--------------------------WARNINGS AND PRECAUTIONS--------------------
` Thyroid C-cell tumors in animals: Human relevance unknown. Counsel
`patients regarding the risk of medullary thyroid carcinoma and the symptoms
`of thyroid tumors (5.1).
` Pancreatitis: Postmarketing reports with exenatide, including fatal and non-
`fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if
`pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider
`other antidiabetic therapies if history of pancreatitis (5.2).
` Hypoglycemia: Increased risk when BYDUREON is used in combination
`with a sulfonylurea. Consider reducing the sulfonylurea dose (5.3).
` Renal Impairment: Postmarketing reports with exenatide, sometimes requiring
`hemodialysis and kidney transplantation. Not recommended if severe renal
`impairment or end-stage renal disease. Use with caution in patients with renal
`transplantationor moderate renal impairment (5.4, 8.6, 12.3).
` Severe Gastrointestinal Disease: Not recommended if severe gastrointestinal
`disease (e.g., gastroparesis) (5.5).
` Hypersensitivity: Postmarketing reports with exenatide of serious
`hypersensitivity reactions (e.g. anaphylaxis and angioedema). In such cases,
`patients are to discontinue BYDUREON and other suspect medications and
`promptly seek medical advice (5.7).
` Macrovascular outcomes: There have been no clinical studies establishing
`conclusive evidence of macrovascular risk reduction with BYDUREON or
`any other antidiabetic drug (5.8).
`------------------------------ADVERSE REACTIONS-----------------------------
` Most common (≥5%) and occurring more frequently than comparator in
`clinical trials: nausea, diarrhea, headache, vomiting, constipation, injection
`site pruritus, injection site nodule, and dyspepsia (5.3, 6.1).
`To report SUSPECTED ADVERSE REACTIONS contact Amylin
`Pharmaceuticals, Inc at 1-877-700-7365 and www.bydureon.com or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`-----------------------------DRUG INTERACTIONS-------------------------------
` May impact absorption of orally administered medications (7.1, 12.3)
` Warfarin: Postmarketing reports with exenatide of increased INR sometimes
`associated with bleeding. Monitor INR frequently until stable upon initiation
`of BYDUREON therapy (7.2, 6.2).
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
` Pregnancy: Based on animal data, may cause fetal harm. Use during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`To report drug exposure during pregnancy call 1-800-633-9081 (8.1).
` Nursing Mothers: Use caution when administering to a nursing woman (8.3).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`Medication Guide.
`
`Revised: 01/2012
`
`13 3
`
`12 CLINICAL PHARMACOLOGY
`12 1 Mechanism of Action
`12 2
`Pharmacodynamics
`12 3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13 1
`Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`Reproductive and Developmental
`Toxicology
`14 CLINICAL STUDIES
`14 1
`24-Week Comparator-Controlled Study
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16 1
`How Supplied
`16 2
`Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`17 1
`Risk of Thyroid C-cell Tumors
`17 2
`Risk of Pancreatitis
`17 3
`Risk of Hypoglycemia
`17.4
`Risk of Renal Impairment
`
`17 5
`Risk of Hypersensitivity Reactions
`
`17.6
`Use in Pregnancy
`17.7
`Instructions
`* Sections or subsections omitted from the full prescribing information
`are not listed.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`BYDUREON safely and effectively. See full prescribing information for
`BYDUREON.
`BYDUREON™ (exenatide extended-release for injectable suspension).
`Initial U.S. Approval: 2012
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
` Exenatide extended-release causes thyroid C-cell tumors at clinically
`relevant exposures in rats. It is unknown whether BYDUREON causes
`thyroid C-cell tumors, including medullary thyroid carcinoma (MTC),
`in humans, as human relevance could not be determined by clinical or
`nonclinical studies (5.1).
` BYDUREON is contraindicated in patients with a personal or family
`history of MTC or in patients with Multiple Endocrine Neoplasia
`syndrome type 2 (MEN 2) (5.1).
