Ardelyx is evaluating novel non-systemic agents for treating type 2 diabetes that stimulate TGR5, a receptor found in the gastro-intestinal tract. During normal digestion, bile acids bind to TGR5 on specialized cells in the gut (L cells) and signal the release of incretins such as GLP-1 and PYY, which leads to insulin secretion and glucose control. In diabetic patients, insulin secretion is diminished in response to this series of signals. Several injectable GLP-1 analogs are used successfully to increase insulin secretion in T2DM patients, but oral agents are highly preferred by patients. Oral DPP-4 inhibitors, also successfully commercialized, can increase the half-life of GLP-1, but tend to have limited efficacy. An agent that stimulates TGR5 at the beginning of this signal cascade represents a promising new approach for glucose control that may allow for improved efficacy along with oral administration.RDX009, a TGR5 agonist, represents a new class of highly potent compounds with minimal systemic exposure that act throughout the GI to elicit a sustained secretion of GLP-1 and PYY peptides.
RDX009 compounds exhibit a robust response in rodents and non-human primates, as measured by increased plasma levels of GLP-1. In a mouse model of diet-induced obesity (DIO), RDX009 compounds combined with a DPP4 inhibitor significantly improved insulin signaling as measured by an oral glucose tolerance test (OGTT).
RDX009 compounds clearly demonstrate that the Ardelyx concept of non-systemic compounds acting exclusively on the surface of the gut can stimulate and propagate a hormonal signal having a profound effect on a metabolic disorder, such as diabetes. RDX009 is moving to lead optimization stage with the potential to begin IND-enabling studies during 2012.
