2.1 Recommended Dosage

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The recommended dosage of BYDUREON BCISE is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.

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Discontinue an immediate- or extended-release exenatide product prior to initiation of BYDUREON BCISE. Patients changing from another extended-release exenatide product to BYDUREON BCISE may do so at the next regularly scheduled dose. Patients changing from immediate-release exenatide to BYDUREON BCISE may experience transient (approximately 2 to 4 weeks) elevations in blood glucose concentrations.

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The day of weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before the new day of administration.

Recommendations Regarding Missed Dose

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If a dose is missed, administer the dose as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, administer subsequent doses once every 7 days (weekly).

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If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, do not administer the missed dose and instead resume BYDUREON BCISE with the next regularly scheduled dose.

2.2 Administration Instructions

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Prior to initiation, train patients and caregivers on proper mixing and injection [see Instructions for Use]. Instruct caregivers to assist pediatric patients with mixing and administration.

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Remove the autoinjector from the refrigerator 15 minutes prior to mixing the injection, in order to reach room temperature.

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Mix by shaking vigorously for at least 15 seconds.

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Inspect BYDUREON BCISE visually before use. After mixing, BYDUREON BCISE should appear as an opaque, cloudy, white to off-white suspension, evenly mixed with no residual medicine along the side, bottom or top of the inspection window. Do not use if particulate matter is present or if discoloration is observed.

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Administer BYDUREON BCISE immediately after the autoinjector is prepared as a subcutaneous injection in the abdomen, thigh, or upper arm region. Advise patients to use a different injection site each week when injecting in the same region.

5.1 Risk of Thyroid C-cell Tumors

In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration–dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls [see Nonclinical Toxicology (13.1)]. A statistically significant increase in malignant thyroid C-cell carcinomas was observed in female rats receiving exenatide extended-release at 27-times clinical exposure compared to controls and higher incidences were noted in males above controls in all treated groups at ≥2-times clinical exposure. The potential of exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 receptor agonists have also induced thyroid C-cell adenomas and carcinomas in male and female mice and rats at clinically relevant exposures. It is unknown whether BYDUREON BCISE will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined.

Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

BYDUREON BCISE is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk of MTC with the use of BYDUREON BCISE and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with BYDUREON BCISE. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

5.2 Acute Pancreatitis

Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON BCISE, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, BYDUREON BCISE should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, BYDUREON BCISE should not be restarted. Consider antidiabetic therapies other than BYDUREON BCISE in patients with a history of pancreatitis. In clinical trials of BYDUREON BCISE acute pancreatitis occurred in 0.4% of patients.

5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Patients receiving BYDUREON BCISE in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.4 Acute Kidney Injury

BYDUREON BCISE may induce nausea and vomiting with transient hypovolemia and may worsen renal function. There have been postmarketing reports of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYDUREON (exenatide) for extended-release injectable suspension. BYDUREON BCISE is not recommended for use in patients with an eGFR below 45 mL/min/1.73 m2[see Use in Specific Populations (8.6)].

5.5 Gastrointestinal Disease

Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of BYDUREON BCISE is not recommended in patients with severe gastrointestinal disease.

5.6 Immunogenicity-Associated Decreased Glycemic Control

In the 28-week treatment period in Trials 1 and 2 in adult patients with type 2 diabetes mellitus [see Clinical Studies (14.2)], BYDUREON BCISE-treated patients who had high titer anti-exenatide antibodies (defined as ≥625) had a lower glycemic response compared to BYDUREON BCISE-treated patients who did not have anti-exenatide antibodies [see Clinical Pharmacology (12.6)].

In the 24-week treatment period in Trial 9 in pediatric patients with type 2 diabetes mellitus [see Clinical Studies (14.6)], BYDUREON-treated patients who had high titer anti-exenatide antibodies (≥625) appeared to have had a lower glycemic response compared to BYDUREON-treated patients who did not have anti-exenatide antibodies. At Week 24, the mean change in HbA1c from baseline in BYDUREON-treated patients was greater (-0.73%) in those with low titer anti-exenatide antibodies (<625) compared to +0.07% in those with high titer anti-exenatide antibodies [see Clinical Pharmacology (12.6)].

If there is worsening glycemic control or failure to achieve targeted glycemic control, consider stopping BYDUREON BCISE and using alternative antidiabetic therapy.

5.7 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with exenatide. If a hypersensitivity reaction occurs, the patient should discontinue BYDUREON BCISE and promptly seek medical advice [see Contraindications (4) and Adverse Reactions (6.2)]. Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP‑1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with BYDUREON BCISE.

5.8 Drug-Induced Thrombocytopenia

Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune-mediated reaction with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYDUREON BCISE immediately and do not re-expose the patient to exenatide. Upon discontinuation, thrombocytopenia can persist due to the prolonged exenatide exposure from BYDUREON BCISE (about 10 weeks) [see Adverse Reactions (6.2)].

5.9 Serious Injection-Site Reactions

There have been postmarketing reports of serious injection-site reactions (e.g., abscess, cellulitis, and necrosis), with or without subcutaneous nodules, with the use of BYDUREON [see Adverse Reactions (6.2)]. Isolated cases required surgical intervention.

