CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`209637Orig1s000
`
`CLINICAL REVIEW(S)
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`

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`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`CLINICAL REVIEW
`Application Type New Drug Application
`Application Number(s) 209637
`Priority or Standard Standard
`Submit Date(s) December 5, 2016
`Received Date(s) December 5, 2016
`PDUFA Goal Date December 5, 2017
`Division/Office DMEP
`Reviewer Name(s) Andreea Ondina Lungu
`Review Completion Date November 22, 2017
`Established/Proper Name Semaglutide
`(Proposed) Trade Name Ozempic
`Applicant Novo Nordisk
`Dosage Form(s) Subcutaneous injection
`Applicant Proposed Dosing
`0.5 mg and 1 mg once weekly
`Regimen(s)
`Applicant Proposed
`Indication(s)/Population(s)
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus
`Approve
`
`Adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`1
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`Table of Contents
`
`Glossary ........................................................................................................................................19
`
`1.
`
`Executive Summary...............................................................................................................22
`1.1.
`Product Introduction......................................................................................................22
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness.............................................22
`1.3.
`Benefit-Risk Assessment ................................................................................................23
`1.4.
`Patient Experience Data.................................................................................................27
`
`2.
`
`Therapeutic Context..............................................................................................................27
`2.1. Analysis of Condition......................................................................................................27
`2.2. Analysis of Current Treatment Options .........................................................................27
`
`3. Regulatory Background .........................................................................................................28
`3.1. U.S. Regulatory Actions and Marketing History.............................................................28
`3.2.
`Summary of Presubmission/Submission Regulatory Activity ........................................28
`3.3.
`Foreign Regulatory Actions and Marketing History .......................................................29
`
`4.
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................29
`4.1. Office of Scientific Investigations (OSI) ..........................................................................30
`4.2.
`Product Quality ..............................................................................................................31
`4.3.
`Clinical Microbiology......................................................................................................31
`4.4. Nonclinical Pharmacology/Toxicology ...........................................................................31
`4.5.
`Clinical Pharmacology ....................................................................................................33
`4.6. Devices and Companion Diagnostic Issues ....................................................................34
`4.7.
`Consumer Study Reviews...............................................................................................34
`
`5.
`
`Sources of Clinical Data and Review Strategy .......................................................................34
`5.1.
`Table of Clinical Studies .................................................................................................34
`5.2.
`Review Strategy .............................................................................................................39
`
`6. Review of Relevant Individual Trials Used to Support Efficacy .............................................39
`6.1.
`Study 3623 – SUSTAIN 1.................................................................................................39
`6.1.1. Study Design ...........................................................................................................39
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`2
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`6.2.
`
`6.3.
`
`6.4.
`
`6.5.
`
`6.6.
`
`6.1.2. Study Results ..........................................................................................................46
`Study 3626 – SUSTAIN 2.................................................................................................57
`6.2.1. Study Design ...........................................................................................................57
`6.2.2. Study Results ..........................................................................................................64
`Study 3624 – SUSTAIN 3.................................................................................................73
`6.3.1. Study Design ...........................................................................................................73
`6.3.2. Study Results ..........................................................................................................78
`Study 3625 – SUSTAIN 4.................................................................................................89
`6.4.1. Study Design ...........................................................................................................89
`6.4.2. Study Results ..........................................................................................................96
`Study 3627 – SUSTAIN 5...............................................................................................113
`6.5.1. Study Design .........................................................................................................113
`6.5.2. Study Results ........................................................................................................119
`Study 3744 – SUSTAIN 6...............................................................................................142
`6.6.1. Study Design .........................................................................................................142
`6.6.2. Study Results ........................................................................................................159
`
`7.
`
`Integrated Review of Effectiveness.....................................................................................206
`7.1. Assessment of Efficacy Across Trials............................................................................206
`7.1.1. Primary Endpoints ................................................................................................206
`7.1.2. Secondary and Other Endpoints...........................................................................209
`7.1.3. Subpopulations.....................................................................................................216
`7.1.4. Dose and Dose-Response .....................................................................................216
`7.1.5. Onset, Duration, and Durability of Efficacy Effects...............................................217
`7.2. Additional Efficacy Considerations...............................................................................217
`7.2.1. Considerations on Benefit in the Postmarket Setting...........................................217
`7.2.2. Other Relevant Benefits........................................................................................217
`Integrated Assessment of Effectiveness ......................................................................218
`
`7.3.
`
`8. Review of Safety..................................................................................................................219
`8.1.
`Safety Review Approach ..............................................................................................219
`8.2.
`Review of the Safety Database ....................................................................................221
`8.2.1. Overall Exposure...................................................................................................222
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`3
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`8.4.
`
`8.2.2. Relevant characteristics of the safety population: ...............................................224
`8.2.3. Adequacy of the safety database: ........................................................................226
`8.3. Adequacy of Applicant’s Clinical Safety Assessments..................................................227
`8.3.1. Issues Regarding Data Integrity and Submission Quality......................................227
`8.3.2. Categorization of Adverse Events.........................................................................227
`8.3.3. Routine Clinical Tests............................................................................................232
`Safety Results...............................................................................................................232
`8.4.1. Deaths...................................................................................................................232
`8.4.2. Serious Adverse Events.........................................................................................235
`8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects..................................241
`8.4.4. Significant Adverse Events....................................................................................248
`8.4.5. Treatment Emergent Adverse Events and Adverse Reactions .............................251
`8.4.6. Laboratory Findings ..............................................................................................295
`8.4.7. Vital Signs..............................................................................................................296
`8.4.8. Electrocardiograms (ECGs) ...................................................................................300
`8.4.9. QT .........................................................................................................................309
`8.4.10.
`Immunogenicity.............................................................................................310
`8.5. Analysis of Submission-Specific Safety Issues ..............................................................310
`8.5.1. Cardiovascular Adverse Events.............................................................................310
`8.5.2. Diabetic Retinopathy ............................................................................................320
`8.5.3. Diabetic Nephropathy...........................................................................................338
`8.5.4. Acute renal Failure................................................................................................343
`8.5.5. Pancreatitis ...........................................................................................................350
`8.5.6. Gallbladder-related Disorders ..............................................................................366
`8.5.7. Neoplasms ............................................................................................................372
`8.5.8. Thyroid neoplasms................................................................................................382
`8.5.9. Hypoglycemia .......................................................................................................388
`8.5.10.
`Immunogenicity.............................................................................................395
`4 Month Safety Update................................................................................................406
`Safety Analyses by Demographic Subgroups ...............................................................411
`
`8.6.
`8.7.
`
`8.7.1.Sex ........................................................................................................................412
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`4
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`8.7.2.Age........................................................................................................................413
`8.7.3.Race......................................................................................................................415
`8.7.4.Ethnicity...............................................................................................................417
`8.7.5.Baseline CV history .............................................................................................419
`8.7.6.Baseline renal function .......................................................................................420
`8.7.7.Geographic region...............................................................................................420
`8.7.8.Antidiabetic background medication ................................................................422
`
`Specific Safety Studies/Clinical Trials ...........................................................................423
`8.8.
`8.9. Additional Safety Explorations.....................................................................................423
`8.9.1. Human Carcinogenicity or Tumor Development ..................................................423
`8.9.2. Human Reproduction and Pregnancy...................................................................424
`8.9.3. Pediatrics and Assessment of Effects on Growth .................................................426
`8.9.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound ..............................426
`8.9.5. Safety Concerns Identified Through Postmarket Experience ...............................427
`8.9.6. Expectations on Safety in the Postmarket Setting................................................427
`8.9.7. Additional Safety Issues From Other Disciplines ..................................................428
`8.10.
`Integrated Assessment of Safety..............................................................................428
`
`9. Advisory Committee Meeting and Other External Consultations .......................................430
`
`10. Labeling Recommendations ................................................................................................434
`10.1.
`Prescription Drug Labeling .......................................................................................434
`10.2.
`Nonprescription Drug Labeling.................................................................................436
`
`11. Risk Evaluation and Mitigation Strategies (REMS) ..............................................................437
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`12. Postmarketing Requirements and Commitments...............................................................437
`
`13. Appendices..........................................................................................................................437
`13.1.
`References................................................................................................................438
`13.2. MedDRA Queries used for the safety analyses ........................................................438
`13.3.
`Financial Disclosure ..................................................................................................445
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`5
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`Table of Tables
`
`Table 1 Listing of Clinical Trials.....................................................................................................35
`Table 2 Trial Flowchart SUSTAIN 1................................................................................................41
`Table 3 Patient Disposition Summary SUSTAIN 1.........................................................................46
`Table 4 Demographics and Baseline Characteristics for Categorical Variables - FAS – SUSTAIN 1
`......................................................................................................................................................47
`Table 5 Demographics and Baseline Characteristics for Continuous Variables - FAS – SUSTAIN 1
`......................................................................................................................................................49
`Table 6 HbA1c – Primary Statistical Analysis- FAS - SUSTAIN 1 ....................................................51
`Table 7 HbA1c - “In Trial” Observation Period – FAS – SUSTAIN 1 ...............................................53
`Table 8 Patients Achieving Various HbA1c Targets at Week 30- FAS – SUSTAIN 1.......................55
`Table 9 Dose Escalation Regimen SUSTAIN 2 ...............................................................................58
`Table 10 Protocol Amendments SUSTAIN 2 .................................................................................62
`Table 11 Patient Disposition SUSTAIN 2 .......................................................................................64
`Table 12 Summary of Important Protocol Deviations SUSTAIN 2 ................................................65
`Table 13 Demographics and Baseline Characteristics for Categorical Variables – FAS- SUSTAIN 2
`......................................................................................................................................................66
`Table 14 Demographics and Baseline Characteristics for Continuous Variables – FAS- SUSTAIN 2
`......................................................................................................................................................67
`Table 15 Mean HbA1c Changes at 56 Weeks – FAS – SUSTAIN 2.................................................69
`Table 16 Body Weight Changes from Baseline to Week 56 – FAS – SUSTAIN 2 ...........................70
`Table 17 Patients Achieving Various HbA1c Targets at Week 56 – FAS – SUSTAIN 2...................71
`Table 18 Trial Flow Chart SUSTAIN 3 ............................................................................................75
`Table 19 Amendments to the Protocol SUSTAIN 3.......................................................................77
`Table 20 Patient Disposition Summary SUSTAIN 3.......................................................................79
`Table 21 Summary of Important Patient-Level Protocol Deviations SUSTAIN 3 ..........................81
`Table 22 Demographics and Baseline Characteristics for Categorical Variables – FAS – SUSTAIN 3
`......................................................................................................................................................82
`Table 23 Demographics and Baseline Characteristics for Continuous Variables– FAS – SUSTAIN 3
`......................................................................................................................................................83
`Table 24 Change in HbA1c from Baseline to Week 56 SUSTAIN 3................................................86
`Table 25 Recommended Insulin Titration SUSTAIN 4...................................................................90
`Table 26 Dose-Escalation Regimen SUSTAIN 4.............................................................................91
`Table 27 Study Procedures SUSTAIN 4 .........................................................................................92
`Table 28 Protocol Amendments SUSTAIN 4 .................................................................................95
`Table 29 Patients Disposition SUSTAIN 4......................................................................................96
`Table 30 Summary of Important Protocol Deviations at Patient Level SUSTAIN 4.......................97
`Table 31 Demographics and Baseline Characteristics for Categorical Variables – FAS – SUSTAIN 4
`......................................................................................................................................................99
`Table 32 Demographics and Baseline Characteristics for Continuous Variables – FAS – SUSTAIN 4
`....................................................................................................................................................100
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`6
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`Table 33 Common Concomitant Illnesses at Baseline SUSTAIN 4 ..............................................101
`Table 34 Frequently Used Concomitant Medications at Baseline SUSTAIN 4 ............................101
`Table 35 HbA1c – Primary Statistical Analysis – FAS – SUSTAIN 4..............................................103
`Table 36 Patients Achieving HbA1c Response after 30 Weeks of Treatment – FAS – SUSTAIN 4
`....................................................................................................................................................104
`Table 37 Change in Body Weight – SUSTAIN 4 ...........................................................................106
`Table 38 Fasting Plasma Glucose – SUSTAIN 4 ...........................................................................107
`Table 39 Systolic Blood Pressure – –FAS – SUSTAIN 4................................................................109
`Table 40 Study Treatments SUSTAIN 5.......................................................................................114
`Table 41 Trial Procedures SUSTAIN 5 .........................................................................................115
`Table 42 Insulin Titration (HbA1c <8%) SUSTAIN 5.....................................................................116
`Table 43 Insulin Down-Titration SUSTAIN 5 ...............................................................................116
`Table 44 Protocol Amendments SUSTAIN 5 ...............................................................................118
`Table 45 Patient Disposition SUSTAIN 5 .....................................................................................119
`Table 46 Observation Periods and Treatment Duration - FAS – SUSTAIN 5 ...............................120
`Table 47 Summary of Important Protocol Deviations at Site Level and Patient Level SUSTAIN 5
`....................................................................................................................................................122
`Table 48 Selected Demographics and Baseline Characteristics for Categorical Variables - FAS –
`SUSTAIN 5...................................................................................................................................125
`Table 49 Selected Demographics and Baseline Characteristics for Continuous Variables - FAS –
`SUSTAIN 5...................................................................................................................................126
`Table 50 Selected Medical History SUSTAIN 5............................................................................126
`Table 51 Baseline Funduscopy Results .......................................................................................127
`Table 52 History of Gallbladder Disease at Screening SUSTAIN 5 ..............................................128
`Table 53 Basal Insulin Dosing at Baseline – FAS – SUSTAIN 5.....................................................129
`Table 54 Selected Other Concomitant Medications SUSTAIN 5 .................................................129
`Table 55 HbA1c (%) - Primary Statistical Analysis - FAS – SUSTAIN 5 .........................................131
`Table 56 Body Weight - FAS – SUSTAIN 5...................................................................................133
`Table 57 Patients Achieving HbA1c Response after 30 Weeks of Treatment – FAS – SUSTAIN 5
`....................................................................................................................................................135
`Table 58 Patients Achieving Weight Loss Targets after 30 Weeks of Treatment – FAS – SUSTAIN
`5..................................................................................................................................................136
`Table 59 Insulin Dose (Geometric Mean) by Treatment Arm and Treatment Week – FAS-
`SUSTAIN 5...................................................................................................................................138
`Table 60 Blood Pressure Change from Baseline to Week 30 – FAS – SUSTAIN 5 .......................139
`Table 61 Study Flowchart SUSTAIN 6 .........................................................................................145
`Table 62 Additional Visits SUSTAIN 6 .........................................................................................146
`Table 63 Medical Events of Special Interest SUSTAIN 6 .............................................................148
`Table 64 Adjudicated Adverse Events SUSTAIN 6.......................................................................149
`Table 65 Assumptions Regarding Expected Number of Events SUSTAIN 6 ................................153
`Table 66 Protocol Amendments SUSTAIN 6 ...............................................................................157
`Table 67 Patient Disposition – All Randomized Patients – SUSTAIN 6 .......................................160
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`7
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`Table 68 Summary of Important Protocol Deviations at Site and Patient Level SUSTAIN 6.......163
`Table 69 Patients Receiving the Wrong Trial Product/DUN SUSTAIN 6 .....................................164
`Table 70 Selected Demographics and Baseline Characteristics for Continuous Variables – FAS –
`SUSTAIN 6...................................................................................................................................168
`Table 71 Selected Demographics and Baseline Characteristics for Categorical Variables – FAS –
`SUSTAIN 6...................................................................................................................................169
`Table 72 Baseline Funduscopy Results SUSTAIN 6 .....................................................................170
`Table 73 Total Number of Patients Fulfilling the Inclusion Criteria by Evidence of CV Disease –
`FAS – SUSTAIN 6 .........................................................................................................................171
`Table 74 History of Cardiovascular Disease at Screening – FAS – SUSTAIN 6.............................172
`Table 75 Vital Signs at Baseline – FAS- SUSTAIN 6......................................................................173
`Table 76 Diabetes Complications at Baseline SUSTAIN 6 ...........................................................174
`Table 77 History of Pancreatitis and Gallbladder Disease at Screening – FAS – SUSTAIN 6.......175
`Table 78 Cardiovascular Medication Ongoing at Baseline – FAS – SUSTAIN 6 ...........................176
`Table 79 Additional Cardiovascular Medication During the Trial – FAS – SUSTAIN 6.................177
`Table 80 Insulin and SU Therapy at Baseline – FAS – SUSTAIN 6................................................178
`Table 81 Additional Diabetes Medication During the Trial – FAS – SUSTAIN 6 ..........................179
`Table 82 EAC-Confirmed First MACE - FAS In-Trial SUSTAIN 6 ...................................................180
`Table 83 Time to First EAC-Confirmed MACE, Pre-Defined Test for Non-Inferiority and Post Hoc
`Test of Superiority; Semaglutide Versus Placebo - FAS In-Trial..................................................182
`Table 84 EAC-Confirmed First MACE, Semaglutide by Dose Versus Placebo - FAS In-Trial –
`SUSTAIN 6...................................................................................................................................182
`Table 85 Expanded Cardiovascular Composite Endpoint (all events), Semaglutide Versus Placebo
`- FAS In-Trial – SUSTAIN 6...........................................................................................................184
`Table 86 First Events for Expanded Cardiovascular Composite Endpoint, Semaglutide Versus
`Placebo - FAS In-Trial – SUSTAIN 6 .............................................................................................185
`Table 87 First and All Expanded Cardiovascular Composite Endpoint, Semaglutide by Dose
`Versus Placebo - FAS In-Trial- SUSTAIN 6 ...................................................................................186
`Table 88 HbA1c - Statistical Analysis - MMRM – FAS In-Trial – SUSTAIN 6 ................................193
`Table 89 Patients Achieving HbA1c Response after 104 Weeks - FAS In-Trial – SUSTAIN 6.......194
`Table 90 Additional Diabetes Medication During the Trial – FAS – SUSTAIN 6 ..........................195
`Table 91 Body Weight - Confirmatory Statistical Analysis - MMRM – FAS In-Trial – SUSTAIN 6196
`Table 92 Patients Achieving Weight Loss Response After 104 Weeks - FAS In-Trial - SUSTAIN 6
`....................................................................................................................................................197
`Table 93 EAC-Confirmed MACE (All Events) – FAS In-Trial – SUSTAIN 6.....................................204
`Table 94 EAC- Confirmed MACE Reported After End of In-Trial Observation Period – FAS –
`SUSTAIN 6...................................................................................................................................204
`Table 95 Statistical Testing of HbA1c (%−Point) Change from Baseline to End-of-Treatment...207
`Table 96 Grouping and Pooling of Phase 3 Trials .......................................................................220
`Table 97 Observation Periods CVOT...........................................................................................221
`Table 98 Exposure by Subgroup Variables – SAS On-Treatment – CVOT ...................................222
`Table 99 Phase 3 Pool Exposure by Study ..................................................................................222
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`8
`
`Reference ID: 4186415
`
`

`

`Clinical Review
`Andreea Ondina Lungu
`NDA 209637
`Ozempic (semaglutide)
`
`Table 100 Exposure – Placebo Pool............................................................................................223
`Table 101 Subject Disposition - CVOT.........................................................................................223
`Table 102 Subject Disposition – Phase 3 excluding CVOT ..........................................................224
`Table 103 Medical Events of Special Interest.............................................................................228
`Table 104 Adjudicated Events ....................................................................................................230
`Table 105 All-Cause Death by SOC and Treatment Arm, CVOT ..................................................232
`Table 106 Deaths – Phase 3 Trials Excluding CVOT ....................................................................234
`Table 107 SAEs CVOT On Treatment ..........................................................................................235
`Table 108 Serious Adverse Events by SOC and Preferred Term Reported by ≥1.0% of Patients in
`Any Arm – SAS On-Treatment - CVOT ........................................................................................236
`Table 109 SAEs- Phase 3 Pool .....................................................................................................237
`Table 110 SAEs (≥0.2% of patients) by Sy