1. Stimulate insulin secretion cells when glucose is high.
2. Restores 1st phase insulin response (first 10 minutes after food ingested) lost early in Type 2 diabetes.*
3. Lowers production of Glucagon concentrates after meals.
4. Slows gastric emptying which limits rise in BG following a meal
5. Reduces fasting and postprandal BG*
6. Reduces caloric intake causing a wt. loss* (in 82 week study an average wt loss of 10 lbs)
* First in class to achieve

The studies showed on average a drop in A1c of 1 point.
Byetta is the first approved drug of a class called incretin mimetics. Incretins are hormones released by the gut that help spur insulin production after meals.

Byetta is a synthetic version of a peptide, or small protein, found in what has been variously described as the saliva or the venom of the Gila monster.

The discovery was made in the early 1990's by Dr. John Eng, a researcher at the Veterans Affairs Medical Center in the Bronx, who was working on a way to discover new hormones. He realized the Gila monster hormone was similar to glucagon-like peptide 1, an incretin hormone produced in the human digestive tract.

Early research by Nauck, first published in Diabetologia in 1986 showed the diminished effect of incretins in type 2 diabetes. This is why Eng was so interest in incretin

The Department of Veterans Affairs declined to patent the substance, saying it was not directly relevant to veterans, so Dr. Eng patented it by himself. He then tried in vain to license it to a drug company before finding Amylin. Amylin in turn licensed rights to Lilly in 2002 for payments that could eventually reach $325 million. Both companies plan to sell the drug in the United States and split the profits evenly.

Analysts have said Byetta could achieve sales of hundreds of millions of dollars a year, or even more than $1 billion.

Although Dr. Nathaniel Clark, the national vice president for clinical affairs at the American Diabetes Association, said Byetta's efficacy in reducing blood sugar levels was similar to that of other drugs, I believe that there are many other reasons for the use of Byetta.

Since 40% of type 2 patients take sulfonylureas, there is obviously a lot of pancreatic burn out occurring. These patients often end up on insulin and either have poor control or suffer from frequent hypoglycemia. Exenatide has been shown to preserve beta cell function and it appears that there is a signal pathway to protect the beta cell.

This pathway appears to go further and has been shown to actually increase the production of insulin in patients who were on the way to total pancreatic burnout. This holds a great deal of promise and future studies will be needed to evaluate the long term effects

Many times when a sulfonylurea with or without metformin is not getting our patients to goal we will add an insulin sensitizer, such as Avandia or Actos, rather than injections of Byetta, or as Dr. Clark said, “others might opt for insulin, which at least initially might require only one injection a day and would be more powerful and cheaper than Byetta”, which is being sold to wholesalers for $145 or $173, depending on dosage, for a 30-day supply. Retail prices will be higher.

However both the insulin sensitizers have the side effect of weight gain, in addition their cost per month without insurance is not much different that Byetta. And while we are talking about weight gain it appears that in both mice and humans there is a greater sense of satiety from the use of Byetta.

And what about the cost vs insulin? Although it does cost more unit wise what about the cost of hypoglycemia? We all know that every time our patients experience hypoglycemia they strive for less control. According to Ginger Graham, chief executive of Amylin, Byetta would be easier to use than insulin. It spurs insulin production only when blood glucose levels are high, so there is less risk of blood sugar levels dropping dangerously low(hypoglycemic) than with insulin injections, she said. Users of Byetta do not

have to increase the monitoring of their blood sugar or adjust their doses as users of insulin do, she said.

If we look at the studies that evaluated the effectiveness of Exenatide they were very favorable. These patients had been maxed out on oral medications and the results are good.

In addition to the open label trial above there were three pivotal Phase 3 studies of BYETTA, commonly refered to as the AMIGO (AC2993: Diabetes Management for Improving Glucose Outcomes) studies, which commenced in December 2001 and concluded in the third and fourth quarters of 2003.

AMIGO 1 (metformin)- Released August 6, 2003. Manuscript accepted for publication in Diabetes Care: This 30-week study included patients with type 2 diabetes unable to achieve glycemic control with metformin alone. Topline results from this first of three pivotal studies showed that BYETTA produced statistically significant, dose-dependent reductions in A1C (the primary endpoint measuring blood glucose control). The average entry A1C was 8.2 percent. Of subjects who completed the study, 46 percent of the subjects receiving the highest dose of BYETTA (10 micrograms twice daily) achieved an A1C less than or equal to seven percent at study end. At the end of the study, the average A1C reduction in the 10-microgram group was 0.9 percentage point (difference from placebo). Subjects receiving BYETTA also showed statistically significant reductions from baseline in body weight, a secondary study endpoint, with an average 5.5-pound reduction in the 10-microgram group (difference from placebo) at study end.

AMIGO 2 (sulfonylurea) – Released November 10, 2003. Results published in Diabetes Care, November 2004: This 30-week study included patients with type 2 diabetes unable to achieve glycemic control with sulfonylurea alone. Topline results from this second of three pivotal studies showed that BYETTA produced statistically significant, dose-dependent reductions in A1C. The average entry A1C was 8.6 percent. Of subjects who completed the study, 41 percent of subjects receiving the highest dose of BYETTA (10 micrograms twice daily) achieved an A1C less than or equal to seven percent at study end. At the end of the study, the average A1C reduction in the 10-microgram group was 1.0 percentage point (difference from placebo). Subjects receiving BYETTA also showed statistically significant reductions from baseline in body weight, a secondary study endpoint, with an average 2.2- pound reduction in the 10-microgram group (difference from placebo) at study end.

