Project: Dual acting peptides for Inflammatory Bowel Disease

The consortium, Pepscan Therapeutics (Pepscan) and Zealand Pharma (Zealand), wish to investigate and develop a novel GLP-2 drug with beneficial properties for treatment of patients suffering from Inflammatory Bowel Disease (IBD). _x000D__x000D_Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder characterized by unpredictable relapsing inflammation of the intestine, followed by spontaneous remission. IBD embraces two distinct conditions: ulcerative colitis (UC) and Crohn’s disease (CD) distinguished by the location and extent of the intestine inflammation. Approximately 2.2 million persons in the United States and Europe are affected by IBD. At present there is no cure for IBD. Current medical treatment of UC and CD focus on symptoms relieving and induction and COtenance of remission, as well as limitation of side effects of medication and avoidance of complications. The treatment primarily targets inflammation and are associated with significant side effects, frequent dosing and high costs. Moreover, many patients experience that the treatment looses effect over time. Due to these therapeutic shortcomings there is a significant unmet need for novel therapeutic approaches in the treatment of IBD._x000D__x000D_Crohn's Disease (CD) is a chronic, non-curable, episodic, inflammatory condition of the gastro-intestinal tract characterized by transmural inflammation (affecting the entire wall of the involved bowel) and skip lesions (areas of inflammation with areas of normal lining in between). CD can affect any part of the gastrointestinal tract from mouth to anus, thus, the symptoms of CD are very variable from one patient to the other. The primary gastrointestinal symptoms are abdominal pain, diarrhea, which may be bloody, and weight loss. Moreover, many patients suffer from intestinal obstruction, abscesses and fistulas._x000D__x000D_There is no known medical or surgical cure for Crohn's Disease. The medical treatments applied are aiming at induction and COtenance of remission of the disease. The treatments include high-dose corticosteroid, traditional immunomodulators (e.g. azathioprine and methotrexate), anti-inflammatory medication, Biological Immunomodulators (e.g. Remicade®). All available treatment regimes are associated with suboptimal efficacy and serious side-effects. Tratment with corticosteroids often induce remission but do not alter the overall course of the disease and COtenance therapy with corticosteroids should be avoided due to their side effects. The traditional immunomodulators azathioprine and methotrexate heal the mucosa but their onset of action is slow. Remicade® therapy introduces rapid mucosal healing, but 60% of treated patients have lost response at week 54. Improvement of symptoms is no longer satisfactory and modification of the clinical course of the disease has become the major goal._x000D__x000D_As the clinical symptoms of IBD reflect superficial mucosal inflammation, treatments that induce healing/growth of the intestinal mucosa may provide particular clinical benefits. If a treatment induces profound and long-lasting mucosal healing, it may reduce complications including need for surgical interventions and therefore such a drug could potentially slow down or even stop the progression of the disease. If the drug had additional anti-inflammatory effects this would represent a new class of therapeutic compounds in the treatment of IBD. The significant unmet medical need for effective and safe therapies makes the commercial potential very attractive. _x000D__x000D_Stabilization of peptides by means of Pepscan’s CLIPS technology, would strongly favor receptor binding as a direct result of pre-organizing the key functionalities in the right position for binding. It would furthermore enhance the resistance to proteolytic degradation. Zealand has a strategy for improving peptides based on a concept of combining 2 or more beneficial properties in one peptide. The consortium believes that this would be an attractive approach for our GLP-2-analogues. This can be achieved in different ways, using a number of different combinations. One example is the ZP2929 project, where Zealand already has developed a successful program in preclinical development, by combining the activities of a GLP-1 and a glucagon agonist in one single molecule that provides both glycaemic control and weight loss._x000D__x000D_The stabilization of the peptide would allow for developing a peptide with efficacy on both the GLP-2 receptor as well as on an anti-inflammatory pathway. Thus by combining the technologies and knowledge of the two companies, the consortium seek to discover novel GLP-2 compounds which will have improved efficacy on the GLP-2 receptor as well as beneficial effects on inflammation.

Acronym DAPIBD (Reference Number: 6000)
Duration 01/04/2011 - 31/03/2013
Project Topic Zealand Pharma has experience in development of peptide therapeutics with activity dual activities. Pepscan has a novel technology for optimzing the performance of peptide therapeutics. Now the two companies want to combine their expertise to develop a superior drug for Inflammatory Bowel Disease.
Project Results
(after finalisation)
The aim of the program was to demonstrate the feasibility of developing a hybrid peptide, combining a CLIPS-stabilized GLP-2 agonist with a suitable anti-inflammatory hybrid P, for the treatment of inflammatory bowel disease. CLIPS technology was developed at Pepscan and has been shown to improve the activity and stability of peptides, and thus provides great opportunities for new therapeutic peptide drugs. The chemical structure-activity-relationship (SAR) knowledge on GLP-2 and the development of the anti-inflammatory component was developed at Zealand Pharma. _x000D_The program generated >60 peptides incorporating CLIPS. All compounds were tested for GLP-2R potency. In addition, 17 GLP-2/a-MSH hybrid peptides were generated and tested in both GLP-2R and a-MSH (MC1R and MC4R) in vitro assays. The program had also planned to select and screen lead compounds in an in vivo setting, however due to delays and time-restrictions this work was not carried out, but may be performed in the near future.
Network Eurostars
Call Eurostars Cut-Off 5

Project partner

Number Name Role Country
2 Pepscan Holding NV Partner Netherlands
2 Zealand Pharma A/S Coordinator Denmark