CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209637Orig1s000
`
`SUMMARY REVIEW
`
`
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`

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`NDA 209637 OZEMPIC (semaglutide)
`
`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`William H. Chon -
`From
`
`Subject
`Cross-Discipline Team Leader Review
`NDA/BLA #
`NDA 209637
`
`Su n ulement#
`
`Applicant
`Novo Nordisk Inc.
`Date of Submission
`December 5, 2016
`
`PDUFA Goal Date
`
`December 5, 2017
`
`Proprietary Name / Non-
`Pro n rieta Name
`
`OZEMPIC (semaglutide)
`
`Dosa
`
`Once weekl subcutaneous in'ection 0.5 my
`
`
`
`Applicant Proposed
`Indication 5 /Po n ulation s
`Recommendation on
`Re 1 ulato Action
`
`Recommended
`Indication(s)/Population(s) (if
`a o olicable
`
`Adjunct to diet and exercise to improve glycemic control
`in adults with lie 2 diabetes mellitus
`Approval
`
`Adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NMEw’original BLA reviews)
`
`1
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`Reference ID: 41 89360
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`Review Team:
`
`Drug Substance Reviewer
`Drug Product Reviewer
`Quality Microbiology Reviewer
`Quality Process Reviewer
`Facilities Reviewers
`Quality Technical Lead
`Nonclinical Reviewer
`Carcinogenicity Statistics Reviewer
`(DB-VI)
`QT-IRT
`Clinical Pharmacology Reviewers
`
`Clinical Reviewer
`Efficacy Statistics Reviewer (DB-II)
`Safety Statistics (DB-VII)
`DMEPA Reviewer
`CDRH/GHDB Consultant
`Immunogenicity
`DPMH Reviewer
`DRISK Reviewer
`DMPP Reviewer
`OPDP Reviewer
`Ophthalmology Consultant
`Office of Scientific Investigation
`Division of Epidemiology
`Project Manager
`
`Joseph Leginus
`Muthukumar Ramaswamy
`Elizabeth Bearr
`Chaoying Ma
`Vidya Pai (CDER) and Christopher Brown (CDRH)
`Suong Tran
`Federica Basso
`Hepei Chen
`
`Janell Chen
`Shalini Wickramaratne Senarath Yapa and Justin
`Earp
`Andreea Lungu
`Jiwei He
`Ya-Hui Hsueh
`Susan Rimmel
`Sarah Mollo
`Mohanraj Manangeeswaran
`Jane Liedtka
`Till Olickal
`Sharon Williams
`Domenic D’Alessandro
`Wiley Chambers
`Cynthia Kleppinger
`Yandong Qiang
`Peter Franks
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`2
`
`Reference ID: 4189360
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`1. Benefit-Risk Assessment
`
`Benefit-Risk Summary and Assessment
`
`Type 2 diabetes mellitus (T2DM) is a condition of chronic impaired glucose homeostasis that results in chronic hyperglycemia and increases the
`risk for microvascular and macrovascular complications. Therapies for T2DM have focused on improving glycemic control as assessed by
`change in hemoglobin A1c (HbA1c), as better glycemic control has been correlated with better clinical outcomes. While there are multiple drug
`products approved both as individual drugs and as fixed combination drug products (FCDP), many patients are unable to achieve glucose targets.
`Thus, patients and prescribers have been advocating for additional therapeutic options to facilitate individualization of therapy in hopes that this
`will improve patients’ ability to achieve glycemic control.
`
`Semaglutide is a once weekly glucagon-like peptide-1 (GLP-1) receptor agonist that has been developed as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In controlled clinical trials, use of semaglutide 0.5 mg or 1 mg once
`weekly resulted reduction in HbA1c (treatment difference compared to placebo of -1.1% to -1.6% at 30 weeks). Additional findings which may
`be desirable for patients include a reduction in body weight (treatment difference compared to placebo of -2.2 to -4.7 kg at 30 weeks).
