Eisai's retinoic acid (RAR)-alpha receptor agonist as a candidate therapy for the treatment of lupus nephritis

Lupus is a chronic inflammatory disease that can affect various parts of the body, especially the skin, joints, blood, and kidneys. For most people, lupus is a mild disease affecting only a few organs. For others, it may cause serious and even life-threatening problems. In particular lupus nephritis claim a significant number of lives. More than 16,000 Americans develop lupus each year. It is estimated that 500,000 to 1.5 million Americans have been diagnosed with lupus. Current treatments focus on the use of steroids and/or NSAIDs. The search for new treatments of autoimmune diseases has rapidly gained momentum over recent years. In particular biological drugs have received considerable attention and indeed the sale of such agents for the treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis reached nearly $7 billion in 2003 (for a detailed evaluation of autoimmune disorders, their markets and drug development activity click here). The first biologic for the treatment of asthma was approved in 2003 and competition is increasing amongst biotech companies poised to market what will be the first new lupus drug in over thirty years. It has been reported that retinoids exert immunosuppressive effects via retinoic acid (RAR)-alpha receptors and selective RAR-alpha ligands are effective in some immune disease models. It their upcoming JPET report Yamauchi et al demonstrate that this therapeutic potential can be extended to the treatment of lupus nephritis since Eisai's RAR-alpha selective retinoid, E6060, is active in a model of this disease.

Lupus is a chronic inflammatory disease that can affect various parts of the body, especially the skin, joints, blood, and kidneys. For most people, lupus is a mild disease affecting only a few organs. For others, it may cause serious and even life-threatening problems. More than 16,000 Americans develop lupus each year. It is estimated that 500,000 to 1.5 million Americans have been diagnosed with lupus. When internal organs are involved lupus is refered to as systemic lupus erythematosus, and 40 to 50% of these patients suffer lupus nephritis. With few effective therapies, renal dysfunction due to lupus nephritis results in the death of a significant proportion of patients.

Current treatments focus on the use of steroids and/or NSAIDs. The search for new treatments of autoimmune diseases has rapidly gained momentum over recent years. In particular biological drugs have received considerable attention and indeed the sale of such agents for the treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis reached nearly $7 billion in 2003 (for a detailed evaluation of autoimmune disorders, their markets and drug development activity click here). The first biologic for the treatment of asthma was approved in 2003 and competition is increasing amongst biotech companies poised to market what will be the first new lupus drug in over thirty years.

Retinoids are vitamin A derivatives used for the treatment of vitamin A deficiency and dermatological disorders, as well as for chemoprophylaxis and therapy of certain cancers. Retinoids are ligands for retinoic acid receptor (RAR) and/or retinoid X receptor (RXR), both of which belong to the steroid receptor superfamily. RAR and RXR each exist as alpha, beta and gamma subtypes. Binding to these receptors modulates gene transcription to regulate cell growth and differentiation.

Although retinoid research has primarily focussed on cancer therapeutics (see our feature Retinoids : An A-Z guide), retinoids have been reported to be active in models of autoimmune disease and may therefore play a therapeutic role in rheumatoid arthritis and multiple sclerosis. A recent study published by Eisai researchers has reported that RAR-alpha activation by the potent agonist, E6060, could reduce antibody production and disease in a model of rheumatoid arthritis.

Dermal complications occur in a significant number of patients with systemic lupus erythematosus and in these patients synthetic retinoids have been shown to ameliorate the dermal disorder. Dermal complications are part of the overall disease process and stem from the same disease etiology as the systemic component of disease. Previous studies have demonstrated that all-trans-retinoic acid is active against renal disease in a model of lupus establishing the therapeutic potential of retinoids however the toxicity of non-selective retinoid agonists restricts their systemic use.

In their JPET article, Yamauchi et al make the important advance by demonstrating the efficacy E6060. Eisai's E6060 is one of the most potent RAR-alpha-selective ligands thus far reported. Mortality of female B/WF1, mice which manifest many of the disease characteristics of patients with lupus nephritis, was reduced by oral E6060 and this paralleled improved renal function as well as the production of autoantibodies and serum IgG2a. The greater selectivity of this molecule suggests that it should have a considerably wider therapeutic window than all-trans-retinoic acid. The safety of E6060 was indeed demonstrated as it failed to produce liver toxicity or anemia, two common adverse effects of non-selective retinoids. It should be noted however that like many retinoids, E6060 was teratogenic.

This study demonstrates the efficacy of E6060 in a model of lupus nephritis. E6060 does appear safe although if developed into the clinic its teratogenic activity should be considered particularly the high incidence of lupus in women of child bearing age. On this point it should be remembered however that methotrexate, a therapeutic agent commonly used in the treatment of autoimmune disease, is also teratogenic and this property alone is unlikely to block the development of E6060.

Source: LeadDiscovery-TherapeuticAdvances