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Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates

Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates

(Publication date: October, 2003)

The autoimmune diseases are receiving increasing attention in the pharmaceutical industry as progress is made in the understanding of immune and inflammatory processes. It is predicted that the annual value of the market for drugs used to treat autoimmune disease will exceed $20 billion in the next few years. Rheumatoid arthritis is one of the more common and difficult to treat autoimmune diseases and there is a great deal of interest in the discovery of novel drugs to treat this condition.

Rheumatoid arthritis is a chronic syndrome characterized by non-specific, usually symmetrical inflammation of the peripheral joints, manifested by the formation of hypertrophied synovia known as panni. Pannus formation mirrors the destruction of articular and peri-articular structures, with or without generalized manifestations. The condition differs from osteoarthritis not only through the obligatory involvement of the immune system but also because disease onset occurs early on in life, generally between the ages of 20 and 50, although it can begin at any age.

Since the birth of the modern pharmaceutical industry just over 100 years ago with the synthesis of aspirin, non-steroidal aspirin-like anti-inflammatory drugs (NSAIDs) have been the mainstay of the treatment of rheumatoid and other forms of arthritis. It is generally accepted that NSAIDs relieve the symptoms of arthritis such as pain and swelling without changing the course of underlying disease. There have been considerable efforts to develop drugs which modify disease progress and these have met with variable success. Immunosuppressants such as cyclosporine or anti-metabolite drugs such as methotrexate are effective but have dose-limiting adverse effects.

During the last few years however, basic research efforts have significantly progressed our understanding of autoimmune disorders such as rheumatoid arthritis. The disease is caused by increased chemotactic and immunostimulatory activity within the joints of sufferers resulting in an influx of inflammatory cell. The presence of activated immune cells increases local levels of cytokines and other inflammatory mediators propagating this process and supporting pannus proliferation and neovasculaturization, cartilage and bone erosion and eventual joint destruction.

Greater understanding of rheumatoid arthritis etiology has given rise to a large number of potential molecular targets for the development of improved therapeutic candidates. LeadDiscovery's state of the art report, "Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates" provides a comprehensive analysis of current and future molecular targets. Likewise the report evaluates new drug development activity categorizing emerging therapeutics according to their molecular targets.

Although significant efforts have resulted in the development of the COX2 inhibitors celebrex and vioxx, one of the most exciting developments in the management of rheumatoid arthritis has been the introduction of the anti-TNF biopharmaceuticals remicade and enbrel. These drugs represent a real step forward in the development of anti-inflammatory therapies. There is now an increasing number of inflammatory cytokines which have become targets for therapeutic intervention with biologicals such as monoclonal antibodies or immuno-fusion proteins. There is also encouraging evidence that cytokines can be targeted by orally active medicinal chemicals.

The increasing knowledge of the immune system has revealed a number of targets for specific regulation of immune cells and in particular the process of antigen presentation and lymphocyte activation. The disease modifying arthritis drug arava selectively suppresses lymphocyte activation by inhibiting nucleotide synthesis and new drugs with similar mechanisms of action are in development. Biologicals which block lymphocyte cell surface receptors are also showing encouraging therapeutic activity.

Methotrexate remains one of the most widely used disease modifying drugs in rheumatoid arthritis and attempts are being made to discover improved anti-proliferatives that are more specific and better tolerated. Related to this is the development of anti-angiogenic agents to prevent the vascularization of inflamed joint tissues. There is considerable overlap in this area with drugs being developed to treat cancer.

This report considers almost 50 molecular targets and more than 150 products being developed by nearly 100 companies therefore representing not only a complete analysis of current areas of research activity but also a thorough examination of therapeutic candidates emerging from this activity. In short "Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates" represents a key tool to anyone wishing to select new drug discovery targets or to evaluate drug development activity relating to rheumatoid arthritis.

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