Prospects for the development of small molecular weight compounds to replace anti-tumour necrosis factor biological agents

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Abstract
Tumour necrosis factor (TNF) blockade, achieved by the soluble receptors and antibodies, has been a major success in the treatment of rheumatoid arthritis (RA).1 The success of this treatment has also established biological agents as a new weapon in the armoury of therapeutic approaches to the treatment of autoimmune diseases. Established data and emerging evidence suggest that anti-TNF biological agents will have a therapeutic role in other autoimmune diseases. Infliximab is already licensed for Crohn’s disease and, recently, anti-TNF biological agents have shown major promise in spondyloarthropathies, psoriatic arthritis, and juvenile idiopathic arthritis.2–8 There is growing evidence that TNF blockade may be important in many other diseases, including sarcoidosis9 and psoriasis.10 Therefore, although the number of patients treated with the various anti-TNF biological agents is rapidly approaching half a million, there is no reason to suggest that the patient pool is anywhere near saturation. Rather, one can expect the number of patients with diseases likely to benefit from this form of treatment to increase. However, there are problems with anti-TNF biological agents that limit their use. From a safety perspective, although TNF blockade has not demonstrated the massive problems of susceptibility to infections once feared, there are clearly problems, especially with patients who have latent tuberculosis.11 There is also the constant problem associated with using proteins as drugs of their administration and dosing. However, by far the biggest constraint in using anti-TNF biological agents is the cost of treatment, which is of the order of $15 000/patient/year. This has led to a relatively low uptake of the treatment in several European countries and to patients being described as “economic failures” in America. One must also add that the difficulty in producing proteins on a mass scale has led to a supply problem, especially for …