2.1 Recommended Dosing

The recommended dose 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.

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.

2.2 Missed Dose

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, patients can resume their usual dosing schedule of once every 7 days (weekly).

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.

2.3 Administration Instructions

•

BYDUREON BCISE is intended for patient self-administration. Prior to initiation, train patients on proper mixing and injection technique to ensure the product is adequately mixed and a full dose is delivered [see Instructions for Use].

•

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

•

Mix by shaking vigorously for at least 15 seconds. After mixing, BYDUREON BCISE should appear as an opaque, white to off-white suspension, evenly mixed with no residual medicine along the side, bottom or top of the inspection window.

•

Inspect visually for particulate matter and discoloration prior to administration (BYDUREON BCISE contains microspheres which appear as white to off-white particles). Do not use if foreign particulate matter is present or if discoloration is observed. Refer patients to the accompanying Instructions for Use for disposal information [see Instructions for Use].

•

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.

•

Do not administer BYDUREON BCISE intravenously or intramuscularly.

•

Refer patients to the accompanying Instructions for Use for complete administration instructions with illustrations [see Instructions for Use].

2.4 Initiating BYDUREON BCISE Therapy

Prior treatment with an immediate- or extended-release exenatide product is not required when initiating BYDUREON BCISE therapy. Discontinue an immediate- or extended-release exenatide product prior to initiation of BYDUREON BCISE.

Patients changing from immediate-release exenatide to BYDUREON BCISE may experience transient (approximately 2 to 4 weeks) elevations in blood glucose concentrations.

Patients changing from another extended-release exenatide product to BYDUREON BCISE may do so at the next regularly scheduled dose.

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 extended-release for injectable suspension). BYDUREON BCISE is not recommended for use in patients with an eGFR below 45 mL/min/1.73 m2see 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

Patients may develop antibodies to exenatide following treatment with BYDUREON BCISE. Anti-exenatide antibodies were measured in BYDUREON BCISE-treated patients in two comparator-controlled 28-week studies of BYDUREON BCISE. Patients with higher titer antibodies may have an attenuated HbA1c response. If there is worsening glycemic control or failure to achieve targeted glycemic control, consider alternative antidiabetic therapy [see Adverse Reactions (6.2)].

5.7 Hypersensitivity

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 (6.3)]. 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 (6.3)].

5.9 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 (6.3)]. Isolated cases required surgical intervention.

5.10 Acute Gallbladder Disease

Acute events of gallbladder disease have been reported in GLP-1 receptor agonist trials. In the EXSCEL trial [see Clinical Studies (14.2)], 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 as well as data from the extension phase of one of these trials [see Clinical Studies (14)]. 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.

Common Adverse Reactions

Table 1 summarizes the adverse reactions with an incidence ≥5% occurring in BYDUREON BCISE-treated 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 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. 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%).

Other Adverse Reactions

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.

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.

Injection-Site Adverse Reactions

In the two comparator-controlled 28-week trials, injection site reactions (including injection site nodule, injection site pruritus, injection site bruising) were observed in 23.9% of patients treated with BYDUREON BCISE. The formation of subcutaneous nodules is consistent with the properties of the microspheres used in BYDUREON BCISE.

Increase in Heart Rate

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

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to exenatide in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Anti-exenatide antibodies were measured at prespecified intervals in the two comparator-controlled studies, and evaluable anti-exenatide antibody measurements were available from 393 BYDUREON BCISE-treated patients. In these trials 40.2% of these patients developed low titer antibodies to exenatide and approximately 33.8% of patients developed high titer antibodies at any time during the studies. The percentage of patients with positive antibody titers peaked at approximately Weeks 8-16 of dosing and then diminished over time.

Change in HbA1c from baseline in patients with low titer antibodies at the last visit was generally comparable to that observed in antibody-negative patients at the last visit. However, patients with higher titer antibodies may have an attenuated HbA1c response.

Amongst BYDUREON BCISE-treated patients evaluable for antibodies (N=393), the incidence of potentially immunogenic injection site reactions (most commonly injection site nodule) during the 28-week studies was approximately 19.6%. These reactions were less commonly observed in antibody-negative patients (15.7%) and patients with low titer antibodies (16.3%) compared with those with high titer antibodies (27.2%).