AMIGO 3 (metformin + sulfonylurea) – Released November 24, 2003. Manuscript accepted for publication in Diabetes Care: This 30-week study included patients with type 2 diabetes unable to achieve glycemic control with two oral treatments (metformin plus a sulfonylurea) prior to entering the study. Topline results from this last of three pivotal studies showed that BYETTA produced statistically significant, dose-dependent reductions in A1C.

The average entry A1C was 8.5 percent. Of subjects who completed the study, 34 percent of the subjects receiving the highest dose of BYETTA (10 micrograms twice daily) achieved an A1C less than or equal to seven percent at study end. At the end of the study, the average A1C reduction in the 10-microgram group was 1.0 percentage point (differencefrom placebo). Subjects receiving BYETTA also showed statistically significant reductions from baseline in body weight, a secondary study endpoint, with an average 1.5-pound reduction in the 10-microgram group (difference from placebo) at study end.

FAQ’s

How can you get Byetta?
It will come in a 60 dose autopen, which will last one month taking 2 doses a day.

Most common side effect was mild to moderate nausea, which dissipated over time.
A reduction in dose of sulfonylurea is recommended when Byetta is started.

Must be kept refrigerated (30 day shelf life in refrigerator once started) and cannot be frozen.

Will cost the patient, if no insurance approximately $2400 dollars a year.

Not recommended for patients on insulin. Nor should patients be taken off of insulin and given Byetta.

Must be taken twice a day one-half hour before breakfast and dinner. If you skip a meal it should not be taken for that meal.

Patients should begin with the 5mcg dose for 30 days before starting higher dose of 10mcg.

Each dose of BYETTA should be administered as a SC injection in the thigh, abdomen, or upper arm at any time within the 60-minute period before the morning and evening meals. BYETTA should not be administered after a meal. If a dose is missed, the treatment regimen should be resumed as prescribed with the next scheduled dose.

And now the legal stuff

HOW SUPPLIED BYETTA is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide. The following packages are available:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen NDC 66780-210-07
10 mcg per dose, 60 doses, 2.4 mL prefilled pen NDC 66780-210-08

Important Safety Information for BYETTA™ (exenatide) injection

Precautions:

· BYETTA is not a substitute for insulin in insulin-requiring patients. BYETTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. The concurrent use of BYETTA with insulin, thiazolidinediones, D-phenylalanine derivatives, meglitinides, or alpha-glucosidase inhibitors has not been studied.

· BYETTA is not recommended for use in patients with end-stage renal disease, severe renal impairment, or severe gastrointestinal disease.

Adverse Reactions:

· Patients receiving BYETTA in combination with a sulfonylurea had an increased risk of
hypoglycemia (14% at 5 mcg and 36% at 10 mcg vs 3% placebo). Patients receiving
BYETTA in combination with metformin plus a sulfonylurea had an increased risk of
hypoglycemia (19% at 5 mcg and 28% at 10 mcg vs 13% placebo). To reduce the risk of
hypoglycemia, clinicians may consider reducing the sulfonylurea dose.
· The most common treatment-emergent adverse event associated with BYETTA (vs placebo) in three 30-week placebo-controlled clinical trials (excluding hypoglycemia) was nausea (44% vs 18%). Other common events were: vomiting (13% vs 4%), diarrhea (13% vs 6%), feeling jittery (9% vs 4%), dizziness (9% vs 6%), headache (9% vs 6%), and dyspepsia (6% vs 3%).

Drug Interactions:
· The effect of BYETTA to slow gastric emptying may reduce the extent and rate of absorption of orally administered drugs, so it should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption.
· Medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, should be taken at least 1 hour before BYETTA injection. If such drugs are to be administered with food, they should be taken with a meal or snack when BYETTA is not administered.

For full Prescribing Information, visit www.BYETTA.com.

Stay tuned for more on this exciting new compound

Mike Samarcos, Dave Rabih, Sue Normandin and Mary Beth Jellegs, contributed to this feature

References:
1 Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964; 24:1076-1082.
2 Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J ClinInvest. 1967; 46:1954-1962.
3 Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. Incretin effects of increasing glucose loads in mancalculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498.
4 Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ. Determinants of the impaired secretionof glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717-23.
5 Tourrel C, Bailbe D, Lacorne M, Meile MJ, Kergoat M, Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes. 2002;51:1443-1452.Incretin Mimetics – Class Backgrounder
6 Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824-830.
7 U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.
8 Schnabel, Catherine A., White, John R. and Campbell, R. Keith. Incretin Mimetics and DPP-IV Inhibitors in the Treatment of Type 2 Diabetes Mellitus. US Pharm. 2004; 11:35-49.
For more information or to schedule any interviews, contact Jamaison Schuler at (317) 655-2111, schulerjr@lilly.com or Eric Shearin at (858) 642-7177, eric.shearin@amylin.com.