Oral GPR142 and GLP-1 agonists for the treatment of Type 2 Diabetes

The increasing global burden of type 2 diabetes (T2D) is of considerable concern at both the individual patient and public health level due to the direct health costs incurred and indirect costs of loss of work productivity. The recent International Diabetes Federation's report (6th Edition, 2014) noted that the current figure of 382 million people with diabetes worldwide is expected to rise to 592 million by 2035.

Glucose control in these patients deteriorates progressively over time, and, after failure of diet and exercise alone, needs on average a new intervention with glucose-lowering agents every 3-4 years in order to obtain or retain good control. In addition, to address the multiple pathophysiological defects that characterise this chronic disease requires multiple drugs to be used in combination.

There continues to be a need to develop new therapies for T2D that will be additive to the currently available treatments to provide further options for disease management. C4X Discovery has two drug discovery approaches to address this need: oral GPR142 and GLP-1 agonists.

Oral GPR142 agonists

Activation of the GPCR receptor GPR142 has been shown to increase insulin production by cells from the pancreas leading but only under conditions of high glucose concentration, potentially avoiding hypoglycaemia sometimes induced unintentionally with other current therapies. In addition, activation of this receptor may also stimulate β-cell proliferation in the pancreas potentially reducing the decline in the capability of these cells to secrete insulin.

Oral GLP-1 agonists

Multiple approved drugs, including the market leader Victoza, are currently prescribed that target the GLP-1 receptor; these have a well-established clinical profile. However, these marketed drugs are peptide based agents rather than small molecules and require administration by injection. C4XD aims to develop a small molecule equivalent that demonstrates similar efficacy but can be given by the oral route. Moreover, this also allows for potential fixed dose combinations with other oral anti-diabetic drugs.