CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209637Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`
`
`Application Type
`
`Application Number
`
`209637
`
`PDUFA Goal Date
`
`December 5, 2017
`
`OSE RCM #
`
`2016-2764; 2016-2766
`
`Reviewer Name(s)
`
`Till Olickal, Ph.D., Pharm.D.
`
`Acting Team Leader
`
`Elizabeth Everhart, MSN, RN, ACNP
`
`Division Director
`
`Cynthia LaCivita, Pharm.D.
`
`Review Completion Date
`
`November 06, 2017
`
`Subject
`
`Review to determine if a REMS is necessary
`
`Established Name
`
`Semaglutide
`
`Trade Name
`
`Ozempic
`
`Name of Applicant
`
`Novo Nordisk Inc.
`
`Therapeutic Class
`
`Antidiabetic drug, glucagon-like peptide 1 receptor agonist.
`
`Formulation(s)
`
`Dosing Regimen
`
`1.34 mg/mL in 1.5 mL pre-filled, disposable, single-patient-use pen
`injector that delivers 0.25 mg, 0.5 mg, or 1 mg per injection and 1.34
`mg/mL in 1.5 mL pre-filled, disposable, single-patient-use pen injector
`that delivers 1 mg per injection.
`Subcutaneously once weekly
`
`
`
`
`
`Reference ID: 4177175
`
`1
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`Table of Contents
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`
`1
`
`Introduction ..................................................................................................................................................................... 3
`
`2 Background ...................................................................................................................................................................... 4
`
`2.1
`
`Product Information ........................................................................................................................................... 4
`
`2.2
`
`Regulatory History............................................................................................................................................... 4
`
`3
`
`Therapeutic Context and Treatment Options .................................................................................................... 5
`
`3.1
`
`Description of the Medical Condition .......................................................................................................... 5
`
`3.2
`
`Description of Current Treatment Options ............................................................................................... 6
`
`4 Benefit Assessment ....................................................................................................................................................... 6
`
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 8
`
`6
`
`Expected Postmarket Use ......................................................................................................................................... 14
`
`7 Risk Management Activities Proposed by the Applicant ............................................................................. 14
`
`8 Discussion of Need for a REMS ............................................................................................................................... 14
`
`9
`
`Conclusion & Recommendations ........................................................................................................................... 15
`
`10
`
`Appendices ................................................................................................................................................................ 16
`
`10.1 Table 1: Change in HbA1c (%) from baseline to the end of treatment period using multiple
`imputation based on retrieved dropouts in FAS .................................................................................................. 16
`
`10.2 Table 2: Change in body weight (kg) from baseline to the end of treatment period using
`multiple imputations based on retrieved dropouts in FAS ............................................................................. 17
`
`10.3 Table 2: Deaths, SAEs, and Discontinuations due to AEs ................................................................... 17
`
`11
`
`References .................................................................................................................................................................. 18
`
`
`
`
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`Reference ID: 4177175
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`2
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`EXECUTIVE SUMMARY
`
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity semaglutide (Ozempic) is necessary to ensure
`the benefits outweigh its risks. Novo Nordisk Inc. submitted a New Drug Application (NDA) 209637 for
`semaglutide with the proposed indication as an adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus. Semaglutide is a selective dipeptidyl peptidase-4 (DPP-4)-
`resistant glucagon-like peptide 1 receptor agonist (GLP-1 RA). The serious risks associated with the use of
`semaglutide are thyroid C- cell tumor, pancreatitis, diabetic retinopathy complications, hypoglycemia
`(with concomitant use of sulfonylurea or basal insulin), renal impairment, and hypersensitivity reactions.
`The applicant’s proposed REMS
`
`
`. The applicant also proposed
`Prescribing Information that includes Boxed Warning, Warnings and Precautions, and a Medication
`Guide as part of labeling to inform patients of the potential risks of thyroid C- cell tumor, pancreatitis,
`diabetic retinopathy complications, and hypoglycemia.
