Treatment of rheumatoid arthritis with PEGylated recombinant human soluble tumour necrosis factor receptor type I: a clinical update

A recombinant form of the high affinity, natural inhibitor of tumour necrosis factor α (TNFα) is currently under development for the treatment of rheumatoid arthritis (RA).1 This molecule is referred to as recombinant-methionyl soluble TNF-type I receptor (r-metHu-sTNF-RI or sTNF-RI). Recombinant sTNF-RI is an Eschericia coli derived recombinant, truncated, monomeric form of the 4-domain soluble TNF-type I receptor. For optimal delivery, a high molecular weight (30 kDa) PEG molecule is attached at the N-terminus (met 1) position to form the molecule intended for clinical investigations (PEG r-metHu-sTNF-RI or PEG sTNF-RI). PEG sTNF-RI, with an approximate molecular weight of 42 kDa, has been designed for long term chronic subcutaneous (SC) administration for the treatment of RA. Preclinical studies to date demonstrate that PEG sTNF-RI is efficacious in rodent2-4 and primate5 models of acute and chronic inflammatory diseases, including E coli induced septic shock.6PEG sTNF-RI has demonstrated efficacy in predictive animal models of RA at doses as low as 0.3 mg/kg every other day.2 The results of these and other7-9 preclinical studies indicate that PEG sTNF-RI is a promising treatment for chronic inflammatory diseases. Eighty two subjects with active (for at least six months), moderate to severe RA (as defined by the American College of Rheumatology) were enrolled into this randomised, double blind, placebo controlled, dose escalation trial of safety and pharmacokinetics.10 Subjects were randomised to PEG sTNF-RI or placebo within one of two dose schedules. In schedule 1, subjects received a single dose of PEG sTNF-RI (100, 300, or 600 μg/kg) or placebo, followed six weeks later by weekly dosing for three weeks. In schedule 2, subjects received a single dose of PEG sTNF-RI (100, 300, or 600 μg/kg) or placebo every other week for six weeks. In addition, a group of subjects within schedules 1 and 2 received only a single dose …

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