`---------------------------INDICATIONS AND USAGE----------------------------
`BYDUREON is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as
`an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus in multiple clinical settings (1.1, 14).
`BYDUREON is an extended-release formulation of exenatide. Do not
`co-administer with BYETTA.
`Important Limitations of Use
` Not recommended as first-line therapy for patients inadequately controlled on
`diet and exercise (5.1).
` Should not be used to treat type 1 diabetes or diabetic ketoacidosis (1.2).
` Use with insulin has not been studied and is not recommended (1.2).
` Has not been studied in patients with a history of pancreatitis. Consider other
`antidiabetic therapies in patients with a history of pancreatitis (1.2, 5.2).
`-------------------------DOSAGE AND ADMINISTRATION---------------------
` Administer 2 mg by subcutaneous injection once every seven days (weekly),
`at any time of day and with or without meals (2.1).
` Administer immediately after the powder is suspended (2.1).
`-------------------------DOSAGE FORMS AND STRENGTHS------------------
`BYDUREON is 2 mg exenatide for extended-release injectable suspension.
`------------------------------CONTRAINDICATIONS------------------------------
` Do not use if personal or family history of medullary thyroid carcinoma or in
`patients with Multiple Endocrine Neoplasia syndrome type 2 (4.1).
` Do not use if history of serious hypersensitivity to exenatide or any product
`components (4.2).
`
`2
`
`3
`4
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`1.1
`Type 2 Diabetes Mellitus
`1.2
`Important Limitations of Use
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`2.2
`Administration
`2.3
`Changing from BYETTA to BYDUREON
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1
`Medullary Thyroid Carcinoma
`4.2
`Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`5.1
`Risk of Thyroid C-cell Tumors
`5.2
`Acute Pancreatitis
`5.3
`Hypoglycemia
`5.4
`Renal Impairment
`5.5
`Gastrointestinal Disease
`5.6
`Immunogenicity
`5.7
`Hypersensitivity
`5.8
`Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1
`Clinical Trial Experience
`6.2
`Post-Marketing Experience
`DRUG INTERACTIONS
`7.1
`Orally Administered Drugs
`7.2
`Warfarin
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`
`6
`
`7
`
`8
`
`Reference ID: 3080263
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`FULL PRESCRIBING INFORMATION
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically
`relevant exposures in rats compared to controls. It is unknown whether BYDUREON causes
`thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human
`relevance could not be determined by clinical or nonclinical studies. BYDUREON is
`contraindicated in patients with a personal or family history of MTC and in patients with
`Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid
`ultrasound monitoring is of uncertain value in patients treated with BYDUREON. Patients
`should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications
`(4.1), Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
`
`1
`
`INDICATIONS AND USAGE
`
`BYDUREON is an extended-release formulation of exenatide, administered as an injection once
`every seven days (weekly).
`
`1.1 Type 2 Diabetes Mellitus
`BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14)].
`
`1.2 Important Limitations of Use
`Because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans, prescribe
`BYDUREON only to patients for whom the potential benefits are considered to outweigh the
`potential risk.
`
`BYDUREON is not recommended as first-line therapy for patients who have inadequate
`glycemic control on diet and exercise.
`
`BYDUREON is not a substitute for insulin. BYDUREON should not be used in patients with
`type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these
`settings.
`
`The concurrent use of BYDUREON with insulin has not been studied and cannot be
`recommended.
`
`BYDUREON and BYETTA® (exenatide) injection both contain the same active ingredient,
`exenatide, and therefore should not be used together.
`
`Based on postmarketing data, exenatide has been associated with acute pancreatitis, including
`fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYDUREON has not been studied
`
`Reference ID: 3080263
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`in patients with a history of pancreatitis. It is unknown whether patients with a history of
`pancreatitis are at increased risk for pancreatitis while using BYDUREON. Other antidiabetic
`therapies should be considered in patients with a history of pancreatitis.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`BYDUREON (2 mg per dose) should be administered once every seven days (weekly). The
`dose can be administered at any time of day, with or without meals.