5.10 Acute Gallbladder Disease

Acute events of gallbladder disease, such as cholelithiasis or cholecystitis, have been reported in GLP-1 receptor agonist trials and postmarketing. In the EXSCEL trial [see Clinical Studies (14.5)], 1.9% of BYDUREON-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in this section are derived from pooled data from the controlled period of the 2 comparator-controlled trials (Trials 1 and 2) in adults as well as data from the extension phase of one of these trials [see Clinical Studies (14.2)]. There were 410 patients exposed to BYDUREON BCISE 2 mg for 28 weeks during the controlled phases, and an additional 116 patients exposed to BYDUREON BCISE 2 mg during an uncontrolled extension for an additional 24 weeks. Overall, there were 526 patients exposed to BYDUREON BCISE 2 mg with a mean duration of exposure of 35 weeks in the controlled and extension phases of the two trials. Across the treatment arms in the controlled periods, the mean age of patients was 55 years, 2% were 75 years or older and 59% were male. The population in these studies was 78% White, 15% Black or African American, 5% Asian; 1% American Indian or Alaska Native; <1 % were Native Hawaiian or Pacific Islander; and <1% were other races. This population included 42% of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.3 years and had a mean HbA1c of 8.5%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m2) in 93% of the pooled study populations.

The safety of BYDUREON, another formulation of exenatide extended-release, in pediatric patients age 10 to less than 18 years with type 2 diabetes was similar to that observed in the adults [see Clinical Studies (14.6)].

Common Adverse Reactions

Table 1 summarizes the adverse reactions with an incidence ≥5% occurring in BYDUREON BCISE-treated adult patients in the pooled data from the controlled and extension phases, including 10 weeks of follow‑up, of the two comparator-controlled 28-week clinical trials. Adverse reactions were identified based on known adverse reactions associated with BYDUREON.

Nausea was a common adverse reaction associated with initiation of treatment with BYDUREON BCISE and usually decreased over time with continued use. The incidence of nausea and/or vomiting was 2% in the first week of therapy compared to 1% in the 4th week of therapy.

Less Common Adverse Reactions

Adverse reactions that occurred in >2% and <5% of adult patients receiving BYDUREON BCISE during the controlled and extension phases, including 10 weeks of follow‑up, of the two comparator-controlled 28-week clinical trials include: headache (4.4%), diarrhea (4.0%), vomiting (3.4%), injection site pruritus (3.2%), dizziness (2.5%), injection site erythema (2.3%), constipation (2.1%).

Adverse Reactions Leading to Discontinuation of Therapy

The incidence of discontinuation of therapy due to adverse reactions was 3.9% for BYDUREON BCISE-treated patients in the two comparator-controlled 28-week trials in adults. The most common classes of adverse reactions leading to discontinuation of therapy for BYDUREON BCISE-treated patients were Gastrointestinal Disorders 2.0% and General Disorders and Administration Site Conditions 1.2%. For BYDUREON BCISE-treated patients, the most frequent adverse reactions leading to discontinuation of therapy within each of these respective classes were diarrhea (0.7%), nausea (0.7%), vomiting (0.5%) and injection-site nodule (0.5%).

Hypoglycemia

Table 2 summarizes the incidence of glucose level <54 mg/dL regardless of hypoglycemia clinical symptoms and the incidence of severe hypoglycemia in the two comparator-controlled 28-week trials of BYDUREON BCISE in adults.

Severe hypoglycemia was defined as clinical symptoms that were considered to result from hypoglycemia in which the patient required the assistance of another person and associated with recovery after oral carbohydrates, intravenous glucose or glucagon administration if no plasma glucose was available.

In the 24-week pediatric placebo-controlled clinical trial [see Clinical Studies (14.6)], 2 (3.4%) of BYDUREON-treated patients with type 2 diabetes had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms and 1 (1.7%) had severe hypoglycemia (defined as an episode with severe cognitive impairment requiring external assistance for recovery.

Injection-Site Adverse Reactions Including Nodules

In the two comparator-controlled 28-week trials in adults, injection site reactions (including injection site nodule, injection site pruritus, injection site bruising) were observed in 23.9% of patients treated with BYDUREON BCISE.

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions

Injection site reactions for BYDUREON BCISE-treated patients were more commonly observed in those with high titer anti-exenatide antibodies (≥625) (27%) compared to those with low titer anti-exenatide antibodies (<625) (16%) or those who did not develop anti-exenatide antibodies (16%) [see Clinical Pharmacology (12.6)].

Increase in Heart Rate

In clinical trials of BYDUREON BCISE in adults, the mean increase from baseline in heart rate was 2.4 beats per minute.

Cholelithiasis and cholecystitis

In the EXSCEL trial [see Clinical Studies (14.5)], 1.9% of BYDUREON-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BYDUREON BCISE or other formulations of exenatide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergy/Hypersensitivity: injection-site reactions (e.g., abscess, cellulitis, and necrosis, with or without subcutaneous nodules), generalized pruritus and/or urticaria, macular or papular rash, angioedema; anaphylactic reaction.

