CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`213051Orig1s000
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`CLINICAL REVIEW(S)
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`

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` Clinical Review
` Andreea Ondina Lungu
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` NDA 213051
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` Oral Semaglutide
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` CLINICAL REVIEW
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` Application Type New Drug Application
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` Application Number(s) 213051
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` Priority or Standard Priority
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` Submit Date(s) March 20, 2019
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` Received Date(s) March 20, 2019
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` PDUFA Goal Date September 20, 2019
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` Division/Office DMEP
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` Reviewer Name(s) Andreea Ondina Lungu
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` Review Completion Date September 18, 2019
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` Established/Proper Name Semaglutide
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` (Proposed) Trade Name Rybelsus
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` Applicant Novo Nordisk
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` Dosage Form(s) oral
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` Applicant Proposed Dosing
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` 7 mg, 14 mg, orally, once daily
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` Regimen(s)
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` Applicant Proposed
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` Indication(s)/Population(s)
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` Recommendation on
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` Regulatory Action
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` Recommended
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` Indication(s)/Population(s)
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` (if applicable)
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` Adjunct to diet and exercise to improve glycemic control in adults
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` with type 2 diabetes mellitus
` Approve
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` Adjunct to diet and exercise to improve glycemic control in adults
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` with type 2 diabetes mellitus
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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` 1
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`Reference ID: 4494441Reference ID: 4497378
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`

`

`
` Clinical Review
` Andreea Ondina Lungu
`
` NDA 213051
`
` Oral Semaglutide
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` Table of Contents
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` Glossary......................................................................................................................................... 14
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` 1. Executive Summary ............................................................................................................... 17
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` Product Introduction...................................................................................................... 17
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` Conclusions on the Substantial Evidence of Effectiveness ............................................ 17
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` Benefit-Risk Assessment ................................................................................................ 19
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` Patient Experience Data................................................................................................. 23
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` 2. Therapeutic Context .............................................................................................................. 23
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` Analysis of Condition...................................................................................................... 23
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` Analysis of Current Treatment Options ......................................................................... 23
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` 3. Regulatory Background ......................................................................................................... 24
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` U.S. Regulatory Actions and Marketing History............................................................. 24
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` Summary of Presubmission/Submission Regulatory Activity ........................................ 24
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` Foreign Regulatory Actions and Marketing History....................................................... 26
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` 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
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` Efficacy and Safety................................................................................................................. 26
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` Office of Scientific Investigations (OSI) .......................................................................... 26
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` Product Quality .............................................................................................................. 26
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` Clinical Microbiology ...................................................................................................... 27
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` Nonclinical Pharmacology/Toxicology ........................................................................... 27
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` Clinical Pharmacology .................................................................................................... 29
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` Devices and Companion Diagnostic Issues .................................................................... 30
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` Consumer Study Reviews ............................................................................................... 30
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` 5. Sources of Clinical Data and Review Strategy ....................................................................... 30
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` Table of Clinical Studies.................................................................................................. 30
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` Review Strategy.............................................................................................................. 35
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` 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 35
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` PIONEER 1 (4233) ........................................................................................................... 35
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` Study Design............................................................................................................ 35
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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`Reference ID: 4494441Reference ID: 4497378
`
`

`

`
` Clinical Review
` Andreea Ondina Lungu
`
` NDA 213051
`
` Oral Semaglutide
`
`
`
`
`
` Study Results........................................................................................................... 40
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` PIONEER 2 (4223) ........................................................................................................... 48
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` Study Design............................................................................................................ 48
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` Study Results........................................................................................................... 53
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` PIONEER 3 (4222) ........................................................................................................... 62
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` Study Design............................................................................................................ 62
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` Study Results........................................................................................................... 66
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` PIONEER 4 (4224) ........................................................................................................... 78
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` Study Design............................................................................................................ 78
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` Study Results........................................................................................................... 82
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` PIONEER 5 (4234) ........................................................................................................... 92
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` Study Design............................................................................................................ 92
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` Study Results........................................................................................................... 96
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` PIONEER 7 (4257) ......................................................................................................... 105
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` Study Design.......................................................................................................... 105
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` Study Results......................................................................................................... 110
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` PIONEER 8 (4280) ......................................................................................................... 119
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` Study Design.......................................................................................................... 119
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` Study Results......................................................................................................... 125
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` Integrated Review of Effectiveness ..................................................................................... 140
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` Assessment of Efficacy Across Trials ............................................................................ 140
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` Primary Endpoints................................................................................................. 140
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` Secondary and Other Endpoints ........................................................................... 142
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` Subpopulations ..................................................................................................... 145
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` Dose and Dose-Response...................................................................................... 145
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` Onset, Duration, and Durability of Efficacy Effects .............................................. 146
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` Additional Efficacy Considerations............................................................................... 146
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` Considerations on Benefit in the Postmarket Setting .......................................... 146
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` Other Relevant Benefits........................................................................................ 146
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` Integrated Assessment of Effectiveness ...................................................................... 147
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`7.
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` 8. Review of Safety .................................................................................................................. 148
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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`Reference ID: 4494441Reference ID: 4497378
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`

