IBD Therapeutic

About

Therapeutic need Inflammatory bowel disease (IBD) is a chronic and incurable disease characterised by episodic and disabling inflammation of the gut. Current therapeutic strategies aim to decrease the frequency and severity of inflammatory episodes to prevent progression of bowel damage and avoid disabling disease with need for surgery. However, these therapeutic options suffer from poor compliance (e.g. salicylates), toxicity (e.g. immunomodulators, steroids), or cost (biologics). Further, there is a significant number of individuals who do not respond to treatment. There is an urgent need for better therapeutics to restrain the personal and economic costs associated with IBD. With clear evidence that intestinal immunity is regulated through microbiome-immune crosstalk, the microbiome has now emerged as a valuable potential source for immune-modifying IBD therapeutics. The technology Gut bacteria that secreted soluble suppressors of the pro-inflammatory NF-κβ pathway were isolated, and a novel class of NF-κβ inhibitory bioactives identified. Based on the bioactives, a lead compound – ‘Compound HC’ – with potent NF-κβ activity (IC50 = 1 nM) was synthesised. Compound HC alleviates colitis in a murine genetic model of IBD (Winnie) (Fig 1), with associated reduction in NF-κβ mediated pro-inflammatory gene expression. Compound HC is proposed to operate via non-competitive inhibition of IKKα/β (IC50 = 0.14 nM / 0.015 nM respectively). Preliminary pharmacokinetic profiling in mice shows that Compound HC is detectable at active concentrations throughout the ileum and colon less than 1 hour following oral administration and remains at concentrations >100×IC50 for >6 hours. Compound HC was also detected in the liver, but not serum. No accumulation of the compound was observed in the liver or ileum after 2 weeks of daily treatment.