Blood and Lymphatic Systems: drug-induced thrombocytopenia.

Drug Interactions: increased international normalized ratio (INR) sometimes associated with bleeding, with concomitant warfarin [see Drug Interactions (7)].

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, ileus, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Indications and Usage (1)].

Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy.

Neurologic: dysgeusia; somnolence.

Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction.

Skin and Subcutaneous Tissue Disorders: alopecia.

8.1 Pregnancy

Risk Summary

Limited data with exenatide, the active ingredient in BYDUREON BCISE, in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be risks to the fetus from exposure to BYDUREON BCISE during pregnancy. BYDUREON BCISE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide extended-release during pregnancy or from exposure to exenatide during pregnancy and lactation, in association with maternal effects. In rats, exenatide extended-release, administered during the period of organogenesis, reduced fetal growth and produced skeletal ossification deficits at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 2 mg/week. In mice, exenatide administered during gestation and lactation, caused increased neonatal deaths at doses that approximate clinical exposures at the MRHD (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryofetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Data

Animal Data

Pregnant rats given subcutaneous doses of 0.3, 1, or 3 mg/kg exenatide extended-release every 3 days during organogenesis had systemic exposures 3-, 8-, and 19-times human exposure, respectively, at the MRHD of 2 mg/week BYDUREON BCISE based on plasma exenatide exposure (AUC) comparison. Reduced fetal growth at all doses and skeletal ossification deficits at 1 and 3 mg/kg occurred at doses that decreased maternal food intake and body weight gain.

In studies evaluating reproduction and development in pregnant mice and rabbits, maternal animals were administered exenatide, the active ingredient in BYDUREON BCISE, by subcutaneous injection twice a day. Differences in embryofetal developmental toxicity from subcutaneously injected exenatide extended-release and exenatide were not evaluated in mice, rats, or rabbits.

In pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis, skeletal variations associated with slowed fetal growth, including changes in number of rib pairs or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that produced maternal toxicity and yielded systemic exposure 200-times the human exposure resulting from the MRHD of BYDUREON BCISE based on AUC comparison.

In pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding systemic exposure up to 6-times the human exposure from the MRHD of BYDUREON BCISE based on AUC comparison.

In maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths at 6 mcg/kg/day were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure equivalent to the human exposure from the MRHD of BYDUREON BCISE based on AUC comparison.

8.2 Lactation

Risk Summary

There is no information regarding the presence of exenatide, in human milk, the effects of exenatide on the breastfed infant, or the effects of exenatide on milk production. Exenatide, the active ingredient in BYDUREON BCISE was present in the milk of lactating mice. However, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for exenatide and any potential adverse effects on the breastfed child from exenatide or from the underlying maternal condition.

Data

In lactating mice subcutaneously injected twice a day with exenatide, the active ingredient in BYDUREON BCISE, the concentration of exenatide in milk was up to 2.5% of the concentration in maternal plasma.

8.4 Pediatric Use

The safety and effectiveness of BYDUREON BCISE as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of BYDUREON BCISE for this indication is supported by a 24-week placebo-controlled trial with BYDUREON with 28-week open-label uncontrolled extension (Trial 9) in 82 pediatric patients 10 years of age and older with type 2 diabetes, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14.2, 14.3, 14.4, 14.6)].

Safety and effectiveness of BYDUREON BCISE have not been established in pediatric patients less than 10 years of age.

8.5 Geriatric Use

In two comparator-controlled 28-week trials, BYDUREON BCISE was studied in 74 patients (18%) who were at least 65 years of age and 10 (2.4%) patients who were at least 75 years of age. In these studies, no meaningful differences in safety and effectiveness were observed between patients ≥65 years of age and younger adult patients, but these studies did not include sufficient numbers of patients ≥75 years of age to determine whether they respond differently from younger adult patients.

In a large cardiovascular outcomes trial [see Clinical Studies (14.5)], BYDUREON was studied in 2,959 patients (40%) who were at least 65 years old and of those, 605 patients (8%) were at least 75 years old.

Use caution when initiating BYDUREON BCISE in geriatric patients because they are more likely to have decreased kidney function [see Use in Specific Populations (8.6)].

8.6 Renal Impairment

Pharmacokinetic studies of adult patients with renal impairment who received BYDUREON BCISE indicate that there is an increase in exenatide exposure in those with mild and moderate renal impairment as compared to patients with normal kidney function. BYDUREON BCISE may induce nausea and vomiting with transient hypovolemia and may worsen kidney function in patients with renal impairment.

Monitor patients with mild renal impairment for adverse reactions that may lead to hypovolemia. BYDUREON BCISE is not recommended for use in patients with eGFR below 45 mL/min/1.73 m2 or end-stage renal disease. If BYDUREON BCISE is used in patients with renal transplantation, closely monitor for adverse reactions that may lead to hypovolemia [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide is a GLP-1 receptor agonist that has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta-cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations.

12.2 Pharmacodynamics

Exenatide improves glycemic control through the actions described below.