`
`Missed Dose
`If a dose is missed, it should be administered as soon as noticed, provided the next regularly
`scheduled dose is due at least three days later. Thereafter, patients can resume their usual dosing
`schedule of once every seven days (weekly).
`
`If a dose is missed and the next regularly scheduled dose is due one or two days later, the patient
`should not administer the missed dose and instead resume BYDUREON with the next regularly
`scheduled dose.
`
`Changing Weekly Dosing Schedule
`The day of weekly administration can be changed if necessary as long as the last dose was
`administered 3 or more days before.
`
`2.2 Administration
`BYDUREON is intended for patient self-administration. BYDUREON is provided in a
`single-dose tray containing: one vial of 2 mg exenatide, one vial connector, one prefilled diluent
`syringe and two needles (one provided as a spare) [see How Supplied/Storage and Handling
`(16.1)]. Do not substitute needles or any other components in the tray.
`
`BYDUREON must be injected immediately after the powder is suspended in the diluent and
`transferred to the syringe. BYDUREON is administered as a subcutaneous (SC) 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. BYDUREON must not be administered intravenously or
`intramuscularly.
`
`See the BYDUREON Instructions for Use for complete administration instructions with
`illustrations. The instructions can also be found at www.bydureon.com.
`
`2.3 Changing from BYETTA to BYDUREON
`Prior treatment with BYETTA is not required when initiating BYDUREON therapy. If the
`decision is made to start BYDUREON in an appropriate patient already taking BYETTA,
`
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`BYETTA should be discontinued. Patients changing from BYETTA to BYDUREON may
`experience transient (approximately two weeks) elevations in blood glucose concentrations.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`BYDUREON is 2 mg exenatide extended-release for injectable suspension for subcutaneous
`administration once every seven days (weekly).
`
`4 CONTRAINDICATIONS
`
`4.1 Medullary Thyroid Carcinoma
`BYDUREON is contraindicated in patients with a personal or family history of medullary
`thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2
`(MEN 2).
`
`4.2 Hypersensitivity
`BYDUREON is contraindicated in patients with a prior serious hypersensitivity reaction to
`exenatide or to any of the product components.
`
`5 WARNINGS AND PRECAUTIONS
`
`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 25-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 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 could not be determined by clinical or nonclinical studies. Serum calcitonin was
`not assessed in the clinical trials supporting the approval of BYDUREON [see Boxed Warning,
`Contraindications (4.1)].
`
`Serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin
`values >50 ng/L. Patients with thyroid nodules noted on physical examination or neck imaging
`should be referred to an endocrinologist for further evaluation. Routine monitoring of serum
`calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in
`patients treated with BYDUREON. Such monitoring may increase the risk of unnecessary
`
`Reference ID: 3080263
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`procedures, due to the low specificity of serum calcitonin testing for MTC and a high
`background incidence of thyroid disease. If serum calcitonin is measured and found to be
`elevated, the patient should be referred to an endocrinologist for further evaluation [see Patient
`Counseling Information (17)].
`
`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, 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 should promptly
`be discontinued and appropriate management should be initiated. If pancreatitis is
`confirmed, BYDUREON should not be restarted. Consider antidiabetic therapies other
`than BYDUREON in patients with a history of pancreatitis.
`
`5.3 Hypoglycemia
`The risk of hypoglycemia is increased when exenatide is used in combination with a
`sulfonylurea. Therefore, patients receiving BYDUREON and a sulfonylurea may require a lower
`dose of the sulfonylurea to minimize the risk of hypoglycemia. It is also possible that the use of
`BYDUREON with other glucose-independent insulin secretagogues (e.g. meglitinides) could
`increase the risk of hypoglycemia.
`
`For additional information on glucose-dependent effects see Mechanism of Action (12.1).