`
`Safety findings from the semaglutide development program were generally consistent with what would be expected for a long-acting GLP-1
`receptor agonist. The most common adverse reactions are nausea and vomiting. The inherent risk for hypoglycemia with semaglutide appears to
`be low, but this is increased when co-administered with insulin (and likely to be increased when co-administered with insulin secretagogues, such
`as sulfonylureas). While no difference in the incidence of pancreatitis was seen in the development program, patients treated with semaglutide
`had increases in serum amylase and lipase. No notable difference in malignancies (including for medullary thyroid cancer) was seen in the
`development program, but duration of exposure was relatively short and may not be sufficient to fully exclude an increased risk. Nonclinical
`findings support that the concern for MTC with long-acting GLP-1 receptor agonists also applies to semaglutide. As a peptide product, it is
`expected that semaglutide will carry some risk for anti-semaglutide antibody formation and hypersensitivity reactions. The observed incidence
`and titer of anti-semaglutide antibodies was relatively low, and no apparent increased risk for clinically significant hypersensitivity events was
`seen.
`
`In support of the semaglutide new drug application (NDA), the applicant has also completed a cardiovascular outcomes trial (CVOT) designed to
`exclude excess cardiovascular risk. This trial ran for two years and accrued a total of 254 first major adverse cardiovascular events (MACE).
`Based on this trial, the applicant has adequately established that there is no excess cardiovascular risk with semaglutide.
`
`An unexpected finding from the CVOT was an increased risk for diabetic retinopathy complications. This was seen early in the trial and the
`increased risk persisted through the two-year observation period of the trial. The patients at greatest risk were those with diabetic retinopathy at
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`3
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`Reference ID: 4189360
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`baseline. Though the definitions and means by which events were identified were considered inadequate had the applicant been pursuing an
`indication of reduced risk for diabetic retinopathy progression, the finding is nevertheless concerning given that improving glycemic control is
`expected to reduce the risk for complications of diabetes. The applicant has posited that this finding is a result of the glucose lowering effect of
`semaglutide and that it is consistent with what would be expected based on findings from other large clinical trials (i.e., the Diabetes Control and
`Complications Trial [DCCT]). While adjusting for change in HbA1c does attenuate the observed hazard ratio, it may not fully explain the
`observed finding. The FDA ophthalmology consultant acknowledged that the finding does raise some concerns, but that this observation would
`be expected and that it does not adversely impact the benefit-risk. A public Advisory Committee meeting was convened to discuss the benefits
`and risks of semaglutide, including the diabetic retinopathy findings. The external ophthalmology experts and other Advisory Committee panel
`members expressed opinions similar to that of the FDA ophthalmology consultant.
`
`The finding of increased risk for diabetic retinopathy complications is concerning, but I do not believe it results in an unfavorable benefit-risk.
`Diabetic retinopathy is but one of several diabetic complications that is expected to be favorably impacted by improved glycemic control. Data
`from the semaglutide development program have not suggested that these other clinical outcomes are similarly adversely impacted. Additionally,
`the data on semaglutide for diabetic retinopathy complications are limited. The longest exposure to semaglutide was two years, and it is notable
`that in the DCCT there was an early worsening of diabetic retinopathy progression with intense glycemic control which reversed after
`approximately three years. Whether longer term treatment with semaglutide would similarly result in a reduced risk of diabetic retinopathy
`progression is unknown, but it may not be feasible or ethical to conduct such a study. While this uncertainty remains, it is reassuring to note that
`diabetic retinopathy can be monitored and that there are effective therapies to treat it such that serious adverse clinical outcomes (e.g., blindness)
`can be avoided with proper ophthalmologic care. The patients at greatest risk were those with diabetic retinopathy at baseline, and those patients
`would generally be expected to have closer ophthalmology follow-up.
`
`In summary, I believe that semaglutide has a favorable benefit-risk profile. The findings from the development program demonstrate the ability
`of semaglutide to improve glycemic control, and the safety profile is generally consistent with other member of the class. Further, the
`cardiovascular safety of semaglutide has been adequately established. Though there was a finding for increased risk of diabetic retinopathy
`complications, I do not believe that it is so substantial as to outweigh the benefits. While the finding raises some question as to the benefit of
`semaglutide with respect to reducing the risk for diabetic retinopathy progression, improved glycemic control should convey a reduced risk for
`other diabetic complications (e.g., diabetic nephropathy, diabetic neuropathy). Further, diabetic retinopathy can be monitored and treated to
`prevent serious clinical outcomes (e.g., blindness).