Glucose-Dependent Insulin Secretion

The effect of exenatide infusion on glucose-dependent insulin secretion rates (ISR) was investigated in 11 healthy subjects. In these healthy subjects, on average, the ISR response was glucose-dependent (Figure 1). Exenatide did not impair the normal glucagon response to hypoglycemia.

Figure 1: Mean (SE) Insulin Secretion Rates During Infusion of Exenatide or Placebo by Treatment, Time, and Glycemic Condition in Healthy Subjects

SE = standard error.
Notes: 5 mmol = 90 mg/dL, 4 mmol/L = 72 mg/dL, 3.2 mmol/L = 58 mg/dL; Study medication infusion was started at time = 0 minutes.
Statistical assessments were for the last 30 minutes of each glycemic step, during which the target glucose concentrations were maintained.
*p <0.05, exenatide treatment relative to placebo.

12.3 Pharmacokinetics

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of BYDUREON BCISE or of other exenatide products.

Immunogenicity of BYDUREON BCISE in Adult Patients

Anti-exenatide antibodies were measured at prespecified intervals in the two controlled studies of BYDUREON BCISE in adults with type 2 diabetes mellitus (Trials 1 and 2) [see Clinical Studies (14.2)]. During the 28-week treatment period in these trials, 125/393 (32%) of the BYDUREON BCISE-treated patients with evaluable anti-exenatide antibody measurements developed high titer antibodies (high titer was defined as ≥625). BYDUREON BCISE-treated patients that had higher titer antibodies had a lower glycemic response compared to BYDUREON BCISE-treated patients who did not have anti-exenatide antibodies during the treatment period [see Warnings and Precautions (5.6)]. The percentage of BYDUREON BCISE-treated patients with positive antibody titers peaked at approximately Weeks 8-16 of dosing.

Amongst BYDUREON BCISE-treated patients evaluable for anti-exenatide antibodies (N=393), injection site reactions were more commonly observed in those with high titer anti-exenatide antibodies (≥625) compared to those with low titer anti-exenatide antibodies (<625) or those who did not develop anti-exenatide antibodies [see Adverse Reactions (6.1)]. There is insufficient data to assess whether the observed anti-exenatide antibodies in adult patients had an effect on the severity of injection site reactions, or on the incidence or severity of hypersensitivity reactions.

A total of 118 adult patients with high titer anti-exenatide antibodies in BYDUREON BCISE trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon and one patient (0.8%) developed cross-reactive antibodies to GLP-1 and/or glucagon.

Immunogenicity of BYDUREON in Pediatric Patients

In a 52-week BYDUREON trial (24-week controlled and 28-week extended treatment period) for the improvement of glycemic control in pediatric patients with type 2 diabetes mellitus (Trial 9) [see Clinical Studies (14.6)], 37/58 (64%) of BYDUREON-treated patients had high titer anti-exenatide antibodies (high titer was defined as ≥625) at any time during the study. In this trial, 60% of these patients had a peak high-titers at approximately Week 12. BYDUREON-treated pediatric patients that had high titer anti-exenatide antibodies appeared to have had a lower glycemic response compared to BYDUREON-treated pediatric patients who did not have anti-exenatide antibodies during this trial [see Warnings and Precautions (5.6)].

There is insufficient data to assess whether the observed anti-exenatide antibodies in pediatric patients had an effect on the incidence or severity of hypersensitivity reactions or injection site reactions.

The potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon has not been evaluated in BYDUREON-treated pediatric patients.

Anti-Drug Antibody Effects on Pharmacokinetics in Adult and Pediatric Patients

The percentage of exenatide-treated adult and pediatric patients (age ≥11 years) with high anti-exenatide antibody titers (≥625) that had steady state exenatide plasma concentrations below limit of quantitation was higher than in those with low anti-exenatide antibody titers (<625).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Thyroid C-cell tumors have been observed in rats and mice with GLP-1 receptor agonists.

A 2‑year carcinogenicity study was conducted with exenatide extended-release, the active component of BYDUREON BCISE, in male and female rats at doses of 0.3, 1.0, and 3.0 mg/kg (2-, 10-, and 27-times human systemic exposure at the maximum recommended human dose (MRHD) of 2 mg/week. BYDUREON BCISE based on plasma exenatide AUC, respectively) administered by subcutaneous injection every other week. In this study there was an increased incidence of C-cell adenomas and C-cell carcinomas at all doses. An increase in benign fibromas was seen in the skin subcutis at injection sites of males given 3 mg/kg. No treatment-related injection-site fibrosarcomas were observed at any dose. The human relevance of these findings is currently unknown.

Carcinogenicity of exenatide extended-release has not been evaluated in mice.

Exenatide, the active ingredient in BYDUREON BCISE, was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with exenatide, the active ingredient in BYDUREON BCISE, at twice-daily subcutaneous doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 163-times the human exposure resulting from the recommended dose of 2 mg/week, based on AUC.

14.1 Overview of Clinical Studies

BYDUREON BCISE has been studied in adult patients with type 2 diabetes mellitus as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione [see Clinical Studies (14.2)].