`
`5.4 Renal Impairment
`BYDUREON should not be used in patients with severe renal impairment (creatinine clearance
`< 30 mL/min) or end-stage renal disease and should be used with caution in patients with renal
`transplantation [see Use in Specific Populations (8.6)]. In patients with end-stage renal disease
`receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal
`side effects. Because BYDUREON may induce nausea and vomiting with transient
`hypovolemia, treatment may worsen renal function. Use BYDUREON with caution in patients
`with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Use in Specific
`Populations (8.6) Clinical Pharmacology (12.3)]. BYDUREON has not been studied in patients
`with end-stage renal disease or severe renal impairment.
`
`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
`
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`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 exenatide. Exenatide has not been found to be directly
`nephrotoxic in preclinical or clinical studies.
`
`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 is not recommended in
`patients with severe gastrointestinal disease.
`
`5.6 Immunogenicity
`Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti-
`exenatide antibodies were measured in all BYDUREON-treated patients in the five comparator-
`controlled 24-30 week studies of BYDUREON. In 6% of BYDUREON-treated patients,
`antibody formation was associated with an attenuated glycemic response. If there is worsening
`glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy
`should be considered [see Adverse Reactions (6.1)].
`
`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 and other suspect medications and promptly seek
`medical advice [see Adverse Reactions (6.2)].
`
`5.8 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with BYDUREON or any other antidiabetic drug.
`
`6 ADVERSE REACTIONS
`
`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 safety of BYDUREON was assessed in five comparator-controlled trials, in patients who
`entered the studies not achieving adequate glycemic control on their current therapy. In a
`double-blind 26 week trial, patients on diet and exercise were treated with BYDUREON 2 mg
`once every seven days (weekly), sitagliptin 100 mg daily, pioglitazone 45 mg daily, or
`metformin 2000 mg daily. In a double-blind 26 week trial, patients on metformin were treated
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`with BYDUREON 2 mg once every seven days (weekly), sitagliptin 100 mg daily, or
`pioglitazone 45 mg daily. In an open-label 26 week trial, patients on metformin or metformin
`plus sulfonylurea were treated with BYDUREON 2 mg once every seven days (weekly) or
`optimized insulin glargine. In two open-label 24 to 30 week studies, patients on diet and
`exercise or metformin, a sulfonylurea, a thiazolidinedione or combination of oral agents were
`treated with BYDUREON 2 mg once every seven days (weekly) or BYETTA 10 mcg twice
`daily.
`
`Withdrawals
`The incidence of withdrawal due to adverse events was 4.9% (N=45) for BYDUREON-treated
`patients, 4.9% (N=13) for BYETTA-treated patients and 2.0% (N=23) for other comparator-
`treated patients in the five comparator-controlled 24-30 week trials. The most common adverse
`reactions leading to withdrawal for BYDUREON-treated patients were nausea 0.5% (N=5)
`versus 1.5% (N=4) for BYETTA and 0.3 % (N=3) for other comparators, injection site nodule
`0.5% (N=5) versus 0.0% for BYETTA and 0.0% for other comparators, diarrhea 0.3% (N=3)
`versus 0.4% (N=1) for BYETTA and 0.3% (N=3) for other comparators, injection site reaction
`0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other comparators and headache 0.2%
`(N=2) versus 0.0% for BYETTA and 0.0% for other comparators.
`
`Hypoglycemia
`
`Table 1 summarizes the incidence and rate of minor hypoglycemia in the five comparator-
`controlled 24-30 week trials of BYDUREON used as monotherapy or as add-on to metformin, a
`sulfonylurea, a thiazolidinedione or combination of these oral antidiabetic agents. In these trials,
`an event was classified as minor hypoglycemia if there were symptoms of hypoglycemia with a
`concomitant glucose <54 mg/dL and the patient was able to self-treat.
