Prime candidates for a medical breakthrough: which protein(s) would be interesting to develop as long acting injectables?

Therapeutic protein drugs are an important class of medicines with applications in a variety of diseases. Most of the proteins are poorly absorbed orally, they are administered parenterally and often, once daily, leading to patient compliance and adherence issues. Long acting drug delivery system are known to improve patient adherence, reduce side effects and increase overall quality of life. Such delivery systems are very useful especially in chronic diseases where treatment should be administered on a regular basis over prolonged periods of time.

One of the adequate chronic condition where treatment with injectable protein drugs is common, is type 2 diabetes mellitus. There are over 340 million type 2 diabetics worldwide with an economic burden of close to half a trillion dollars annually. One of the drug groups which concentrates a great focus in the last decade is glucagon-like peptide-1 (GLP-1) receptor agonists. These macromolecules are glucose regulators which stimulate insulin secretion, decrease glucagon secretion, slows gastric emptying and increase satiety. They are considered safer than insulin secretagogues as they induce lower risk of hypoglycemia, but poses a major disadvantage as they are administered parenterally from one to three times a day.

I think that the leading protein among them for developing long acting injectables is Liraglutide. This drug has a great potential to be entrapped in a sustained release delivery system since it exhibits both hydrophilic and lipophilic properties owing to the palmitic acid moiety attached to the GLP-1 molecule. This attached moiety leads to the self-association of liraglutide molecules contributing to their binding to albumin and resulting in their release under a constant rate. If it will be encapsulated in a smart sustained release system, it will give a constant blood concentration within the therapeutic index, keeping glucose levels at a near normal range and avoiding hyper or hypo-glycemic events.

Another interesting protein that is not only administered to type 2 diabetes patients but also in type 1, is Pramlintide (Symlin™). This drug is a protein mimetic of the pancreatic hormone-Amylin. Amylin is secreted along with insulin and plays a role in glycemic regulation by slowing gastric emptying and inhibiting the action of glucagon. It is administered along with insulin (not in the same injection) and administered to people with persistent hyperglycemia. Usually, people who are experiencing frequent hyperglycemia events do not adhere properly to their therapeutic treatment and are considered, therefore, a challenging population which is likely to gain many advantages from long acting injectables. This long acting system might reduce the frequency of hyperglycemia, hopefully avoiding the long-term complications of untreated chronic high glucose levels.

Another advantage in creating a long acting injectables for anti-diabetic drugs, is that it could be easily combined with a sensor that will release the drug in a constant rate, in a reaction to certain threshold, keeping the patient in normal range of blood glucose.