Exenatide (also Exendin-4, marketed as Byetta) is the first of a new class of medications approved for the treatment of Type 2 diabetes. It is an incretin mimetic, which has glucoregulatory effects. It is to be used in conjunction with oral medications such as metformin and/or a sulfonylurea to improve glucose control. The medication is injected twice per day using a specially designed pen. The typical human response is both an improvement of the release of internal insulin by the pancreas and suppression of pancreas glucagon release, behaviors more typical of individuals without blood sugar control problems. In the presence of exenatide, these responses are greater when the blood sugar is elevated.

Development History

The known incretins, GLP-1 and GIP, normally produced by the small intestine are not suitable as a treatment because of their very short half-life. An incretin researcher, doing an online search for proteins of similar known amino acid structure noticed that exenatide, a protein in the saliva of the poisonous North American Gila monster reptile, had a similar structure. Further investigation revealed that injected exenatide triggered very similar responses to endogenous incretins yet had a relatively long physiologic response half-life. These observations lead to development of exenatide as a medical treatment.

Commercially, exenatide is produced by direct chemical synthesis. Given the history of the drug, and though it is -- strictly speaking -- not so, it is sometimes referred to as "lizard spit".

It was first marketed in the US in April 2005, as Byetta.

Mode of action

Exenatide works to help improve glucose control in at least four ways:

• Exenatide augments pancreas response to release a higher, more appropriate amount of insulin in response to eating meals; this helps lower the rise in blood sugar rise from eating to more normal, flatter response levels. If blood sugar levels get closer to normal, the pancreas response to produce insulin is reduced. Other drugs (like injectable insulin itself) are effective at lowering blood sugar, but can "overshoot" their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
• Exenatide also suppresses pancreas release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
• Exenatide helps slow down gastric emptying (the rate at which sugar enters the bloodstream) which also helps avoid hyperglycemia.
• Exenatide has a subtle yet prolonged effect to reduce appetite, overeating and weight gain. Most people using Exenatide slowly lose weight. Though mild, clinical trials have demonstated that the weight reducing effect continues at the same rate through 2.25 years of continued use.

While other treatment options share one or more of the first three characteristics, many diabetics specialists view exenatide as a significant improvement over other available diabetic medications. In addition to its strong safety profile, the improved weight control is important for diabetes treatment; except for metformin, all other available drugs for improving glucose control have been associated with weight gain.

Long-acting-release formulation

Eli Lilly & Co., Amylin Pharmaceuticals and Alkermes, Inc. are currently developing a long-acting-release (LAR) formula of the drug, which would be injected once per week. The initial trials for the medication have shown the LAR formulation to be as effective as the original twice-daily injectible form, with a similar safety and weight loss profile.

External links

• Byetta website
• Byetta prescribing information (with clinical studies references)
• NY Times Article on Byetta

Exenatide

NEW YORK, June 26 (Reuters) - Nastech Pharmaceutical Co. Inc. (NSTK.O: Quote, Profile, Research) said on Monday it had reached an agreement with Amylin Pharmaceuticals, Inc. (AMLN.O: Quote, Profile, Research) to develop a nasal spray formulation of exenatide, a treatment for type 2 diabetes.

Nastech would receive milestone payments of up to $89 million and royalties on product sales if development were successful and the program moved forward.