`
`Table 1:
`
`Incidence (% of subjects) and Rate (episodes/subject year) of Minor† Hypoglycemia in the
`Monotherapy Trial and in the Combination Therapy Trials
`
`26-Week Monotherapy Trial
`
`BYDUREON 2 mg (N = 248)
`
`Sitagliptin 100 mg (N = 163)
`
`Pioglitazone 45 mg (N = 163)
`
`Metformin 2000 mg QD (N = 246)
`26-Week Add-on to Metformin Trial
`
`BYDUREON 2 mg (N = 160)
`
`Sitagliptin 100 mg (N = 166)
`
`Pioglitazone 45 mg (N = 165)
`
`2.0% (0.05)
`
`0.0% (0.00)
`
`0.0% (0.00)
`
`0.0% (0.00)
`
`1.3% (0.03)
`
`3.0% (0.12)
`
`1.2% (0.03)
`
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`26-Week Add-on to Metformin or Metformin + Sulfonylurea Trial
`
`With Concomitant Sulfonylurea Use (N = 136)
`
`BYDUREON 2 mg (N = 70)
`
`Titrated Insulin Glargine (N = 66)
`
`Without Concomitant Sulfonylurea Use (N = 320)
`
`BYDUREON 2 mg (N =163)
`
`20.0% (1.11)
`
`43.9% (2.87)
`
`3.7% (0.11)
`
`19.1% (0.64)
`Titrated Insulin Glargine‡ (N = 157)
`24-Week Monotherapy or add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or
`Combination of Oral Agents Trial
`
`With Concomitant Sulfonylurea Use (N = 74)
`
`BYDUREON 2 mg (N = 40)
`
`BYETTA 10 mcg (N = 34)
`
`Without Concomitant Sulfonylurea Use (N = 178)
`
`BYDUREON 2 mg (N = 89)
`
`12.5% (0.72)
`
`11.8% (0.31)
`
`0.0% (0.00)
`
`0.0% (0.00)
`BYETTA 10 mcg (N = 89)
`30-Week Monotherapy or add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or
`Combination of Oral Agents Trial
`
`With Concomitant Sulfonylurea Use (N = 107)
`
`BYDUREON 2 mg (N =55)
`
`BYETTA 10 mcg (N = 52)
`
`Without Concomitant Sulfonylurea Use (N = 186)
`
`BYDUREON 2 mg (N = 93)
`
`14.5% (0.55)
`
`15.4% (0.37)
`
`0.0% (0.00)
`
`BYETTA 10 mcg (N = 93)
`Abbreviations: N = The number of intent-to-treat patients
`Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
`† Reported event that has symptoms consistent with hypoglycemia with a concomitant glucose <54 mg/dL and the
`patient was able to self-treat.
`‡ 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.
`
`1.1% (0.02)
`
`There were no reported events of major hypoglycemia in these five comparator-controlled 24-30
`week trials. Major hypoglycemia was defined as loss of consciousness, seizure or coma (or other
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`mental status change consistent with neuroglycopenia in the judgment of the investigator or
`physician) which resolved after administration of glucagon or glucose or required third party
`assistance to resolve because of severe impairment in consciousness or behavior. Patients were
`to have a concomitant glucose <54 mg/dL.
`
`Immunogenicity
`Anti-exenatide antibodies were measured at prespecified intervals (4-14 weeks) in all
`BYDUREON-treated patients (N=918) in the five comparator-controlled studies of
`BYDUREON. In these five trials, 452 BYDUREON-treated patients (49%) had low titer
`antibodies (≤125) to exenatide at any time during the trials and 405 BYDUREON-treated
`patients (45%) had low titer antibodies to exenatide at study endpoint (24-30 weeks). The level
`of glycemic control in these patients was generally comparable to that observed in the 379
`BYDUREON-treated patients (43%) without antibody titers. An additional 107 BYDUREON-
`treated patients (12%) had higher titer antibodies at endpoint. Of these patients, 50 (6% overall)
`had an attenuated glycemic response to BYDUREON (<0.7% reduction in HbA1c); the remaining
`57 (6% overall) had a glycemic response comparable to that of patients without antibodies [see
`Warnings and Precautions (5.6)]. In the 30-week trial in which anti-exenatide antibody
`assessments were performed at baseline and at 4-week intervals from week 6 to week 30, the
`mean anti-exenatide antibody titer in the BYDUREON-treated patients peaked at week 6 then
`declined by 56% from this peak by week 30.