`
`DRISK and DMEP have determined that if approved, a REMS is not necessary to ensure the benefits of
`semaglutide outweigh its risks. Semaglutide would join the class of GLP-1 RAs as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus. In the clinical trial,
`semaglutide appeared efficacious in both its primary and secondary outcomes. The most concerning
`adverse reactions associated with the use of semaglutide are thyroid C-cell tumor, pancreatitis, and
`diabetic retinopathy. The Medication Guide, Boxed Warning, and Warnings and Precautions, which will
`be maintained as part of approved labeling, will be used to communicate the risks. Available REMS
`assessment data of the other approved GLP-1 RA (Bydureon, Tanzeum, Trulicity and Victoza) indicate
`acceptable knowledge of these risks suggesting that these risk messages of potential risk of MTC and
`pancreatitis have been communicated to the relevant prescriber groups. In addition, there are no new
`post-marketing safety signals for the drug class warranting continuation of the communication activities.
`DMEP and DRISK have determined that additional measures beyond labeling are not necessary to
`ensure the benefits outweigh the risks of semaglutide.
`
` 1
`
` Introduction
`
`
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) semaglutide (Ozempic) is necessary to
`ensure the benefits outweigh its risks. Novo Nordisk Inc. submitted a New Drug Application (NDA)
`209637 for semaglutide with the proposed indication as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus. This application is under review in the Division
`of Metabolism and Endocrinology Products (DMEP). The applicant’s proposed REMS
`
`
` The applicant also proposed Prescribing Information that includes Boxed
`Warning, Warnings and Precautions and a Medication Guide as part of labeling to inform patients
`regarding the potential risks of thyroid C- cell tumor, pancreatitis, diabetic retinopathy complications
`and hypoglycemia.
`
`
`
`
`
`Reference ID: 4177175
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`
`3
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`(b) (4)
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`(b) (4)
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`2 Background
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`2.1 PRODUCT INFORMATION
`
`Semaglutide is a NME NDA type 505(b)(1) pathway application.a It is a glucagon-like peptide 1 receptor
`agonist (GLP-1 RA), proposed for indication as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus. Glucagon-like peptide 1 (GLP-1), an incretin hormone
`secreted from cells in the gastrointestinal tract after ingestion of a meal, has three main effects on
`glucose metabolism: (1) stimulation of insulin release from the pancreatic islets through a glucose-
`dependent activation of the GLP-1 receptor, (2) suppression of glucagon release, and (3) delay in gastric
`emptying mediated through post-prandial GLP-1 receptor activation. These effects on glucose
`metabolism result in lowering of fasting plasma glucose (FPG) and postpradial plasma glucose (PPG) and
`weight loss. GLP-1 RAs are designed to mimic the effect of endogenous GLP-1. Due to the very short
`half-life of less than 1.5 minutes after intravenous administration, native GLP-1 is not suitable for
`therapeutic use. The pharmacokinetic and hence the pharmacodynamic effect needs to be protracted to
`achieve the full therapeutic potential of GLP-1. The principal mechanism of protraction resulting in the
`long half-life is albumin binding, which results in decreased renal clearance and protection from
`metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4
`enzyme.1, 2 Semaglutide is supplied as 1.34 mg of semaglutide per mL solution in a 1.5 mL pre-filled,
`disposable, single-patient-use pen injector that delivers 0.25 mg, 0.5 mg, or 1 mg per subcutaneous
`injection and second pen as 1.34 mg of semaglutide per mL solution in a 1.5 mL pre-filled, disposable,
`single-patient-use pen injector that delivers 1 mg per subcutaneous injection. The proposed starting
`dose of semaglutide is 0.25 mg subcutaneously once weekly, titrating to 0.5 mg once weekly after 4
`weeks. After an additional 4 weeks, the dosage may be increased to 1 mg once weekly to further
`improve glycemic control, if needed.1,b Semaglutide, like other members of the GLP-1 RAs, has a Boxed
`Warning to inform healthcare providers (HCPs) about the potential risk of medullary thyroid cancer
`(MTC). Semaglutide is not currently approved in any jurisdiction.
`
`2.2 REGULATORY HISTORY
`
`The following is a summary of the regulatory history for semaglutide (NDA 209637) relevant to this
`review:
`
` 09/19/2008: Investigation New Drug (IND) 079754 submission was received.
