Thursday, May 25, 2006

Advances in autoimmune disease therapeutics

DailyUpdates 25th May, 2006: Today both featured items from DailyUpdates focus on autoimmune disease and remarkably neither are biologics. The first, a press release from Synta announces the advancement of an IL-12/IL-23 inhibitor in development for rheumatoid arthritis and IBD; the second is a review of potassium channels as targets for the treatment of multiple sclerosis. Information on this content as well as all other reports and press releases can be accessed here.

Improving nerve conductance as an approach to multiple sclerosis - targeting the potassium channel: Today’s headline research article also focuses on autoimmunity, this time multiple sclerosis. This inflammatory disease of the central nervous system is characterized by demyelination, with a relative sparing of axons. Patients suffer many neurologic signs and symptoms which have been attributed to the underlying conduction deficits. Today’s headline paper published by Susan Judge and Christopher Bever at the University of Maryland reviews the intriguing concept that restoring the conductance of damaged neurons could improve neurologic function. Two broad-spectrum potassium channel blockers have yielded promising activity in the clinical despite the prevalence of use-limited toxicity. The review will hopefully direct drug development groups towards the more selective targeting of potassium channel subtypes and hence the development of more clinically useful therapeutics.

Targeting the IL-12 family - Synta advances apilimod, STA-5326: Rheumatoid arthritis is a chronic, progressive autoimmune disease that is characterized primarily by inflammatory joint damage producing chronic pain, loss of function and disability. The condition affects approximately 1% of the worldwide population. Given the inflammatory nature of this disease, numerous candidate molecular targets exist. These include T- and B-cell surface molecules - see our recent reports:

Autoimmune Disorders & Transplant Rejection - T-cells Targeted Therapeutics

BAFF & APRIL: Emerging Targets for autoimmune disease

In addition a vast array of inflammatory mediators has also been investigated for candidate targets. In a third report Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates, one area of focus is the IL-12 family. IL-12 is a novel cytokine cloned from B-cell lines and has a broad array of potent biologic activities, acting as the master regulator of the TH1 pathway, which drives major chronic inflammatory diseases, including rheumatoid arthritis. IL-12 deficient mice develop experimental disease with reduced frequency and severity. Cambridge Antibody Technology have developed a human anti-IL-12 monoclonal, ABT-874 which was licensed out to Abbott and is currently is in Phase II studies for autoimmune diseases, including psoriasis and multiple sclerosis. Today’s headline news item highlights data from Synta Pharmaceuticals who are also targeting IL-12. In this case however the candidate, apilimod mesylate (STA-5326) is an orally active molecule that inhibits the transcription of IL-12 as well as IL-23, two cytokine which are related through the sharing of a common p40 subunit and binding to IL12 receptor beta-1. The release announces that two separate Phase 2a clinical studies have been initiated, one in patients with rheumatoid arthritis and another in those with a second autoimmune disease, common variable immunodeficiency (CVID). Apilimod mesylate is currently in a large multinational Phase 2b trial for Crohn’s disease.


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