`
`A total of 246 patients with antibodies to exenatide in the BYETTA and BYDUREON clinical
`trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No
`treatment-emergent cross reactive antibodies were observed across the range of titers.
`
`Other Adverse Reactions
`
`BYDUREON
`Tables 2 and 3 summarize adverse reactions with an incidence ≥5% reported in the five
`comparator controlled 24-30 week trials of BYDUREON used as monotherapy or as add-on to
`metformin, a sulfonylurea, a thiazolidinedione or combination of these oral antidiabetic agents.
`
`Reference ID: 3080263
`
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`MPI EXHIBIT 1020 PAGE 9
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`
`

`

`Table 2: Treatment-Emergent Adverse Reactions Reported in 5% of BYDUREON-Treated Patients in
`Monotherapy Trial
`
`26-Week Monotherapy Trial
`BYDUREON
`Sitagliptin
`2 mg
` 100 mg
`N = 248
`N = 163
`%
`%
`11.3
`3.7
`Nausea
`10.9
`5.5
`Diarrhea
`10.5
`6.7
`Injection Site Nodule†
`8.5
`2.5
`Constipation
`8.1
`9.2
`Headache
`7.3
`1.8
`Dyspepsia
`N = The number of intent-to-treat patients.
`Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
`† Patients in the sitagliptin, pioglitazone and metformin treatment groups received weekly placebo injections.
`
`Pioglitazone
`45 mg
`N = 163
`%
`4.3
`3.7
`3.7
`1.8
`8.0
`4.9
`
`Metformin
`2000 mg
`N = 246
`%
`6.9
`12.6
`10.2
`3.3
`12.2
`3.3
`
`Table 3: Treatment-Emergent Adverse Reactions Reported in 5% of BYDUREON-Treated Patients in
`24-30 week Add-on Combination Therapy Trials
`26-Week Add-On to Metformin Trial
`BYDUREON
`Sitagliptin
`2 mg
` 100 mg
`N = 160
`N = 166
`%
`%
`24.4
`9.6
`Nausea
`20.0
`9.6
`Diarrhea
`11.3
`2.4
`Vomiting
`9.4
`9.0
`Headache
`6.3
`3.6
`Constipation
`5.6
`0.6
`Fatigue
`5.0
`3.6
`Dyspepsia
`5.0
`1.2
`Decreased appetite
`5.0
`4.8
`Injection Site Pruritus†
`26-Week Add-on to Metformin or Metformin + Sulfonylurea Trial
`BYDUREON
`Insulin glargine
`2 mg
`Titrated
`N = 233
`N = 223
`%
`%
`12.9
`1.3
`9.9
`7.6
`9.4
`4.0
`6.0
`0.0
`
`Pioglitazone
`45 mg
`N = 165
`%
`4.8
`7.3
`3.0
`5.5
`1.2
`3.0
`2.4
`0.0
`1.2
`
`Nausea
`Headache
`Diarrhea
`Injection Site Nodule
`
`Reference ID: 3080263
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`10 of 27
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`MPI EXHIBIT 1020 PAGE 10
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`
`

`

`30-Week Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or
`Combination of Oral Agents Trial
`BYDUREON
`BYETTA
`2 mg
`10 mcg
`N = 148
`N = 145
`%
`%
`27.0
`33.8
`16.2
`12.4
`10.8
`18.6
`18.2
`1.4
`10.1
`6.2
`8.8
`5.5
`7.4
`4.1
`
`7.4
`7.4
`6.1
`6.1
`5.4
`
`Nausea
`Diarrhea
`Vomiting
`Injection Site Pruritus
`Constipation
`Gastroenteritis viral
`Gastroesophageal
`reflux disease
`Dyspepsia
`Injection site erythema
`Fatigue
`Headache
`Injection site
`hematoma
`24-Week Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione or
`Combination of Oral Agents Trial
`BYDUREON
`BYETTA
`2 mg
`10 mcg
`N = 129
`N = 123
`%
`14.0
`Nausea
`9.3
`Diarrhea
`5.4
`Injection site erythema
`N = The number of intent-to-treat patients.