`
` 12/17/2013: FDA grants SUSAR waiver for NN9535-3744, SUSTAIN™ 6 trials.
`
` 08/16/2014: Type C meeting written responses on NN9535-3744 and potential postmarketing
`trial.
`
` 08/18/2014: FDA agreed with the applicant’s initial pediatric study plan and acknowledged the
`request for a partial waiver from PREA requirements from conducting pediatric studies in the
`pediatric population with T2DM less than 10 years of age.
`
`
`a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
`
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
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`Reference ID: 4177175
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` 08/02/2016: Applicant’s background package for pre-NDA meeting stated that a REMS
`addressing the risk of MTC would be submitted and it would be aligned with the REMS for other
`currently approved GLP-1 agonist products.
`
` 12/05/2016: NDA 209637 submission for semaglutide with the proposed indication as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus,
`received. The applicant also proposed a REMS
`
`
`
`
`.
`
` 06/01/2017: A Post Mid-cycle meeting was held between the Agency and the Applicant via
`teleconference. The applicant proposed submitting a revised REMS that would be updated from
`the original REMS that was included with the application, to include diabetic retinopathy
`information. Since diabetic retinopathy is still being assessed and going to an advisory
`committee to seek external advice, and because the review is still ongoing, FDA stated that this
`should not be submitted and that discussion of any REMS would take place at a later date.
`
` 10/18/2017: Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) was convened
`to discuss risk-benefit profile of semaglutide with long-term use for glycemic control. The AC
`voted 16/0/1 in [favor/against/abstain] approval. A REMS proposal was not discussed.
`
`3 Therapeutic Context and Treatment Options
`
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`
`Diabetes is a group of diseases (e.g., Type I diabetes, Type II diabetes, gestational diabetes, maturity-
`onset diabetes of youth or latent autoimmune diabetes in adults) characterized by high levels of blood
`glucose due problems with the production and/or function of insulin. Complications of diabetes include
`vision loss, kidney injury, lower extremity amputation, heart attacks, and strokes. In addition, people
`with poorly controlled diabetes may experience decreased sense of well-being, impaired quality of life,
`cognitive impairment, depression, and periodontal disease among many other adverse effects.3 Per the
`Centers of Disease Control and Prevention (CDC), diabetes affects over 30.3 million Americans (9.4 % of
`the US population). In 2015, there were 1.5 million new cases of diabetes (6.7 per 1,000 persons) were
`diagnosed among U.S. adults aged 18 years or older.c Diabetes is the 7th leading cause of death in the US
`in 2015. The estimated cost of diabetes in the US in 2012 was $245 billion.4,d
`
`Type 2 diabetes often begins with insulin resistance and as the need for insulin rises, pancreatic beta cells
`gradually lose the ability to produce sufficient quantities of the hormone. However, the role of insulin
`resistance versus beta cell dysfunction differs among individuals. Glucose control tends to be more
`challenging over time. Risk factors for the development of Type 2 diabetes include older age, obesity,
`family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical
`inactivity, and race/ethnicity.5
`
`
`c Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
`
`d Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
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`Reference ID: 4177175
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`(b) (4)
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`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`
`The treatment of type 2 diabetes usually begins with lifestyle modifications (e.g., exercise, balanced
`nutrition, weigh management) and treatment with metformin. Diabetes is a complex, chronic illness
`requiring continuous individualized medical care and treatment strategies with multifactorial risk
`reduction targets beyond glycemic control. Standard of care guidelines for treatment of diabetes and
`associated cardiovascular disease recommend lifestyle interventions such as cessation of smoking, diet
`and exercise, as well as treatment with antiglycemic, antihypertensive, and lipid lowering drugs with the
`aim of achieving recommended goals for body weight, blood glucose, blood pressure, cholesterol, and
`triglycerides.6, 7 When adequate control is not achieved with the life modification measures, other
`therapies are prescribed. About 45% of adult patients with incident diabetes had anti-hyperglycemic
`therapy intensified within 1 year of starting anti-hyperglycemic medication; usually, intensification
`occurred within 6 months. The first intensification was most often accomplished by increasing dosage of
`initial medication (78%) and least often by adding or switching to insulin (<1%).8 Other types of drugs
`used in the treatment of type 2 diabetes include drugs in the following classes: sulfonylureas,
`thiazolidinediones, dipeptidyl peptidase- 4 (DPP-4) inhibitors, sodium-glucose co-transporter 2 (SGLT-2)
`inhibitors, GLP-1 receptor agonists, and insulin. Although these agents can substantially reduce
`diabetes-related morbidity and mortality, the extent of treatment benefits may be limited by a lack of
`treatment adherence. Inflexible treatment regimens restrict the patients’ lifestyle and can contribute to
`lack of adherence and failure to achieve the desired glycemic control.9 Therefore, there is a medical
`need for the development of safe and effective anti-hyperglycemic therapies formulated is ways that
`may increase compliance with therapy.
