Drug Insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis

Drugs that inhibit tumor necrosis factor (TNF) provide considerable benefit in treatment of rheumatoid arthritis (RA); however, there is an unmet medical need for alternative therapies with higher clinical benefit and lower safety risk and cost. The potential to treat RA by targeting TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor, is outlined in this Review. The success of agents that inhibit tumor necrosis factor (TNF), such as infliximab, adalimumab and etanercept, has led to a desire for orally available small molecules that have a better safety profile and are less costly to produce than current agents. One target for anti-TNF therapy that is currently under investigation is TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor. Inhibitors of this enzyme with drug-like properties have been made and tested in the clinic. These inhibitors include TMI-005 and BMS-561392, both of which have entered into phase II clinical trials. This article summarizes preclinical and clinical findings regarding the use of inhibitors of TNF-converting enzyme for the treatment of rheumatoid arthritis. Key Points Biologic anti-tumor necrosis factor (TNF) agents, including etanercept, infliximab and adalimumab, reduce the severity of symptoms for individuals with rheumatoid arthritis (RA) There is still an unmet medical need for orally available, small-molecule inhibitors of TNF TNF-converting enzyme (TACE) has been validated in preclinical models for the treatment of RA Clinical trials have not determined whether TACE inhibitors have a suitable efficacy or toxicity profile for use in patients with RA TACE-selective inhibitors have been made, and could be used in the future as therapeutics