Exendin-4 1, Insulin 2 and pTH 3

Exendin-4/Exenatide

Considering the prevalence of diabetes worlwide (25.8 million diabetic patients in the United States and 33 million in the European Union alone) incretin based therapies represent an increasingly important approach for improving blood glucose control. Among them, exendin-4 belongs to the glucagon-like peptide (GLP-1) agonist class of drugs approved by both the FDA and EMA in the past decade for the treatment of type 2 diabetes mellitus.

 

Exendin-4 is a 39 amino acid peptide hormone, originally isolated from the saliva of the lizard known as the Gila monster (Heloderma suspectum), having 53% sequence homology with mammalian native GLP-1. GLP-1 has a very short half-life which precluded it from becoming a therapeutic. Subsequently Exenatide (a synthetic version of exendin-4) was identified as a DPP IV (dipeptidylpeptidase IV) resistant peptide, showing extended circulating half-life compared to the highly unstable GLP-1 peptide, with consequently higher potency and longer duration of action. The actions of exenatide, mimicking several glucoregulatory actions of the endogenous incretin GLP-1, are partially mediated through binding to the human pancreatic GLP-1 receptor, leading to glucoregulatory action and include:

  • glucose dependant enhancement of both synthesis and secretion of insulin (reduced risk of severe hypoglycemia)
  • glucose dependant suppression of inappropriately high glucagon secretion
  • slowing of gastric emptying
  • reduction of food intake and body weight (anorectic effect-weight loss)
  • increased satiety
  • increase in beta-cell mass and markers of beta-cell function

Exenatide is currently available as a twice daily (Byetta) or weekly (Bydureon) subcutaneous injectable form.

 

Arisgen’s oral Exenatide ARG015

 

Arisgen has focused on alternative routes of administration of exendin-4 that would not only improve patient compliance (and related adherence to the treatment, particularly critical in the case of chronic illness such as diabetes) but also offering a delivery route and pharmacokinetic profile that mimics the physiological profile of incretin secretion.

 

In this context, preclinical data in rodents and Dog have fully demonstrated and validated the very rapid onset of action of the exenatide formulated ARG015 following oral administration, mimicking the fast acting physiological mode of action. A fast-acting drug product offers significant benefits in method of administration, as the ARG015 capsul could be taken shortly before a meal.