`
`In a 2016 consensus statement on the management of type 2 diabetes, recommendations by the
`American Association of Clinical Endocrinologists and the American College of Endocrinology suggest that
`GLP-1 receptor agonists are at the top of the list of second-line treatment of type 2 diabetes.10 GLP-1
`receptor agonists currently approved in the US include exenatide (twice-daily injection), liraglutide
`(once-daily injection), exenatide extended release (once-weekly injection), albiglutide (once-weekly
`injection), dulaglutide and (once-weekly injection), lixisenatide (once-daily injection) and combination
`products of insulin degludec & liraglutide (once-daily injection) and insulin glargine & lixisenatide
`(once-daily injection).
`
`Exenatide (Byetta11) had a communication plan REMS to mitigate the risk of pancreatitis and renal failure
`but the REMS was eliminated upon completion of all communication activities. The following GLP-1 RA
`Victoza12 (liraglutide), Bydureon13 (exenatide), Trulicity14, Xultophy (insulin degludec & liraglutide)15 , and
`Tanzeum (albiglutide)16 were required to have a REMS with a communication plan to address the
`increased risks of medullary thyroid cancer (MTC) and acute pancreatitis. The REMS for Bydureon and
`Victoza, were released after DMEP and DRISK determined that the communication activities have been
`completed. Most recently DRISK completed reviews for both Trulicity17 and Tanzeum18 that support
`releasing these REMS as they were meetings the goals of the REMS, all communication plan activities
`have been completed, there was no new safety information that warranted the need for the REMS to be
`extended.
`
` 4
`
` Benefit Assessment
`
`
`The efficacy of semaglutide for the indication as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus was evaluated was demonstrated in five key efficacy
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`Reference ID: 4177175
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`phase 3 trials (3623-SUSTAIN 1, 3626- SUSTAIN 2, 3624- SUSTAIN 3, 3625-SUSTAIN 4, 3627- SUSTAIN 5)
`and a cardiovascular outcome trial (CVOT) (3744- SUSTAIN 6). Semaglutide has been studied as
`monotherapy and in combination with metformin, metformin and sulfomylureas, metformin and/or
`thiazolidinedione, and basal insulin. The efficacy of semaglutide was compared with placebo, sitagliptin,
`exenatide ER, and insulin glargine. Trials 3623, 3627 and the CVOT were placebo-controlled, and Trials
`3626, 3624, and 3625 were active-controlled. SUSTAIN 1 was a 30-week double-blind trial where a total
`of 388 patients inadequately controlled with diet and exercise, were randomized to semaglutide 0.5 mg
`or 1 mg once-weekly (OW) or placebo. SUSTAIN 2 was a 56-week, double-blind trial where a total of
`1231 patients were randomized to semaglutide 0.5 or 1 mg once-weekly or sitagliptin 100 mg once-
`daily, all in combination with metformin (94%) and/or thiazolidinediones (6%). SUSTAIN 3 was a 56-week
`open-label trial where a total of 813 patients on metformin alone (49%), metformin with sulfonylurea
`(45%) or other (6%) were randomized to semaglutide 1 mg once-weekly or exenatide 2 mg once-weekly.