`
`Note: Percentages are based on the number of intent-to-treat patients in each treatment group.
`
`† Patients in the sitagliptin, pioglitazone and metformin treatment groups received weekly placebo injections.
`
`2.1
`0.0
`3.4
`4.8
`11.0
`
`35.0
`4.1
`2.4
`
`Nausea was the most common adverse reaction associated with initiation of treatment with
`BYDUREON, and usually decreased over time.
`
`Injection Site Reactions
`In the five comparator-controlled 24-30 week trials, injection site reactions were observed more
`frequently in patients treated with BYDUREON (17.1%) than in patients treated with BYETTA
`(12.7%), titrated insulin glargine (1.8%) or those patients who received placebo injections
`(sitagliptin (10.6%), pioglitazone (6.4%), and metformin (13.0%) treatment groups). These
`reactions for patients treated with BYDUREON were more commonly observed in antibody-
`positive patients (14.2%) compared with antibody-negative patients (3.1%), with a greater
`incidence in those with higher titer antibodies [see Warnings and Precautions (5.6)]. Incidence
`of injection site reactions for patients treated with BYETTA was similar for antibody positive
`patients (5.8%) and antibody negative patients (7.0%). One percent of patients treated with
`BYDUREON withdrew due to injection site adverse reactions (injection site mass, injection site
`nodule, injection site pruritus, and injection site reaction).
`
`Reference ID: 3080263
`
`11 of 27
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`MPI EXHIBIT 1020 PAGE 11
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`MPI EXHIBIT 1020 PAGE 11
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`

`

`Small, asymptomatic subcutaneous injection site nodules are seen with the use of BYDUREON.
`In a separate 15-week study in which information on nodules were collected and analyzed, 24
`out of 31 subjects (77%) experienced at least one injection site nodule during treatment; 2
`subjects (6.5%) reported accompanying localized symptoms. The mean duration of events was
`27 days. The formation of nodules is consistent with the known properties of the microspheres
`used in BYDUREON.
`
`BYETTA
`In three 30-week controlled trials of BYETTA (N=963) add-on to metformin and/or
`sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence of 1% and reported
`more frequently than with placebo included nausea (44% BYETTA, 18% placebo), vomiting
`(13% BYETTA, 4% placebo), diarrhea (13% BYETTA, 6% placebo), feeling jittery (9%
`BYETTA, 4% placebo), dizziness (9% BYETTA, 6% placebo), headache (9% BYETTA, 6%
`placebo), dyspepsia (6% BYETTA, 3% placebo), asthenia (4% BYETTA, 2% placebo),
`gastroesophageal reflux (3% BYETTA, 1% placebo), hyperhidrosis (3% BYETTA, 1% placebo)
`and decreased appetite (1% BYETTA, <1% placebo). Similar types of adverse reactions were
`observed in 24-week and 16-week controlled trials of BYETTA used as monotherapy or as add-
`on to a thiazolidinedione, with or without metformin, respectively.
`
`6.2 Post-Marketing Experience
`
`BYETTA
`The following additional adverse reactions have been reported during post-approval use of
`BYETTA. Because these events are reported voluntarily from a population of uncertain size, it
`is generally not possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.
`
`Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, mac