodies to TNFR: Fc have been detected thus far in human studies. CONCLUSIONS: Preliminary data indicate that TNFR: Fc is an excellent candidate for future long-term studies in the treatment of rheumatoid arthritis.

Publisher

SAGE Publications

Subject

Pharmacology (medical)

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