`SUSTAIN 4 was a 30-week open-label trial where a total of 1089 patients were randomised to
`semaglutide 0.5 mg or 1 mg once-weekly, or insulin glargine once-daily on a background of metformin
`(48%) or metformin and sulfonylurea (51%). SUSTAIN 5 was a 30-week double-blind where a total of
`397 patients inadequately controlled with basal insulin with or without metformin were randomized to
`semaglutide 0.5 or 1 mg once-weekly or placebo. SUSTAIN 6 was a 104-week double-blind trial where
`3,297 patients with type 2 diabetes and high risk of cardiovascular events were randomized to
`semaglutide 0.5 mg or 1 mg once-weekly or placebo in addition to standard-of-care. The placebo-
`controlled trials were double-blinded within dose groups (0.5 mg and 1.0 mg). No blinding of dose was
`performed. Double-blinding was also attained for the sitagliptin-controlled trial 3626 via a double
`dummy design. The insulin-controlled trial 3625 and the exenatide-controlled trial 3624 were both
`open-label. The applicant stated the open-label design was necessary due to the complexity of blinding
`insulin and the complexity of preparing a placebo version of exenatide ER.
`
`At the time of this writing, labeling negotiations were still ongoing with the Applicant. The following
`section is a summary of relevant efficacy information for semaglutide. The primary efficacy endpoint in
`the 5 key efficacy trials was change in HbA1c from baseline to the end of the planned treatment period.
`The key secondary endpoint in the 5 key efficacy trials was change in body weight from baseline to the
`end of the planned treatment period. The primary objective in the placebo-controlled trials 3623 and
`3627 was to demonstrate superiority of OW dosing of 2 dose levels of semaglutide vs placebo on
`glycemic control after 30 weeks of treatment. The primary objective in the active-controlled trials 3626,
`3624 and 3625 was to compare the effect of OW dosing of semaglutide vs active comparator on
`glycemic control. The secondary objectives in all the trials were to compare the effects of semaglutide
`on inducing and maintaining weight loss as well as other parameters of efficacy, safety and tolerability.
`The CVOT had a primary objective of studying the safety of semaglutide.
`
`Both doses of semaglutide (0.5 mg and 1.0 mg) demonstrated superiority to placebo in terms of change
`in HbA1c from baseline, in a monotherapy Trial 3623 as well as Trial 3627 with basal insulin background
`therapy. Both doses of semaglutide also demonstrated superiority to active comparators sitagliptin and
`insulin glargine for the HbA1c primary endpoint. Semaglutide 1.0 mg also demonstrated superiority to
`exenatide ER.e,19 In all the key efficacy trials, both doses of semaglutide also demonstrated superiority to
`placebo and the active comparators in terms of change in body weight from baseline. In the CVOT, both
`doses of semaglutide demonstrated superiority to placebo in terms of change in HbA1c and body weight
`
`
`e Section 505-1 (a) of the FD&C Act: FDAAA factor (C): The expected benefit of the drug with respect to such disease
`or condition.
`
`Reference ID: 4177175
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`at Week 104 as well as change in HbA1c at Week 30 for subjects on premix insulin at baseline and for
`subjects on sulfonylurea (SU) monotherapy at baseline, although change in HbA1c at Week 104 was not
`a pre-specified secondary endpoint.e,1919 The efficacy results are summarized in Table 1 and 2 in the
`Appendix.
`
` 5
`
` Risk Assessment & Safe-Use Conditions
`
`
`At the time of this review, labeling negotiations were still ongoing with the Applicant. The following
`section is a summary of relevant safety information to date for semaglutide. The safety analysis of
`semaglutide is primarily based on seven phase 3 studies (3623-SUSTAIN 1, 3626- SUSTAIN 2, 3624-
`SUSTAIN 3, 3625-SUSTAIN 4, 3627- SUSTAIN 5, 4091, and 4092), which enrolled 4807 subjects (3150
`patients in the semaglutide arm, and 1657 in the comparator arm), as well as a two year cardiovascular
`outcomes trial (CVOT) (3744-SUSTAIN 6).