The effectiveness of BYDUREON BCISE as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus was also supported by adequate and well-controlled studies of BYDUREON, another extended-release exenatide product, in adult and pediatric patients aged 10 years and older with type 2 diabetes mellitus [see Clinical Studies (14.3, 14.4, 14.6)].

Cardiovascular (CV) outcomes were studied in the EXSCEL trial that enrolled adult patients with type 2 diabetes mellitus and multiple risk factors for CV disease or established CV disease [see Clinical Studies (14.5)].

14.2 BYDUREON BCISE Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

BYDUREON BCISE versus BYETTA, Both as Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents

A 28-week, randomized, open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON BCISE to BYETTA in adult patients with type 2 diabetes and inadequate glycemic control with diet and exercise alone or with oral antidiabetic therapy, including metformin, a sulfonylurea, a thiazolidinedione, or a combination of any two of these therapies (Trial 1 - NCT01652716). Patients were randomly assigned to receive BYDUREON BCISE 2 mg given subcutaneously once every 7 days (weekly) (n=229) or BYETTA (10 mcg twice daily) (n=146), in addition to existing oral antidiabetic agents. Patients assigned to BYETTA initiated treatment with 5 mcg twice daily then increased the dosage to 10 mcg twice daily after 4 weeks.

A total of 375 adult patients were studied: 278 (74%) were Caucasian, 61 (16%) Black or African American, 25 (7%) Asian, 5 (1%) listed as other, 5 (1%) American Indian or Alaska Native, and 1 (<1%) Native Hawaiian or Other Pacific Islander. Patients were treated with diet and exercise alone (13%), a single oral antidiabetic agent (49%), or combination therapy of oral antidiabetic agents (38%). The mean baseline HbA1c was 8.5%.

The primary endpoint was change in HbA1c from baseline to Week 28.

Efficacy Results:

The results for the primary endpoint at Week 28 are summarized in Table 4. Treatment with BYDUREON BCISE 2 mg once weekly (QW) resulted in a statistically significantly greater reduction in HbA1c compared to BYETTA 10 mcg twice daily. The mean reduction in HbA1c was non-inferior compared with BYETTA 10 mcg twice daily at the pre-specified non-inferiority margin +0.4% in this study. BYDUREON BCISE 2 mg QW was statistically superior to BYETTA 10 mcg twice daily (ANCOVA p-value=0.0032).

The proportions of subjects achieving HbA1c <7.0% at Week 28 were 40% in BYDUREON BCISE group compared to 38% in BYETTA group. Subjects with missing values at Week 28 counted as non-responders. The mean changes from baseline to Week 28 for fasting plasma glucose were -36 mg/dL and -27 mg/dL for BYDUREON BCISE and BYETTA, respectively, and for body weight were -1.4 kg and -1.9 kg for BYDUREON BCISE and BYETTA, respectively.

BYDUREON BCISE versus Sitagliptin and Placebo, All as Add-on to Metformin Therapy

A 28-week open-label (oral medication blinded), comparator- and placebo-controlled trial was conducted to compare the safety and efficacy of BYDUREON BCISE to sitagliptin and placebo in adult patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (Trial 2 - NCT01652729). Patients were randomly assigned to receive BYDUREON BCISE 2 mg given subcutaneously once every 7 days (weekly) (n=181), sitagliptin 100 mg/day (n=122) or placebo (n=61), in addition to their existing metformin therapy.

A total of 364 adult patients were studied, 296 (81%) were Caucasian, 49 (14%) Black or African American, 14 (4%) Asian and 3 (<1%) American Indian or Alaska Native, 1 (<1%) Native Hawaiian or Other Pacific Islander, and 1 (<1%) was classified otherwise. The mean baseline HbA1c was 8.5%.

The primary endpoint was change in HbA1c from baseline to Week 28.

Efficacy Results:

Results for the primary endpoint at 28 weeks are summarized in Table 5. In this study, treatment with BYDUREON BCISE 2 mg once weekly resulted in a statistically significant mean reduction in HbA1c compared to placebo. BYDUREON BCISE 2 mg was statistically superior to placebo (ANCOVA p-value=0.02).

The proportions of subjects who achieved an HbA1c <7.0% at Week 28 were 41%, 31%, and 26% in BYDUREON BCISE, Sitagliptin and Placebo groups, respectively. Subjects with missing values at Week 28 counted as non-responders. The mean changes from baseline to Week 28 for fasting plasma glucose were -24 mg/dL, -19 mg/dL and -1 mg/dL for BYDUREON BCISE, Sitagliptin and Placebo, respectively, and for body weight were -1.4 kg, -1.2 kg, and 0.4 kg for BYDUREON BCISE, Sitagliptin and Placebo, respectively.

14.3 BYDUREON Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus - Monotherapy

BYDUREON, another exenatide extended-release product, has been studied as monotherapy in adult patients with type 2 diabetes mellitus.

BYDUREON Monotherapy versus Metformin, Sitagliptin, and Pioglitazone

A 26-week, randomized, comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to metformin, sitagliptin, and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with diet and exercise (Trial 3 - NCT00676338). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every seven days (weekly), titrated metformin from 1000 to 2500 mg/day, sitagliptin 100 mg/day or titrated pioglitazone from 30 to 45 mg/day, all dosed according to approved labeling.

