The compounds covered by the agreement detail an orphan G protein-coupled receptor (GPCR), the 19AJ receptor, which is located primarily on pancreatic islet beta cells, the same cells that are the source of insulin in the human body. If proven safe and effective in humans, a 19AJ agonist has the potential to become either a monotherapy or in combination with other drugs acting through different pathways.
Arena has also discovered lead compounds that are selective agonists of this receptor. In animals, these small molecules increase the sensitivity of islet beta cells to increased levels of glucose, leading to increased insulin secretion under conditions of hyperglycaemia. This is in contrast to the widely used sulfonylurea drugs, which cause insulin to be secreted even in the presence of normal or low blood sugar levels.
The main advantage of this therapy over current therapy is the relative stabilizing of glucose levels. The treatment does not allow the release of insulin in the absence of glucose.
Further animal studies with these lead compounds have shown improved oral glucose tolerance. When administered chronically to diabetic rodents, the compounds significantly reduced fasting blood sugar and glycosylated haemoglobin (HbA1c) levels.
Under the terms of the agreement, Arena will receive an upfront payment of $17.5 million and could receive up to $295 million for achievement of pre-specified milestones for each compound developed under the collaboration.
Arena will also receive royalties according worldwide sales of marketed products. In addition, Arena will receive research funding of $4.8 million over two years. Johnson & Johnson Pharmaceutical R&D, an affiliate of Ortho-McNeil, will be responsible for future development for products resulting from the collaboration.
The focus for this compound is patients with type 2 diabetes who are not using insulin and are not achieving target blood glucose concentrations with diet plus metformin and/or sulfonylureas.
Current therapeutic steps available to this patient population are additional oral medications, the addition of insulin to the oral agent regimen or insulin therapy alone. These approaches are often not very successful and are usually associated with side effects, particularly weight gain.
The population of people with diabetes currently using oral medications is reckoned to be 11.9 million in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom, which comprise the seven largest pharmaceutical markets worldwide, of which an estimated 5.9 million people are in the United States.
Current research into 19AJ agonists has built up a head of momentum with a handful of companies jostling to become the first to release this compound as a viable treatment.
Amylin Pharmaceuticals', Exenatide is a 39-amino acid peptide that exhibits several anti-diabetic, or glucose lowering, actions. It is the first member of a new class of therapeutic medications known as incretin mimetic agents. Exenatide (synthetic exendin-4) in a global agreement with Eli Lilly, is being investigated for its potential in treating type 2 diabetes. A New Drug Application (NDA) was submitted to the FDA mid-2004.