`
`Two of those seven studies were placebo-controlled trials (3623-SUSTAIN 1 and 3627- SUSTAIN 5), with
`the remaining five comparing semaglutide to an active comparator [i.e., sitagliptin (3626- SUSTAIN 2
`and 4092), exenatide extended-release (3624- SUSTAIN 3), insulin glargine (3625-SUSTAIN 4), and oral
`anti-diabetic drugs (4091)]. In considering the safety data from the phase 3 studies (excluding the
`CVOT), the safety profile of semaglutide appears to be consistent with what has been seen with other
`GLP-1 receptor agonists.
`
`The SUSTAIN 6 trial was a multi-national, randomized, double-blind, and placebo-controlled
`cardiovascular outcome trial designed to assess cardiovascular safety of semaglutide. The pre-specified
`primary CV endpoint was time from randomization to first major adverse cardiovascular events (MACE).
`In addition to the primary MACE endpoint, some secondary CV-related endpoints including expanded
`MACE, all-cause death, and primary MACE (on-treatment +42 days) were also investigated using time to
`event analysis methods. SUSTAIN 6 was designed to rule out a hazard ratio of 1.8 for major adverse
`cardiovascular events. A total of 3297 subjects were included in the intent to treat (ITT) population, with
`1648 randomized to semaglutide and 1649 randomized to placebo (both administered in addition to
`their standard-of-care treatment). The median treatment exposure time was 104 weeks for both
`treatment arms.
`
`Deaths and serious adverse events were generally balanced in both safety pools.20 The proportion of
`patients with events is shown on the Table 3 in the Appendix. Semaglutide treated patients were
`approximately twice more likely to discontinue due to an adverse event. This was primarily due to
`gastrointestinal (GI) adverse events, and it appears to be dose-dependent.
`
`Deaths
`
`No deaths were reported in any of the two placebo-controlled trials (3623, and 3627).20
`
`There were 16 deaths in the phase 3 pool (excluding the CVOT). All cases were sent to the EAC for
`adjudication to identify all potential causes of death. A total of 10 patients (0.3%) randomized to
`semaglutide died, and 6 patients (0.4%) randomized to comparator products died.20
`
` A
`
` total of 62 deaths (3.8%) were observed in the semaglutide arm and 60 deaths (3.6%) were observed
`in the placebo arm in the SUSTAIN 6. All-cause mortality was not different between semaglutide and
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`Reference ID: 4177175
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`placebo groups. There were 123 reported deaths during the treatment period (3.8% of patients on
`semaglutide, and 3.7% of patients on placebo arm). Approximately half of the events in each treatment
`arm belonged to the cardiac disorders system organ class.20
`
`Serious Adverse Events (SAE)
`
` A
`
` higher proportion of patients were reported with serious adverse events (SAEs) on semaglutide 1 mg
`(7.3%) compared to semaglutide 0.5 mg (5.8%), or placebo (5.3%). However, the number of SAEs was
`small, which limits the ability to draw definitive conclusions in placebo pool.20
`
`The proportion of patients with SAEs was higher with semaglutide (0.5 mg and 1.0 mg) than with
`comparator products in phase 3 pool. SAEs within the system organ class (SOC) of gastrointestinal
`disorders were reported by a higher proportion of patients with semaglutide 0.5 mg (1.3%) than with
`semaglutide 1 mg (0.7%) and comparator products (0.5%). The proportion of patients who discontinued
`treatment prematurely due to AEs was higher with semaglutide than with comparator products. This
`difference was mostly due to GI AEs (nausea, vomiting, and diarrhea) leading to discontinuation in the
`semaglutide groups, and this appeared to be dose-related. Other AEs more frequently leading to
`premature treatment discontinuation with semaglutide than with placebo included decreased appetite,
`decreased weight, and increased lipase.20
`
`The proportion of patients reporting SAEs during the trial SUSTAIN 6 was lower with semaglutide (0.5
`mg: 32.1% of patients, 1.0 mg: 29.2% of patients) than with placebo (34.9% of patients). Most of the
`SAEs reported were in the cardiac disorders SOC. The proportion of patients reporting SAEs within this
`SOC was generally lower with semaglutide than placebo. The proportions of patients with AEs leading to
`premature discontinuation and the corresponding rates were higher with semaglutide than with
`placebo. AEs in the SOC GI disorders and the PT decreased appetite (within the SOC metabolism and
`nutrition disorders) were the most frequent AEs leading to premature discontinuation. In general, the
`proportions of patients with AEs leading to premature discontinuation in SOC GI disorders were lower
`with placebo than with either dose of semaglutide.20
`
`Adverse events of special interest for the GLP-1 RA class include thyroid C-cell cancer and pancreatitis.f
`
`Thyroid Neoplasms
`
`Thyroid neoplasms were analyzed separately because of the theoretical concern of C-cell hyperplasia
`with long-acting GLP-1 RAs. Additionally, the non-clinical data showed an association between
`semaglutide and c-cell adenomas and carcinomas in rats and mice. It is unknown whether semaglutide
`causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human
`relevance could not be determined. Thyroid C-cell tumors in rodents are a known class effect for
`glucagon-like peptide (GLP-1) receptor agonists.