A total of 820 patients were studied: 552 (67%) were Caucasian, 102 (12%) were East Asian, 71 (9%) were West Asian, 65 (8%) were Hispanic, 25 (3.0%) were Black, 4 (0.5%) were Native American, and 1 was classified otherwise. The mean baseline HbA1c was 8.5%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON 2 mg once weekly (QW) resulted in mean HbA1c reduction that was statistically significantly greater compared to sitagliptin 100 mg/day. The mean reduction in HbA1c was non-inferior compared with metformin 1000-2500 mg/day (mean dose 2077 mg/day at study endpoint). Non-inferiority of BYDUREON 2 mg QW to pioglitazone 30-45 mg/day (mean dose 40 mg/day at study endpoint) in reducing HbA1c after 26 weeks of treatment was not demonstrated (the mean change from baseline in HbA1c after 26 weeks was -1.6% with BYDUREON and -1.7% with pioglitazone). The non-inferiority margin was set at +0.3% in this study. The results for the primary endpoint at 26 weeks are summarized in Table 6.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 56%, 52%, 40%, and 55% for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively. Patients who did achieve HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -41 mg/dL, -36 mg/dL, -20 mg/dL and -46 mg/dL, and for body weight were -2.0 kg, -2.0 kg, -0.8 kg and +1.5 kg for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively.

14.4 BYDUREON Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus - Combination Therapy

BYDUREON, another exenatide extended-release product, has been studied in combination with metformin, sulfonylurea, thiazolidinedione, SGLT2 inhibitor and basal insulin in adult patients with type 2 diabetes mellitus.

BYDUREON versus Sitagliptin and Pioglitazone, All as Add-on to Metformin Therapy

A 26-week double-blind comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to sitagliptin and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (Trial 4 - NCT00637273). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly), sitagliptin 100 mg/day or pioglitazone 45 mg/day, in addition to their existing metformin therapy.

A total of 491 patients were studied 168 (34.2%) were Caucasian, 143 (29.1%) were Hispanic, 119 (24.2%) were Asian, 52 (10.6%) were Black, 3 (0.6%) were Native American, and 6 (1.2%) were classified otherwise. The mean baseline HbA1c was 8.5%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

In this study, treatment with BYDUREON 2 mg QW resulted in a statistically significant mean HbA1c reduction compared to sitagliptin 100 mg/day. There was a numerically greater reduction in HbA1c with BYDUREON compared to pioglitazone, but there was not sufficient evidence to conclude superiority of BYDUREON 2 mg QW to pioglitazone 45 mg/day in reducing HbA1c after 26 Weeks of treatment. Results for the primary endpoint at 26 Weeks are summarized in Table 7.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 46%, 30%, and 39% for BYDUREON, sitagliptin, and pioglitazone, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -32 mg/dL, -16 mg/dL and -27 mg/dL, and for body weight were -2.3 kg, -0.8 kg and +2.8 kg for BYDUREON, sitagliptin, and pioglitazone, respectively.

BYDUREON versus Insulin Glargine, Both as Add-on to Metformin or Metformin + Sulfonylurea Therapy

A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to titrated insulin glargine in patients with type 2 diabetes whose glycemic control was inadequate with metformin or metformin plus sulfonylurea therapy (Trial 5 - NCT00641056). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or insulin glargine once daily in addition to their existing oral antidiabetic therapy. Insulin glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL.

The mean dose of insulin glargine was 10 units/day at baseline and 31 units/day at endpoint. At Week 26, 21% of insulin glargine-treated patients were at fasting glucose goal.

A total of 456 patients were studied: 379 (83.1%) were Caucasian, 47 (10.3%) were Hispanic, 25 (5.5%) were East Asian, 3 (0.7%) were Black, and 2 (0.4%) were West Asian. Background therapy was either metformin (70%) or metformin plus sulfonylurea (30%). The mean baseline HbA1c was 8.3%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.5%. The mean reduction in HbA1c seen in insulin glargine arm at 26 weeks was -1.3%. The difference in observed effect size between BYDUREON and glargine in this trial excluded the pre-specified non-inferiority margin of +0.3%.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 57% and 48% for BYDUREON and insulin glargine, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose in this study were -38 mg/dL and -50 mg/dL, and for body weight were -2.6 kg and +1.4 kg for BYDUREON and insulin glargine, respectively.

BYDUREON versus Liraglutide, Both as Add-on to Metformin, a Sulfonylurea, Metformin + Sulfonylurea, or Metformin + Pioglitazone Therapy

A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to liraglutide in patients with type 2 diabetes whose glycemic control was inadequate with metformin, a sulfonylurea, metformin plus sulfonylurea, or metformin plus pioglitazone therapy (Trial 6 - NCT01029886). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or liraglutide uptitrated from 0.6 mg/day to 1.2 mg/day, then 1.8 mg/day in addition to their existing oral antidiabetic therapy. Each titration was to be completed after at least one week, but could be delayed if the patient had severe nausea or vomiting as established by the investigator. Patients not tolerating the 1.8 mg/day dose of liraglutide by Week 4 were discontinued from the study.

