Project: Innovative GLP-1R modulators for Type-2 Diabetes treatment.

Diabetes mellitus is one of the most costly chronic diseases with prevalence and incidence constantly increasing in developed countries. In the EU-27 alone, based on data from the European Union Public Health Information System (EUPHIX), the number of people with diabetes is expected to rise from 31 million in 2007 to 37 million in 2025. This marked increase in type 2 diabetes mellitus (T2D) and its associated end organ damage is the result of a combination of various factors, including malnutrition and lack of exercise. _x000D_Release of the hormone glucagon-like peptide 1 (GLP-1) from intestinal L-cells in response to food intake potentiates insulin secretion from the pancreas (the “incretin” effect) and leads to inhibition of glucagon secretion. Via this dual function the release of GLP-1 results in lowering of blood glucose levels. In contrast to insulin administration, GLP-1 has a lower potential to induce hypoglycemia because its effects are glucose-dependent and do not occur when plasma glucose decreases below normal levels. GLP-1 also leads to inhibition of gastrointestinal fat absorption, gastric emptying and to appetite suppression. Incretin-based therapies, including GLP-1 mimetics, therefore have a broader range of beneficial effects and appear to be safer with respect to hypoglycemia than insulin. The effects include lowering blood glucose, reduced glycosylated hemoglobin and body weight, and secondarily blood pressure, lipids and other parameters, leading overall to a reduced cardiovascular risk. _x000D_GLP-1 effects are mediated by a specific receptor called glucagon-like-peptide-1 receptor (GLP-1R), a member of the class B G-protein coupled receptor (GPCR) family comprised of 15 peptide-binding receptors. While these receptors present important and attractive therapeutic targets, the nature of their cognate ligands poses actual challenges in therapeutic drug design._x000D_Molecules that are able to activate or modulate GLP-1R and overcome the pharmacokinetic limitations of the cognate ligand GLP-1 (e.g. very short half life in the range of minutes), have been developed and are available for treatment of T2D (e.g. exenatide and liraglutide). They are peptide mimetics resistant to enzymatic degradation by DPP-IV and therefore have a significantly longer half life than GLP-1. Many Big Pharma and Biotech companies focus research on identifying and developing newer GLP-1 mimetics with improved properties compared to these first generation mimetics. _x000D_GLP-1 mimetics, approved and in development, with even longer half life are associated with side effects like immunogenicity (antibody generation), potential carcinogenesis and gastrointestinal side effects. Pancreatitis is hypothesized being due to continuous receptor stimulation. The identification of potent small molecule GLP-1R agonists has failed so far._x000D_The goal of this project is to identify and develop up to an early stage Protein Epitope Mimetics (PEM) and/or small molecules that modulate GLP-1R activity, demonstrate a plasma glucose lowering activity in animal models and have an overall profile superior to existing treatments._x000D__x000D_To achieve this goal the consortium will address the following specific aims:_x000D_• Generation of novel functional assays for the detection of GLP-1R agonists and modulators addressing the specific features of this receptor_x000D_• Rational design and production of target focused libraries, based on structural information for the GLP-1R_x000D_• Identification of hits through high-throughput screening (HTS) of a diverse set of compound libraries_x000D_• Development of optimized preclinical candidates through a medicinal chemistry program_x000D_• Assessment of in vivo activity in disease relevant models_x000D_• Intellectual Property protection and business development activities to secure further compound development and exploitation of potential drug candidates._x000D__x000D_Axxam is a privately owned science-driven biotechnology company funded in 2001 and based in Milan. The company offers early stage discovery research services for the life science industry as well as carrying out its own internal discovery research. Axxam has developed innovative technologies, including new functional readout systems, like Photina® and chAMPion, that will be used in the project, for improving the drug discovery process._x000D_Polyphor is a privately held Swiss biotech company founded in 1996 and committed to identify innovative, high quality products for its own drug portfolio or for Ps in Pharma and Biotech industry. The company has developed the proprietary innovative PEM Technology, built-up an attractive PEMdrug portfolio and evolved into a clinical stage biotech. Its most advanced product is currently in Phase II trials. A proprietary, diverse library composed of PEM and an outstanding compound screening library of small molecular weight compounds will be used in the project as drug discovery tools._x000D_

Acronym	InsuSecret (Reference Number: 6152)
Duration	01/07/2011 - 31/12/2014
Project Topic	The project targets the development of innovative Protein Epitope Mimetics and different classes of small molecules to modulate GLP-1R and stimulate insulin secretion, as novel therapeutic agents for treatment of Type-2 Diabetes.
Project Results (after finalisation)	o Based on Axxam's chAMPion technology a novel and innovative screening assay was established_x000D_o This assay was successfully applied for HTS of three compound libraries from Polyphor_x000D_o Promising hits were identified from Polyphor's Protein Epitope Mimetics (PEM) library and confirmation of hits was achieved_x000D_o A hit-to-lead and a lead optimization program were successfully performed to improve potency and in vitro properties _x000D_o Lead candidates(s) were characterized in a functional assay based on human pancreatic islets and activity was demonstrated_x000D_o First in vivo studies in rat were performed with one lead candidate, indicating overall good tolerability, favorable systemic _x000D_ exposure and a glucose lowering effect based on the first part of a proof-of-concept study
Network	Eurostars
Call	Eurostars Cut-Off 5

Project partner

Number	Name	Role	Country
2	Axxam SpA	Coordinator	Italy
2	Polyphor AG	Partner	Switzerland