Dual MMP and TACE inhibition as a treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the more common autoimmune diseases along with multiple sclerosis, type I diabetes and Crohn’s disease. Approximately one in five people in the western world suffer from autoimmune diseases and some estimates indicate that 75% of these are women. In total it is predicted that the annual value of the market for drugs used to treat autoimmune disease will soon exceed $20 billion. An estimated 5 million individuals suffer from RA (for further information on the rheumatoid arthritis market click here)

Corticosteroids are the most dramatically effective short-term anti-inflammatory drugs; however, their clinical benefit in RA often diminishes with time. Corticosteroids do not predictably prevent the progression of joint destruction, although a recent report suggested that they might slow erosions. Furthermore, severe rebound follows the withdrawal of corticosteroids in active disease. Because of their long-term systemic side effects, corticosteroids are usually given only after a careful and prolonged trial of less hazardous drugs.

Future directions for the development of rheumatoid arthritis therapeutics are ever focusing on disease modifying drug classes (LeadDiscovery's "Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates" is recommended for readers requiring a full overview of DMARDs click here).

Two molecular targets for DMARDs, which are evaluated in detail in our recent report, are the matrix metalloproteinases (MMPs) and the related ADAM (A Disintegrin and Metalloprotease) family.

The recent clinical success of anti-TNF-alpha agents such as the soluble TNF-alpha receptor (Enbrel) and anti-TNF-alpha antibody (Remicade) has validated TNF-alpha as a target for RA therapeutics and signaled the rapid surge in DMARD development. More recently however emphasis has shifted to the development of small molecules that are able to prevent TNF-alpha-mediated activity without the requirement of parenteral injection, high cost, and the possibility of antibody formation associated with Enbral and Remicade. TNF-alpha, a key cytokine involved in RA etiology is expressed as a pro-form that requires cleavage by TNF converting enzyme (TACE) a member of the ADAM family. TACE is highly expressed by CD68+ macrophage-like synovial cells within the synovium of RA patients and has become a target for drug development.

Collagen destruction is a feature of RA and early clinical changes appear in the surface layers with the majority of cartilage collagen destruction occurring at the cartilage-pannus junction. MMPs, which are important in collagen breakdown, include 25 zinc-dependent and calcium-dependent proteinases in mammalian systems. MMPs can be classified into at least five main groups including the collagenases (eg MMP-1 & MMP-13); gelatinases (eg MMP-9); matrilysins (eg MMP-7); and MT-MMPs (eg MMP-14).

Some workers consider MMP-1 may be the foremost collagenase in RA since MMP-1 has been detected at sites of cartilage erosion in rheumatoid joints and enzyme levels correlate with the progression of RA in terms of joint damage. Despite this, development of Roche’s trocade, was halted after Phase III trials in RA after benefit was shown to be limited. Inhibitors with a broader spectrum of activity may therefore be required.

To address this issue researchers at Wyeth in collaboration with those from Amgen and The Kennedy Institute of Rheumatology have reported the identification of a novel dual TACE/MMP, TMI-1. This molecule inhibits TACE and several MMPs including MMP-1, -2, -7, -9, -13, -14 with nanomolar IC50s in vitro. In cell-based assays it inhibits LPS- induced TNF-alpha secretion at submicromolar concentrations, and perhaps more importantly, TMI-1 potently inhibits TNF-alpha secretion by human synovium tissue explants of RA patients. In vivo, using a murine model of RA TMI-1 is highly effective in reducing clinical severity when given prophylactically, and with higher doses therapeutic activity was reported. In the latter, a more clinically relevant case, activity was seen following oral dosing with 100mg/kg TIM-1.

This important study not only demonstrates the oral efficacy of a dual TACE/MMP inhibitor when given therapeutically to mice with experimental RA, but it also for the first time demonstrates activity of a dual TACE/MMP inhibitor in synovium cultures from RA patients. Of additional proof of concept interest it should be noted that membrane bound TNF-alpha has been proposed to play a role in RA etiology. Thus the use of TACE inhibitors could lead to sub-optimal DMARD activity by increasing membrane bound TNF-alpha. On the basis of the present study this phenomenon does not appear to occur of if it does then it does not appear significant in the experimental models used thus further establishing TACE inhibitors as validates targets for RA therapeutics.

Entry date Wednesday, April 14, 2004

Adapted from Zhang et al, J Pharmacol Exp Ther. 2004 Apr;309(1):348-55.