A total of 911 patients were studied: 753 (82.7%) were Caucasian, 111 (12.2%) were Asian, 32 (3.5%) were American Indian or Alaska Native, 8 (0.9%) were Black, 6 (0.7%) were multiple races, and 1 (0.1%) was Pacific Islander. Background therapy was either a single oral antidiabetic agent (35%) or a combination of oral antidiabetic agents (65%). The mean baseline HbA1c was 8.4%.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation).

Efficacy Results:

Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.3%. The mean reduction in HbA1c seen in the liraglutide arm at 26 weeks was -1.5%. The HbA1c reduction with BYDUREON did not meet predefined non-inferiority criteria compared to liraglutide 1.8 mg/day. The non-inferiority margin was set at +0.25% in this study. Results for the primary endpoint at 26 weeks are summarized in Table 8.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 48% and 56% for BYDUREON and liraglutide, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -32 mg/dL and -38 mg/dL, and for body weight were -2.7 kg and -3.6 kg for BYDUREON and liraglutide, respectively.

BYDUREON in Combination with Dapagliflozin versus BYDUREON Alone and Dapagliflozin Alone, All as Add-On to Metformin

A 28-week double-blind comparator-controlled trial was conducted to compare the efficacy of BYDUREON and dapagliflozin (an SGLT2 inhibitor) to BYDUREON alone and dapagliflozin alone in patients with type 2 diabetes with inadequate glycemic control with metformin therapy (Trial 7 - NCT02229396). All patients entered a 1- week placebo lead–in period. Patients with HbA1c ≥8.0% and ≤12% and on metformin at a dose of at least 1,500 mg per day were randomly assigned to receive either BYDUREON 2 mg given subcutaneously once every 7 days (weekly) plus dapagliflozin 10 mg once daily, BYDUREON 2 mg given subcutaneously once weekly, or dapagliflozin 10 mg once daily.

A total of 694 patients were studied; 580 (83.6%) were Caucasian, 96 (13.8%) were Black, 5 (0.7%) were Asian, 2 (0.3%) were American Indian or Alaska Native, and 11 (1.6%) were classified otherwise. The mean baseline HbA1c was 9.3%.

The primary endpoint was change in HbA1c from baseline to Week 28.

Efficacy Results:

At Week 28, BYDUREON in combination with dapagliflozin provided statistically significantly greater reductions in HbA1c (-1.77%) compared to BYDUREON alone (-1.42%, p=0.012) and dapagliflozin alone (-1.32%, p=0.001). BYDUREON in combination with dapagliflozin provided statistically significantly greater reductions in FPG (-57.35 mg/dL) compared to BYDUREON alone (-40.53, p <0.001) and dapagliflozin alone (-44.72 mg/dL, p=0.006).

BYDUREON versus Placebo, Both as Add-On to Basal Insulin or Basal Insulin + Metformin Therapy

A 28-week, double-blind, placebo-controlled trial was conducted to compare the safety and efficacy of BYDUREON to placebo when added to basal insulin glargine, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control (Trial 8 - NCT02229383). Patients on sulfonylurea therapy discontinued sulfonylurea. Patients on metformin continued the same dose of metformin. All patients initially entered an 8-week insulin dose-titration phase. Insulin glargine was to be titrated every 3 days with an aim of achieving a target fasting plasma glucose concentration of 72 to 99 mg/dL. Following the titration period, patients with HbA1c ≥7.0% and ≤10.5% were then randomly assigned to receive either BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or placebo once every 7 days (weekly).

A total of 460 patients were studied: 400 (87.0%) were White, 47 (10.2%) were Black or African American, 6 (1.3%) were Asian, 1 (0.2%) was American Indian or Alaska Native, 1 (0.2%) was Pacific Islander, and 5 (1.1%) were classified otherwise.

The primary endpoint was the change in HbA1c from baseline to Week 28.

Efficacy Results:

Compared to placebo, treatment with BYDUREON resulted in a statistically significant reduction in mean HbA1c from baseline to Week 28 (Table 9).

The mean change in fasting plasma glucose from baseline to Week 28 was -12.50 mg/dL for BYDUREON and -2.26 mg/dL for placebo. The mean change from baseline to Week 28 in body weight was -0.92 kg for BYDUREON and +0.38 kg for placebo.

Analyses include measurements post rescue therapy and post premature discontinuation of study medication.

14.5 EXSCEL Cardiovascular Outcomes Trial in Adult Patients with Type 2 Diabetes

EXSCEL was a multinational, placebo-controlled, double-blind, randomized, parallel group pragmatic study that evaluated cardiovascular (CV) outcomes during treatment with BYDUREON (exenatide) for extended-release injectable suspension in adult patients with type 2 diabetes and any level of CV risk when added to the current usual care (NCT01144338).

A total of 14,752 adult patients were randomized 1:1 to either BYDUREON 2 mg given subcutaneously once weekly or placebo and followed as in routine clinical practice for a median of 38.7 months with a median treatment duration of 27.8 months.