`
`There were only 4 adjudicated events of malignant thyroid neoplasm in the phase 3 pool and 3
`adjudicated events of malignant thyroid neoplasm in SUSTAIN 6.20 No meaningful conclusions can be
`
`f Section 505-1 (a) of the FD&C Act: FDAAA factor (E): The seriousness of any known or potential adverse events
`that may be related to the drug and the background incidence of such events in the population likely to use the
`drug.
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`Reference ID: 4177175
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`made based on these events, however it was noted that there was one semaglutide treated patient with
`histopathologic evidence of thyroid C-cell hyperplasia. The patient with histopathologic evidence of C-
`cell hyperplasia had thyroid abnormalities at baseline that make it unlikely that the case was a result of
`exposure to semaglutide.
`
`Serum calcitonin was also measured centrally during the phase 3 trials; a value >20 ng/L was considered
`to be a value of special interest. No notable change in mean serum calcitonin was seen in any treatment
`arm in any safety pool. In the phase 3 pool, the incidence of marked outliers was similar between
`comparator and semaglutide. In SUSTAIN 6, a slight increase in the incidence of serum calcitonin
`greater than 50 or greater than 100 was seen with semaglutide, however, the number of outliers was
`very small.
`
`If approved, labeling will be consistent with other GLP-1 RAs and risk of MTC will be included as Boxed
`Warnings.
`
`Pancreatitis
`
`Pancreatitis was identified as a medical event of special interest (MESI), as the use of incretin-based
`drugs has been associated with development of pancreatitis. The potential for an increased risk of
`pancreatitis was evaluated through review of the MedDRA coded adverse events. There were few cases
`of ‘confirmed’ pancreatitis seen in the phase 3 pool and in SUSTAIN 6.20
`
`No significant difference was seen between treatment groups, but it is notable that all the events from
`the comparator arm in the Phase 3 pool came from patients treated with exenatide extended-release. A
`total of 42 events were referred for adjudication with 12 events of pancreatitis confirmed by the EAC in
`the phase 3 pool. Of the 12 confirmed events, 11 occurred during the on-treatment observation period
`(5 [0.4%] with semaglutide 0.5 mg, 3 [0.2%] with semaglutide 1 mg, and 3 [0.2%] with comparator). All
`of the comparator events occurred with exenatide ER. An additional event of chronic pancreatitis with
`semaglutide 0.5 mg was confirmed during the in-trial period. The 29 non-confirmed events were mainly
`reported as elevated pancreatic enzymes or suspicion of pancreatitis. In the non-incretin subset of the
`phase 3 pool, only 2 events were confirmed, both with semaglutide 0.5 mg.
`
`The review of the MedDRA coded events yielded similar findings. A total of 20 AEs in 18 patients were
`captured in the phase 3 pool (5 patients [0.4%] treated with semaglutide 0.5 mg, 6 patients [0.3%]
`treated with semaglutide 1 mg, 7 patients [0.4%] treated with comparator). Of the 7 patients from the
`comparator pool, 5 were treated with exenatide ER and 2 were treated with sitagliptin. Only 3 events
`were identified in the non-incretin subset, 2 with semaglutide 0.5 mg, and one with sema