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4189360
`
`4
`
`

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`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`Dimension
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`Benefit
`
`Evidence and Uncertainties
`
` Type 2 diabetes mellitus (T2DM) is a condition of chronic impaired
`glucose homeostasis leading to chronic hyperglycemia and an
`increased risk for microvascular (e.g., retinopathy, nephropathy) and
`macrovascular (e.g., myocardial infarction, stroke) complications.
`The Center for Disease Control estimates that there are over 29
`million patients with type 2 diabetes mellitus in the United States.
` Based on the results of the Diabetes Control and Complication Trial
`and the United Kingdom Prospective Diabetes study, improved
`glycemic control (as measured using hemoglobin A1c [HbA1c]) is
`believed to result in improved clinical outcomes (i.e., reduced
`microvascular complications).
` There are currently 12 classes of medications (generally with
`multiple members in each class), approved to improve glycemic
`control in patients with T2DM. Many of these medications are also
`approved as fixed combination drug products (FCDPs).
` There are different safety concerns for each class. Metformin is
`often considered first-line therapy with the choice of subsequent
`therapies individualized by prescribers based on the patient.
` While approved antidiabetic agents have been shown to improve
`glycemic control, data on the ability of individual agents to improve
`clinical outcomes are limited in terms of drug products and studied
`populations.
` Use of semaglutide improved glycemic control with treatment
`difference compared to placebo in mean HbA1c of -1.1 to -1.6% at
`30 weeks.
` Subjects treated with semaglutide were also found to have a
`treatment difference compared to placebo in mean body weight
`ranging from -2.2 to -4.7 kg.
`
`Conclusions and Reasons
`Type 2 diabetes mellitus is a serious and life
`threatening condition that if left untreated leads
`an increased risk for morbidity and mortality.
`
`Despite the many available treatment options,
`many patients continue to have difficulty with
`achieving the desired degree of glycemic
`control. Further, T2DM is a progressive
`disorder and patients typically need additional
`agents as the course of the disease progresses.
`
`Semaglutide has demonstrated the ability to
`improve glycemic control. Other findings that
`may be desirable for patients include a
`reduction in body weight.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4189360
`
`5
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`Dimension
`
`Evidence and Uncertainties
`
` The most common adverse reactions were gastrointestinal events
`(i.e., nausea/vomiting).
` Class safety concerns include pancreatitis, medullary thyroid tumors,
`and acute kidney injury. Findings from the development program do
`not change these concerns
` No evidence of increased cardiovascular risk.
` Finding of increased risk of progression of diabetic retinopathy was
`seen in the two year cardiovascular outcomes trial, primarily in
`subjects with retinopathy at baseline. Whether this will ultimately
`reverse (as would be expected based on the DCCT and other large
`clinical trials) or persist is unknown.
`
`Risk
`
`Risk
`Management
`
` The identified risks for semaglutide are generally consistent with the
`other members of the class. Labeling should be similar to other long-
`acting GLP-1 receptor agonists.
` The approval of other GLP-1 receptor agonists has included a
`communication plan REMS for purposes of informing prescribers of
`the risk for MTC and pancreatitis. The assessment of the data from
`these REMS has suggested that this risk has been sufficiently
`communicated for the class. Thus, no REMS is recommended for
`semaglutide.
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4189360
`
`Conclusions and Reasons
`The safety profile of semaglutide is generally
`consistent with other long-acting GLP-1
`receptor agonists. The cardiovascular safety of
`semaglutide has been adequately established.
`An increased risk for diabetic retinopathy
`complications was seen with semaglutide in the
`CVOT which is contrary to what would be
`expected with a therapy that improves glycemic
`control. While it is unknown whether long-
`term therapy with semaglutide will lead to a
`reduced risk for progression of diabetic
`retinopathy (which is what would be expected
`based on large, prospective clinical trials such
`as the DCCT), it is worth noting that a reduced
`risk of diabetic retinopathy progression is not
`the only clinical benefit expected with
`improved glycemic control. Additionally,
`diabetic retinopathy can be monitored and there
`are effective therapies to prevent serious
`adverse clinical outcomes (e.g., blindness).
`This risk can be managed and does not by itself
`result in an unfavorable benefit-risk
`assessment.
`The risks associated with semaglutide can be
`handled with adequate labeling. Given the
`extensive experience with other long-acting
`GLP-1 receptor agonists and their
`communication plan REMS for MTC and
`pancreatitis, the risk appears to have been
`adequately communicated for the class and I do
`not recommend a REMS for semaglutide. The
`finding of increased risk for diabetic
`
`6
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`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`Dimension
`
`Evidence and Uncertainties
`
` The increased risk for diabetic retinopathy complications is
`unexpected and of some concern. Whether this will be a short-term
`risk or remain a long-term safety concern is unknown. However,
`diabetic retinopathy can be monitored and managed. This risk can be
`managed through labeling.
`
`Conclusions and Reasons
`retinopathy complications was unexpected and
`of some concern, but this can be monitored and
`there are effective treatments. Routine diabetic
`ophthalmologic care should be sufficient to
`mitigate this risk, and I believe that
`communication of this risk can be handled with
`labeling.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 4189360
`
`7
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`2. Background
`
`Diabetes mellitus is a disease of impaired glucose homeostasis that results in chronic
`hyperglycemia. There are two main types of diabetes mellitus: type 1 diabetes mellitus (T1DM;
`characterized by autoimmune destruction of pancreatic β-cells and loss of insulin secretion) and
`type 2 diabetes mellitus (T2DM; characterized by resistance to insulin activity with inadequate
`insulin production to maintain euglycemia). Chronic hyperglycemia in turn leads to an increased
`risk for microvascular (e.g., retinopathy, nephropathy) and macrovascular (e.g., myocardial
`infarction, stroke) complications. Based on the results of the Diabetes Control and Complication
`Trial (DCCT) 1 and the United Kingdom Prospective Diabetes study (UKPDS) 2, improved
`glycemic control (as measured using hemoglobin A1c [HbA1c]) is believed to result in improved
`clinical outcomes.
`
`The development of therapies to treat T2DM has focused on developing agents that can improve
`glycemic control as assessed by the ability to reduce HbA1c, and this has served as the basis for
`approval of antidiabetic agents. Recently, studies of some antidiabetic drugs have reported
`improved clinical outcomes in patients with T2DM. These findings are limited to a few drug
`products 3, 4 and were conducted in a population with high cardiovascular risk. Whether these
`findings can be generalized to the entire population of patients with T2DM is unknown.
`
`There are currently 11 classes of antidiabetic drugs with most classes having multiple members
`(Table 1). Many of these drug products are also available as FCDPs.
`
`Biguanides
`
`Table 1: Summary of FDA approved drugs to improve glycemic control in diabetes
`Drug Class
`Drug Products
`Insulin and insulin analogs
`Multiple products including basal, prandial, and mixed insulin
`products
`Metformin (as an immediate release and an extended release
`formulation)
`Chlorpropamide, Glimepiride, Glipizide, Glyburide
`Rosiglitazone, Pioglitazone
`Repaglinide, Nateglinide
`Acarbose, Miglitol
`Sitagliptin, Saxagliptin, Alogliptin, Linagliptin
`
`Sulfonylureas
`Thiazolidinediones
`Meglitinides
`Alpha glucosidase inhibitors
`Dipeptidyl peptidase-4 (DPP-4)
`inhibitors
`Glucagon-like peptide-1 (GLP-1)
`receptor agonists
`
`Exenatide (as a twice daily and as a once weekly), Liraglutide,
`Albiglutide, Dulaglutide, Lixisenatide
`
`1 The Diabetes Control and Complications Trial Research Group. “The effect of intensive treatment of diabetes on
`the development and progression of long-term complications in insulin-dependent diabetes mellitus”. NEJM, 1993;
`329 (14): 977-986.
`2 UK Prospective Study Group. “Intensive blood-glucose control with sulphonylureas or insulin compared with
`conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)”. Lancet, 1998; 352
`(9131): 837-853.
`3 Zinman B, et al. “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes”. NEJM, 2015;
`373: 2117-2128.
`4 Marso SP, et al. “Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes”. NEJM, 2016; 375: 311-322.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`8
`
`Reference ID: 4189360
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`
`Cross Discipline Team Leader Review
`
`
`Sodium glucose cotransporter-Z
`Canagliflozin. Dapagliflozin. Empagliflozin
`
`(SGLT2) inhibitors
`
`| Amylin analogs
`Pramlintide
`
`I Bile acid sequestrants
`Colesevelam
`
`I Dopamine agonists
`Bromocriptine
`
`|
`I
`I
`
`Despite the number of available therapies, many patients with T2DM continue to have difficulty
`in achieving glycemic targets. While reasons for this are likely multifactorial, it has been
`suggested that more therapeutic options are needed to allow for better individualization of
`therapy.
`
`Novo Nordisk (hereafter referred to as the applicant) has submitted a new drug application
`(NDA) seeking approval for semaglutide, a once weekly GLP-1 receptor agonist. Semaglutide
`would be the seventh GLP-1 receptor agonist drug product to be marketed in the United States,
`and the fourth once weekly GLP—1 receptor agonist.
`
`(hm “. . . as
`(5x4) for semaglutide.
`(m4) proposed
`The applicant
`an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`meuims-u
`
`(b) (0
`
`The applicant has proposed two therapeutic doses for semaglutide (0.5 mg once weekly and 1 mg
`once weekly) as well as a titration dose of 0.25 mg once weekly. The titration dose is to be
`administered for the first four weeks followed by an increase to the 0.5 mg dose. If additional
`glycemic control is required, patients can increase to the 1 mg dose. The drug product will be
`available in pre-filled, multi—dose pens for subcutaneous injection. One pen will allow for
`selection of the two different dosage strengths (i.e., 0.25 mg, and 0.5 mg). The other pen will
`deliver only the 1 mg dose.
`
`3.
`
`Product Quality
`
`Drug Substance:
`
`m“) peptide that is an analog of glucagon—like peptide-1 (GLP-l)
`Semaglutide is a
`which differs from endogenous GLP-l through three modifications:
`
`(1) Substitution of arginine for lysine at position 34
`(2) Attachment of a long fatty acid derivative at position 26, and
`(3) Modification of position 8 of the peptide backbone, substituting amino-isobutyric acid for
`alanine
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
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`Reference ID: 41 89360
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`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`These modifications are intended to result in slowed degradation and reduced renal clearance,
`thus contributing to the prolonged half-life and allowing for once-weekly subcutaneous
`administration.
`
`The molecular formula and chemical structure of semaglutide are shown below:
`
`
`
`
`
`
`
`
`
`
` 7 70 to 20 O
`H
`H
`30
`3
`Halt-N _ LE_G_1_F-1_s_n_v_s—s—v—L—e—G—-o—A—A—N _L_e_F-|_A-w-L—.v—R—c-n—G-on
`
`cu, cu, olecular Formula: Cm! 1301N45059
`
`Source: Excerpted from section 5.1 of Dr. Leginus’ Drug Substance Review
`
`Manufacturing of semaglutide is
`
`(Figure l).
`
`0W)
`
`CDER Cross Discipline Tm Leader Review Template 2015 Edition
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`
`10
`
`Reference ID: 41 89360
`
`

`

`NDA 209637 OZEMPIC (semaghitide)
`Cross Discipline Team Leader Review
`
`Figure 1: Overview of sema utide manufacturin
`
`
`
`Source: Excerpted from section 5.2 of Dr. Leginus’ Drug Substance review
`
`
`
`For detailed discussion of the semaglutide drug substance manufacturing, see Dr. Leginus’
`review. The available data on the manufacturing process including characterization of product-
`related and process-related impurities is acceptable and support approval.
`
`Drug Product:
`
`The semaglutide drug product consists of semaglutide in a clear, colorless solution at a
`concentration of 1.34 mg/mL. The semaglutide solution will be packaged in a 1.5 mL glass
`
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`

`NDA 209637 OZEMPIC (semaglutide)
`
`Cross Discipline Team Leader Review
`
`cartridge that is subsequently incorporated into a pen injector delivery system. This section of
`the review will focus on the drug product manufacturing through the primary container closure
`system (i.e., the 1.5 mL glass cartridge). Discussion of the pen injector is found below, under
`“Device”.
`
`The drug product is manufactured by
`
`«no
`
`process and in—process controls to be adequate.
`
`. Dr. Ma has found the manufacturing
`
`Table 2: Composition of semaglutide drug product
`Name of ingredients
`Quantity per mlm Reference to standards
`
`Active dmg substance
`
`Novo Nordisk A S
`
`
`
`Semaglutide
`
`Excipients
`
`Disodium phosphate. dihydrate
`
`Propylene glycol
`
`Hydrochloric acid
`
`Sodium hydroxide
`
`I
`
`USP P11. Eur.
`
`USP JP Ph. Eur.
`
`USP JP Ph. Eur.
`
`.
`
`.
`
`pH adjustment
`
`USP JP Ph. Eur.
`
`pH adjustment
`
`USP JP Ph. Eur.
`
`(ll) (4)
`
`1To reach pH ”.4
`Source: Excerpted from P3 of Dr. Ma’s review
`
`The primary container closure consists of a chemically inert, 1.5 mL cartridge made of colorless
`glass that is sealed with a
`(mo rubber disc and rubber plunger. The rubber disc
`consists oi
`(m4) rubber non-contact side) and
`m” rubber (contact side). The rubber
`plunger is made of
`)(4) rubber. Compatibility of the semaglutide drug product with the
`primary container closure is supported by 36 months of real-time stability data. Leachable and
`extractable data were also adequate.
`
`Of note, photostability testing demonstrated that the drug product is sensitive to light (Table 3).
`When exposed to light (i.e., 1.4 million lux hours and 585 Wh/m2 over 26 hours), semaglutide
`content was noted to decrease and impurity content (primarily high molecular weight proteins)
`increased. When the drug product is stored in the pen injector with the cap in place, no such
`degradation was noted.
`
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`

`

`NDA 209637 OZEMPIC (semaglutide)
`
`Cross Discipline Team Leader Review
`
`
`
`
`Table 3: Photo stability results
`Test item
`Dark control
`1.5 ml
`PDSZ90 pen-injector
`‘ Comments
`
`cartridge
`Macroscopy
`Colorless or ahiiost colorless liquid free from turbidity
`Drug product packaged in pen
`
`and essentially free from particulate matter
`injector (with cap) on is protected
`pH
`7.40
`‘ 7.39
`7.38
`‘
`from degradation. Exposure to light
`Content ofseniaglutide.
`1.34
`‘ -
`1.34
`"55111th in an iiiCIease “II-m1“?
`content.
`
`lllfl'lllL
`(b)(0
`Higli molecular weight
`proteins
`Hydrophilic impurities
`
`
`
`Hydrophobic impurities l
`
`Hydrophobic impurities 2
`
`Sum of impurities
`
`Phenol. lllgv‘lllL
`
`
`
`
`
`Source: Excerpted from section P2 of the Drug Product Review
`
`Based on the provided stability data, Dr. Ramaswamy agrees with the applicant’s proposed 36-
`month shelf-life when stored at 5°C, and the proposed 56 day in-use period when stored at 5 to
`30°C. The semaglutide pen injector should be stored with the cap on as the secondary packaging
`is adequate to protect against degradation due to light exposure.
`
`The manufacturing process was found to be adequate. For detailed discussion of the drug
`product manufacturing process and the drug product in its primary container closure, see Dr.
`Ma’s and Dr. Ramaswamy’s reviews.
`
`Microbiology:
`
`(I!) (4)
`
`(I'm. Antimicrobial effectiveness testing of
`at the lower specification limit demonstrated that it meets the USP<51> acceptance
`criteria.
`
`(I!) (4)
`
`The manufacturing processes were found to be adequate to assure microbiological quality.
`
`Device:
`
`Semaglutide is to be marketed in a PDSZ90 pen injector that will contain 1.5 mL of semaglutide
`1.34 mg/mL. Two pen injectors are proposed. The initial proposal was to have one pen injector
`labeled to deliver doses of 0.25 mg, 0.5 mg, or 1 mg and the other labeled to deliver doses of 1
`mg. Differences between the two pen injectors include the imprint on the drum displaying dose,
`the maximum dose stop, and color.
`
`The to—be-marketed device was not used in the phase 3 clinical trials, however, differences
`between the device are cosmetic and do not alter the fimction of the device.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NME’original BLA reviews)
`
`13
`
`Reference ID: 41 89360
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`The design and performance of the proposed pen injector were reviewed. The design
`verification and dose accuracy testing comply with ISO 11608-1.
`
`The assessment of the initial proposal identified user errors in selecting the correct pen injector.
`This was attributed to confusion from both pen injectors being labeled for administration of the 1
`mg dose. Dr. Susan Rimmel from the Division of Medication Errors Prevention and Analysis
`felt that this error could be corrected by either marketing a single pen injector or by relabeling
`the pen injectors such that the 1 mg dose could not be selected with the pen injector labeled for
`multiple dosage strengths. The applicant has opted to pursue the latter approach and has
`resubmitted the proposed devices such that one is labeled for delivery of 0.25 mg or 0.5 mg, and
`the other is labeled for delivery of the 1 mg dose only. In review of the changes, Dr. Rimmel
`believes that these are self-evident and that no additional data are required. Dr. Rimmel also has
`additional labeling recommendations to promote the safe use of the product and to mitigate any
`confusion. See Dr. Rimmel’s consult review for details.
`
`Dr. Sarah Mollo from the Center for Devices and Radiologic Health has reviewed the proposed
`device and the performance characteristics. Based on the provided device data, the design and
`performance review of the pen injector supports approval.
`
`Facilities:
`
`No preapproval inspections were conducted, but the application and inspectional documents
`were reviewed. Based on this review, the facilities reviewers did not identify any manufacturing
`or facility risks which would preclude approval of semaglutide.
`
`4. Nonclinical Pharmacology/Toxicology
`The review of the submitted nonclinical data was completed by Dr. Federica Basso. Findings
`from Dr. Basso’s review are summarized here. For detailed discussion, see Dr. Basso’s
`nonclinical review.
`
`Nonclinical pharmacology studies demonstrated that semaglutide binds to and activates the
`human GLP-1 receptor. In Wistar rats and diabetic db/db mice, this in turn led to an increase in
`glucose-stimulated plasma insulin, a decrease in blood glucose, and a decrease in body weight
`gain. Dose-related increases in glucose-dependent insulin secretion (along with decreases in
`glucose levels) were seen in rats, mice, and minipigs. Administration of semaglutide was also
`associated with reduced food intake.
`
`Semaglutide was well absorbed following subcutaneous injection with a bioavailability of 86%
`in monkeys. Binding to plasma protein was high with albumin being the primary binding site.
`Following injection, semaglutide is found primarily in plasma/blood. In pigmented rats,
`semaglutide was also found in the bile ducts. Metabolites of semaglutide make up only a small
`proportion of semaglutide related materials in the circulation. Urine and feces are the main
`excretion routes for semaglutide related materials. Low amounts of intact semaglutide were
`detected in the urine or feces.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`14
`
`Reference ID: 4189360
`
`

`

`NDA 209637 OZEMPIC (semaglutide)
`Cross Discipline Team Leader Review
`
`Toxicity studies of up to 3-, 6-, and 12-months duration were conducted in mice, rats, and
`monkeys, respectively. Dose-limiting reductions in food intake and body weight were seen in all
`species. Findings of C-cell hyperplasia were seen in mice starting at 17x the clinical exposure
`(MRHD). At 175x the clinical exposure, liver necrosis and centrilobular hypertrophy were
`observed in rats (primarily males). ECG abnormalities and myocardial vacuolation and
`degeneration were seen at 27x the clinical exposure. A no observed adverse effect level for
`cardiac effects was determined to be 5x the clinical exposure.
`
`Two-year carcinogenicity studies were conducted in mice and rats. The increase in the incidence
`of C-cell adenomas and carcinomas was seen in both species (at an exposure equal to the clinical
`exposure in rats, and at 2x and 5x the clinical exposure in female and male mice, respectively).
`C-cell carcinomas were increased in male rats starting at 0.7x the clinical exposure.
`
`Developmental and reproductive toxicology studies were conducted in rats, rabbits and monkeys.
`No effects were observed on male fertility. An increase in estrus cycle length and a reduction in
`the number of corpora lutea were observed in females. These findings were observed at the
`clinical exposure, and may be due to the pharmacologic effect of reducing food consumption and
`body weight. Decreases in maternal body weight gain, embryofetal growth retardation and
`mortality, and embryofetal skeletal and visceral malformations were observed in rats at clinical
`exposures. These may also be mediated by the pharmacologic effect on food consumption and
`body weight, though mechanistic studies showed that semaglutide causes embryotoxicity in rats
`through a GLP-1 receptor-me