Ninety six percent of the patients in both treatment groups completed the study in accordance with the protocol, and the vital status was known at the end of the study for 98.9% and 98.8% of the patients in the BYDUREON and placebo group, respectively. The mean age at study entry was 62 years (21 to 92 years with 8.5% of the patients ≥75 years). Approximately 62.0% of the patients were male, 75.8% were Caucasian, 9.8% were Asian, 6.0% were Black, and 20.5% were Hispanic or Latino. The mean BMI was 32.7 kg/m2 and the mean duration of diabetes was 13.1 years. Approximately 49.3% had mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 to ≤89 mL/min/1.73 m2) and 21.6% had moderate renal impairment (eGFR ≥30 to ≤59 mL/min/1.73 m2).

The mean HbA1c was 8.1%. At baseline, 1.5% of patients were not treated with either oral antidiabetic medications or insulin, 42.3% were treated with one oral antidiabetic medication and 42.4% were treated with two or more oral antidiabetic medications. Usage of oral antidiabetic medications included metformin (76.6%), sulfonylurea (36.6%), DPP-4 inhibitors (14.9%), thiazolidinediones (3.9%), and SGLT2 inhibitors (0.9%). Overall insulin usage was 46.3% (13.8% with insulin alone and 32.6% with insulin and one or more oral antidiabetic medications).

Overall, at baseline, 26.9% of patients did not have established cardiovascular (CV) disease, while 73.1% had established CV disease. The concomitant use of CV medications (e.g., ACE inhibitors, angiotensin receptor blockers, diuretics, beta blockers, calcium channel blockers, antithrombotic and anticoagulants, and lipid-lowering agents) was similar in the BYDUREON and placebo groups. At baseline, the mean systolic blood pressure was 135.5 mmHg, the mean diastolic blood pressure was 78.1 mmHg, the mean LDL was 95.0 mg/dL, and the mean HDL was 44.0 mg/dL.

The primary endpoint in EXSCEL was the time to first confirmed Major Adverse Cardiac Event (MACE) from randomization. MACE was defined as occurrence of either a cardiovascular (CV)-related death, or a nonfatal myocardial infarction (MI) or a nonfatal stroke. All-cause mortality, CV-related death, and fatal or nonfatal MI or stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure were also assessed as secondary endpoints.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiple tests using a hierarchical testing strategy.

MACE Results:

BYDUREON did not increase the risk of MACE in adult patients with type 2 diabetes mellitus (HR: 0.91; 95% CI: 0.832, 1.004; P<0.001 for non-inferiority; P=0.06 for superiority). See results in Table 10 and Figure 2. The incidence of MACE in patients with and without established CV disease was 13.4% in the BYDUREON group versus 14.6% in the placebo group and 6.0% (BYDUREON) versus 5.9% (placebo), respectively. Five hundred and seven (507) patients (6.9%) died in the BYDUREON group versus 584 (7.9%) in the placebo group.

Figure 2: Time to First Adjudicated MACE in Adult Patients with Type 2 Diabetes (EXSCEL)

HR=hazard ratio, CI=confidence interval.

14.6 Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus

The efficacy and safety of BYDUREON 2 mg given subcutaneously once weekly or placebo was evaluated in a 24-week randomized, double-blind, placebo-controlled, parallel-group study (Trial 9 - NCT01554618) in 82 patients aged 10 to 17 years with type 2 diabetes treated with diet and exercise alone or in combination with a stable dose of oral antidiabetic agents and/or insulin. This study included a 28-week open-label long-term extension in which patients in both treatment groups received BYDUREON 2 mg given subcutaneously once weekly after the 24-week controlled period.

In this trial, 88% of patients completed the assessment period. The mean age at study entry was 15.1 years (13% were 11 to 12 years old, 59% were 13 to 16 years old and 28% were older than 16 years). Approximately 42% of the patients were male, 43% were White, 4% were Asian, 31% were Black or African American, 6% were American Indian or Alaska Native, and 44% were Hispanic or Latino. The mean body weight was 100.6 kg (67% were in ≥97 weight percentile group, 26% in ≥85 to <97 and 6% in ≥3 to <85), mean BMI was 36.4 kg/m2 and the mean duration of diabetes was 2.3 years.

At baseline, mean HbA1c was 8.17%, 12.2% of patients were not treated with either oral antidiabetic medications or insulin, 40.2% were treated with one oral antidiabetic medication and 1.2% were treated with two oral antidiabetic medications. 79.3% of patients were receiving metformin and 1.2% were receiving sulfonylurea. Overall insulin usage was 46.3% (8.5% with insulin alone and 37.8% with insulin and one other oral antidiabetic medication).

The primary endpoint of the study was the change in HbA1c from baseline to Week 24.

Efficacy Results:

BYDUREON was superior to placebo in reducing HbA1c (Table 11).

The mean changes from baseline to Week 24 for body weight were -0.17 kg with (SE 0.7) and +0.88 kg (SE 1.0) for BYDUREON and placebo, respectively.