Drug Insight: Tumor Necrosis Factor Converting Enzyme as a Pharmaceutical Target for Rheumatoid Arthritis

Marcia L Moss; Liora Sklair-Tavron; Raphael Nudelman

Disclosures

Nat Clin Pract Rheumatol. 2008;4(6):300 

In This Article

Summary and Introduction

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.

The cytokine tumor necrosis factor (TNF) has an important role in inflammatory processes in rheumatoid arthritis (RA) and in other immune-mediated disorders.[1,2] Consequently, TNF has emerged as an important target for the development of therapeutic strategies for treating RA and Crohn's disease. The TNF inhibitors that have been approved for clinical use to treat RA are infliximab, adalimumab and etanercept. Infliximab is a chimeric mouse-human monoclonal antibody, whereas adalimumab is a fully humanized monoclonal antibody; both agents are specific for TNF. Etanercept is a fusion protein comprising the ligand-binding portion of the human p75 TNF receptor (TNFRII) and the Fc fragment of human IgG1. The TNF inhibitors cause their primary effect by blocking the interaction of TNF with cell-surface receptors (Figure 1).

Anti-TNF Therapies and Their Effect on TNF Signaling.
Etanercept, a fusion protein of TNFRII and the Fc region of IgG1, and the anti-TNF antibodies infliximab and adalimumab, bind to TNF and prevent the molecule from interacting with its two receptors, TNFRI and TNFRII, thereby stopping signaling events. These large inhibitor molecules prevent binding of either sTNF or proTNF to their membrane receptor targets. TACE processes proTNF from the cell membrane to yield sTNF. Inhibitors of TACE block signaling by the soluble, but not membrane-bound, form of TNF. Abbreviations: proTNF, precursor TNF; sTNF, soluble TNF; TACE, TNF-converting enzyme; TNF, tumor necrosis factor; TNFRI, TNF receptor I; TNFRII, TNF receptor II.

The ultimate goals of RA treatments are the prevention or control of joint damage and the prevention of functional loss. Despite the optimal use of other disease-modifying antirheumatic drugs (DMARDs) -- in particular, methotrexate -- the outcome for many patients with RA includes severe functional decline and considerable adverse effects. Thus, biologic anti-TNF agents, often used in combination with methotrexate, are now the first choice of treatment when other DMARDs fail in clinical practice.[3,4,5]

TNF antagonists, used alone or in combination with methotrexate, are superior to methotrexate alone or placebo in improving the signs and symptoms of RA, slowing radiographic progression of structural joint damage, and reducing functional disability.[6,7,8] Indirect comparisons indicate that efficacy does not differ substantially among biologic anti-TNF drugs.[5] Treatment with TNF antagonists early in the course of disease has a considerably greater benefit than treatment with previous standard therapies, with a higher number of responders, a higher degree of response and possible arrest of joint damage.[9,10] Owing to financial considerations, however, it is often not possible to treat patients at the earlier stages of the disease.

Efficacy trials have shown that anti-TNF drugs have good tolerability profiles, but have recorded rare but serious adverse events, such as infections and lymphoma, that could not be assessed reliably.[5,11] A meta-analysis that pooled data from clinical trials of adalimumab and infliximab reported that patients treated with anti-TNF drugs experienced twice as many serious infections as did those taking placebo.[11] Keane et al. reported that the most common serious infection in patients treated with infliximab was tuberculosis.[12] There is insufficient evidence to allow us to draw conclusions about an increased risk of specific malignancies.[13] Injection site reactions (adalimumab and etanercept) and infusion reactions (infliximab) were the most commonly and consistently reported adverse events in the meta-analysis.[11] Some infusion reactions seemed to be more serious than injection site reactions. Nevertheless, less than 2% of patients discontinued anti-TNF therapy and withdrew from the clinical trials because of infusion reactions.

The benefit of anti-TNF drugs to patients is considerable and might outweigh the risk of infections, especially in cases of severe erosive RA. Although the cost of therapy remains an important problem, there is still an unmet medical need for novel approaches (oral therapies) that carry higher clinical benefit, lower cost and a lower risk of adverse events than current treatments.

The focus of this Review is on small molecular inhibitors of TNF-converting enzyme (TACE) that slow the progression of RA by preventing the release of soluble TNF from its membrane-bound precursor. The rationale for using TACE inhibitors for the treatment of RA is discussed. In addition, findings are reported from preclinical and clinical tests of orally available compounds that have improved the selectivity of such inhibitors for TACE over the closely related matrix metalloproteinases (MMPs).

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