In the January 23rd edition of TherapeuticAdvances we focussed on the development of TNF-alpha related molecules as anti-inflammatory treatments. For example, Etanercept (Enbrel) is a decoy receptor for TNF-alpha that has been launched for the treatment of rheumatoid arthritis. Likewise, Infliximab is a chimeric MAb against TNF-alpha launched for the treatment of Crohn's disease and rheumatoid arthritis. An alternative approach to the blockade of TNF-alpha is through the use of antisense technology to prevent its production. For example, ISIS 25302 is able to reduce inflammation in various animal models of inflammatory bowel disease (IBD).

IBD is an umbrella term used to describe two distinct clinical conditions, ulcerative colitis and Crohn's disease, both of which are chronic digestive diseases resulting from an abnormal immune system response to stimuli in the digestive tract. Ulcerative colitis primarily occurs in the colon and causes inflammation in the upper layers of the large intestine, while Crohn's disease usually appears in the small intestine and causes inflammation deeper within the wall of the intestine. IBD usually begins at a young age, is medically incurable, often requires surgery, and can recur over a lifetime. The cause of IBD is unknown although it is generally considered that a genetic predisposition contributes to an unregulated intestinal immune response to an environmental, dietary, or infectious agent. In 2001, the number of prevalent cases of IBD has been estimated to have totaled over 1.5 million in the major pharmaceutical markets. Currently in excess of $0.5 billion, IBD related sales have been forcasted to increase by 3-10% each year for the next 5 years. Current treatment options are sub-optimal and the present focus is on the identification of inflammatory mediators involved in IBD. A greater understanding of inflammatory pathways and new "biologic agents" that will emerge from this knowledge will expand the IBD market and provide improved options for the patient.

In the current edition of TherapeuticAdvances we focus on SangStat’s RDP58 that, like ISIS 25302 also blocks TNF-mediated activity by inhibiting TNF synthesis however in addition it also upregulates heme oxygenase-1 (HO-1). This enzyme degrades heme into carbon monoxide (CO), iron, and biliverdin and is ubiquitously distributed in mammalian tissues. HO-1 is strongly and rapidly induced by a variety of stimuli and agents that cause oxidative stress under pathological conditions and is therefore important in the response of tissues to oxidative stress and inflammation. Increased HO-1 expression has been proposed to reduce inducible nitric oxide synthase (iNOS) activity through accelerated degradation of heme thereby exerting a protective effect in animal models of inflammation. Thus the dual activity of RDP58, on the one hand leading to a decreased production of TNF, and on the other an up-regulation of HO-1 is expected to produce a pharmacological profile consistent with effective treatment of IBD.

The therapeutic activity of RDP58 has been investigated in the dextran sodium sulphate (DSS) model of chronic colitis in two recent studies. In the first study (Ann Rheum Dis 2002 Nov;61 Suppl 2:ii19-24) oral administration of RDP58 markedly reduced the severity of DSS colitis as determined by clinical and quantitative histological criteria. RDP58 almost completely prevented colonic epithelial cell death induced by DSS treatment and also inhibited both colonic accumulation of neutrophils and TNF expression. In a second study, the ability of RDP58 to reduce disease activity and histological damage was confirmed and furthermore improved therapeutic efficacy of RDP58 over 5-ASA, a standard treatment of IBD was demonstrated. Further toxicology and bioavailability studies in Rhesus monkeys, dogs and mice demonstrated that RDP58 was not distributed systemically and that it was well tolerated. The therapeutic efficacy of RDP58 combined with a lack of bioavailibility and toxicity suggest that RDP58 may be a promising new therapeutic for IBD. The completion of a UK multiple dose-escalation Phase I trial in 27 healthy volunteers, demonstrating the safety of RDP58 has thus prompted SangStat to enter this molecule into Phase II evaluation in ulcerative colitis and Crohn's disease patients. This molecule apparently represents a licensing opportunity.

Entry date February, 2003

Adapted from Murthy et al, Inflamm Res 2002 Nov;51(11):522-31 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk