Exenatide

Exenatide (marketed as Byetta) is the first of a new class of medications (incretin mimetics) approved for the treatment of type 2 diabetes. It is manufactured and marketed by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide is a synthetic version of exendin-4, a hormone in the saliva of the Gila monster, a lizard native to several Southwestern American states. It displays properties similar to human GLP-1.

Exenatide is a 39 amino acid peptide that mimics the GLP-1 incretin, an insulin secretagogue with glucoregulatory effects. While it may lower blood glucose levels on its own, it can also be combined with other medications such as pioglitazone, metformin, sulfonylureas, and/or insulin to improve glucose control. The approved use of exenatide is with either sulfonylureas, metformin and thiazolinediones. The medication is injected twice per day (s.c) using a pre-filled pen device. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite - all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose, lessening the risk of hypoglycemia.

Development history
The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP are produced by the endocrine cells of the intestine following ingestion of food. GLP-1 and GIP stimulate insulin secretion from the beta cells of the islets of Langerhans in the pancreas. Only GLP-1 causes insulin secretion in the diabetic state; however; GLP-1 itself is ineffective as a clinical treatment for diabetes as it has a very short half-life in vivo. Exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo. Thus, it was tested for its ability to stimulate insulin secretion and lower blood glucose in mammals and was found to be effective in the diabetic state. In studies on rodents it has also been shown to increase the number of beta cells in the pancreas.

Commercially, exenatide is produced by direct chemical synthesis. Historically, exenatide was discovered as a protein naturally secreted in the saliva and concentrated in the tail of the Gila monster. This discovery lead to source from which to test the protein as a GLP-1 alternative. While the exenatide protein was structurally analogous to GLP-1, it had a much longer half-life after injection; this enabled consideration and development of exenatide as a diabetes mellitus treatment strategy. Given this history, exenatide is sometimes referred to as "lizard spit". Subsequent clinical testing lead to the discovery of the also very desirable glucagon and appetite suppressant effects.

It received US Patent 5,424,286 which was filed May 24, 1993.

It received FDA approval in the US in April 2005 and is currently marketed as Byetta. Exenatide is approved "as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a biguanide, or a combination of metformin and a sulfonylurea but have not achieved adequate glycemic control". It has now been approved for use with thiazolidinediones such as pioglitazone or rosiglitazone.

Patent extension per 35 USC 156 requested on June 25, 2005 by Amylin Pharmaceuticals on behalf of John Eng.

Trademark - August 30, 2005.

As of October 2007, more than 3 million prescriptions for Byetta have been written in the USA.

Safety warning: The FDA announced in October 2007 it has reviewed 30 postmarketing reports of acute pancreatitis in patients taking Byetta, a drug used to treat adults with type 2 diabetes. An association between Byetta and acute pancreatitis is suspected in some of these cases.

Healthcare professionals should instruct patients taking Byetta to seek prompt medical care if they experience unexplained persistent severe abdominal pain which may or may not be accompanied by vomiting. If pancreatitis is suspected, Byetta should be discontinued. If pancreatitis is confirmed, Byetta should not be restarted unless an alternative etiology is identified.

FDA has asked and the maker of Byetta, Amylin Pharmaceuticals, Inc. has agreed to include information about acute pancreatitis in the PRECAUTIONS section of the product label. This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA is not advising practitioners to discontinue prescribing the product. FDA intends to update this sheet when additional information or analyses become available.

Mode of action
Exenatide is believed to facilitate glucose control in at least four ways:
 * Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; however, other drugs (like injectable insulin) 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 pancreatic 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 and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
 * Exenatide has a subtle yet prolonged effect to reduce appetite and thus may prevent weight gain. Most people using Exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated that the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain.
 * Exenatide reduces liver fat content. Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice and more recently in man.

In an open-label randomized controlled trial of 551 patients, exenatide treatment for 26 weeks was associated with 2.3 kg weight loss; however, gastrointestinal symptoms were more common in the exenatide group, including nausea (57.1%), vomiting (17.4%) and diarrhea (8.5%). For most patients, the nausea is mild to moderate and goes away entirely after a few days or weeks. Medical professionals who work with Byetta have stated that much of what is reported as nausea is actually a feeling of fullness. It is speculated that Byetta makes most patients need to eat less and until an adjustment is made to smaller portions, the result is the fullness feeling.

Advantages: While other treatment options share one or more of the first three characteristics, some diabetics specialists view exenatide as a significant improvement over other available diabetic medications, although most doctors do not use it as primary therapy at this time. Except for metformin and acarbose, all other available drugs for improving glucose control have been associated with weight gain. Disadvantages: In addition to gastrointestinal adverse reactions, a relative disadvantage of exenatide is that it is administered by injection. See side effects section below.

Indications

 * Adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, or a combination of metformin and sulfonylurea, but who have not been able to achieve adequate control of blood glucose
 * Use with insulin, thiazolidinediones, meglitinides, and glucosidase inhibitors has not been studied
 * Some physicians are using exenatide as primary monotherapy, although this is not currently an FDA approved usage.

Note: Since the major action of this drug is to enhance the release of endogenous insulin from the pancreas, exenatide is not for use in Type 1 diabetes.

Side effects

 * May increase risk of sulfonylurea-induced hypoglycemia.
 * Gastrointestinal side effects have raised concern among some health care professionals; however, they have not been adaquately studied.
 * Patients taking exenatide (Byetta) may be at risk for acute pancreatitis according to FDA (see safety warning above).

Future Research
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 approximately twice as effective as the original twice-daily injectable form, with a similar safety, lower nausea rates and greater weight loss profile. A Phase III study showed that 50% of patients treated with exenatide LAR had an A1C of 6.5% or better, and 75% reached 7.0%. Scientists at the National Institutes of Health in Bethesda MD and other academic institutions are also working on gene therapy based methods to administer Exendin-4 without the need for expensive daily injections. A research group led by Hee-Sook Jun published a paper in Diabetes indicating that the delivery of GLP-1 through the use of an Adenoviral vector was sufficient to result in the 'long term cure of diabetes'.