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. Ardelyx’s RDX009 program has identified several proprietary classes of TGR5 agonists. We have engineered these pharmacophores to have minimal systemic exposure yet retain agonist activity. These agonists represent 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.
One of the challenges in the field has been the development of compounds that can stimulate GLP-1 secretion without causing untoward effects resulting from unwanted stimulation of TGR5 at systemic sites. For example, investigators working with systemic TGR5 agonists in mouse models have reported undesired effects on the gall bladder, which becomes enlarged due to delayed emptying, increased filling, or a combination of these effects. Ardelyx’s non-systemic TGR5 agonists avoid these effects when dosed in the same mouse models, both in single- and repeat-dose experiments. Using its proprietary technology, Ardelyx has been able to develop lead compounds whose physical properties allow them to remain nearly completely in the lumen of the intestines thereby allowing excellent stimulation of TGR5, but avoiding TGR5-mediated inhibition of gall bladder emptying. Ardelyx’s RDX009 compounds have exhibited a robust response in rodents and non-human primates, as measured by increased plasma levels of GLP-1.
The RDX009 program clearly demonstrates that the Ardelyx concept of non-systemic agents acting exclusively on the surface of the gut can stimulate and propagate a hormonal signal and have a profound effect on a metabolic disorder, such as diabetes, while avoiding unwanted side effects. Ardelyx expects to progress RDX009 to lead optimization stage during 2012.