Evaluation of anti-exenatide antibodies in select patients with high-titer antibodies have demonstrated the potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon, but the clinical significance of these antibodies is not currently known. In the BYDUREON BCISE clinical trials, 133 patients developed high titer antibodies to exenatide and 118 of these patients had samples and data for the cross-reactivity assay; one patient (0.8%) developed cross-reactive antibodies to GLP-1 and/or glucagon. No information regarding the presence of neutralizing antibodies is currently available.

6.3 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, generalized pruritus and/or urticaria, macular or papular rash, angioedema; anaphylactic reaction.

Blood and Lymphatic Systems: drug-induced thrombocytopenia [see Warnings and Precautions (5.8)]

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, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Indications and Usage (1)].

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 embryo-fetal 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

Safety and effectiveness of BYDUREON BCISE have not been established in pediatric patients. BYDUREON BCISE is not recommended for use in pediatric patients.

8.5 Geriatric Use

In two comparator-controlled 28-week trials, BYDUREON BCISE was studied in 74 patients (18.0%) who were at least 65 years old and 10 patients who were at least 75 years old. No meaningful differences in safety and efficacy were observed between these patients and the overall population, but the small sample size for patients ≥75 years old limits conclusions. In a large cardiovascular outcomes trial, BYDUREON was studied in 2959 patients (40.3%) who were at least 65 years old and of those, 605 patients (8.2%) were at least 75 years old. Use caution when initiating BYDUREON BCISE in elderly patients because they are more likely to have decreased renal function.

8.6 Renal Impairment

Pharmacokinetic studies of renally impaired patients receiving BYDUREON BCISE indicate that there is an increase in exposure in moderate and mild renally impaired patients as compared to patients with normal renal function. BYDUREON BCISE may induce nausea and vomiting with transient hypovolemia and may worsen renal function.

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 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

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 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

BYDUREON BCISE has been studied 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.

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 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 (NCT01652716).

A total of 375 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%. Patients were randomly assigned to receive BYDUREON BCISE 2 mg 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 dose to 10 mcg twice daily after 4 weeks.

The primary endpoint was change in HbA1c from baseline to Week 28. 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 patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (NCT01652729).

A total of 364 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%. Patients were randomly assigned to receive BYDUREON BCISE 2 mg once every 7 days (weekly) (n=181), sitagliptin 100 mg/day (n=122) or placebo (n=61), in addition to their existing metformin therapy.

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

BYDUREON, another formulation of exenatide extended-release, has been studied as monotherapy and in combination with metformin, sulfonylurea, thiazolidinedione, SGLT2 inhibitor and basal insulin.

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 (NCT00676338).

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%. Patients were randomly assigned to receive BYDUREON 2 mg 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.

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

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 (NCT00637273).

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%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg/day or pioglitazone 45 mg/day, in addition to their existing metformin therapy.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). 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 (NCT00641056).

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%. Patients were randomly assigned to receive BYDUREON 2 mg 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.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). 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 (NCT01029886).

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%. Patients were randomly assigned to receive BYDUREON 2 mg 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.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). 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 SGLT-2 inhibitor) to BYDUREON alone and dapagliflozin alone in patients with type 2 diabetes with inadequate glycemic control with metformin therapy (NCT02229396).

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%. 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 once every 7 days (weekly) plus dapagliflozin 10 mg once daily, BYDUREON 2 mg once weekly, or dapagliflozin 10 mg once daily.

The primary endpoint was change in HbA1c from baseline to Week 28. 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 (NCT02229383).

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. 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 once every 7 days (weekly) or placebo once every 7 days (weekly).

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

14.2 EXSCEL Cardiovascular Outcomes Trial in 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 extended-release for injectable suspension) in patients with type 2 diabetes and any level of CV risk when added to the current usual care (NCT01144338).

A total of 14,752 patients were randomized 1:1 to either BYDUREON 2 mg 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 SGLT-2 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 multiples tests using a hierarchical testing strategy.

BYDUREON did not increase the risk of MACE in 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 Patients with Type 2 Diabetes

HR=hazard ratio, CI=confidence interval.