`

`
` Clinical Review
` Andreea Ondina Lungu
`
` NDA 213051
`
` Oral Semaglutide
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` Safety Review Approach .............................................................................................. 148
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` Review of the Safety Database .................................................................................... 151
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` Overall Exposure ................................................................................................... 151
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` Relevant characteristics of the safety population:............................................... 153
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` Adequacy of the safety database ......................................................................... 157
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` !βζ̣͍ΚΨ͟ ̕π !̡̡̇ϵΨΚ̲̎ϳ̨ ̇ϵ̎ϵΨΚ̇ ϶Κπζ̲͟ !̨̨ζ̨̨̍ζ̨̲̎.................................................. 157
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` Issues Regarding Data Integrity and Submission Quality ..................................... 157
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` Categorization of Adverse Events ......................................................................... 158
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` Routine Clinical Tests ............................................................................................ 162
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` Safety Results ............................................................................................................... 163
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` Deaths ................................................................................................................... 163
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` Serious Adverse Events......................................................................................... 168
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` Dropouts and/or Discontinuations Due to Adverse Effects ................................. 172
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` Significant Adverse Events .................................................................................... 176
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` Treatment Emergent Adverse Events and Adverse Reactions ............................. 179
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` Laboratory Findings .............................................................................................. 187
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` Vital Signs .............................................................................................................. 187
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` Electrocardiograms (ECGs).................................................................................... 190
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` QT.......................................................................................................................... 191
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` Immunogenicity............................................................................................. 192
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` Analysis of Submission-Specific Safety Issues.............................................................. 192
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` Gastrointestinal disorders..................................................................................... 192
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` Renal Disorders ..................................................................................................... 194
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` Hepatic Disorders.................................................................................................. 199
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` Gallbladder-related Disorders .............................................................................. 204
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` Pancreatitis ........................................................................................................... 206
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` Cardiovascular Adverse Events............................................................................. 213
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` Neoplasms............................................................................................................. 218
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` Hypoglycemia........................................................................................................ 228
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` Diabetic Retinopathy ............................................................................................ 233
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` Lactic acidosis........................................................................................................ 239
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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` 4
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`Reference ID: 4494441Reference ID: 4497378
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`

`

`
` Clinical Review
` Andreea Ondina Lungu
`
` NDA 213051
`
` Oral Semaglutide
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` Immunogenicity .................................................................................................... 243
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` Creatine Kinase ..................................................................................................... 247
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` Hypovolemia ......................................................................................................... 248
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` 4 Month Safety Update................................................................................................ 249
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` Safety Analyses by Demographic Subgroups ............................................................... 250
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` Sex ........................................................................................................................ 251
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` Age........................................................................................................................ 252
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` Race...................................................................................................................... 256
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` Ethnicity .............................................................................................................. 257
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` Weight ................................................................................................................. 258
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` Baseline renal function.................................................................................... 259
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` Geographic region............................................................................................. 261
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` Antidiabetic background medication ........................................................... 263
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` Specific Safety Studies/Clinical Trials ........................................................................... 265
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` Additional Safety Explorations ..................................................................................... 265
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` Human Carcinogenicity or Tumor Development .................................................. 265
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` Human Reproduction and Pregnancy................................................................... 266
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` Pediatrics and Assessment of Effects on Growth ................................................. 267
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` Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 267
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` Safety Concerns Identified Through Postmarket Experience............................... 268
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` Expectations on Safety in the Postmarket Setting ............................................... 268
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` Additional Safety Issues From Other Disciplines .................................................. 268
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` Integrated Assessment of Safety.............................................................................. 268
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` 9. Advisory Committee Meeting and Other External Consultations....................................... 271
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` 10. Labeling Recommendations ................................................................................................ 271
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` Prescription Drug Labeling ....................................................................................... 272
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` Nonprescription Drug Labeling................................................................................. 273
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` 11. Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 273
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` 12. Postmarketing Requirements and Commitments............................................................... 274
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` 13. Appendices .......................................................................................................................... 274
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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` 5
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`Reference ID: 4494441Reference ID: 4497378
`
`

`

`
` Clinical Review
`
` Andreea Ondina Lungu
`
`
` NDA 213051
`
`
` Oral Semaglutide
`
`
`
`
`
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` References ................................................................................................................ 274
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` MedDRA Queries used for the safety analyses ........................................................ 274
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` Financial Disclosure .................................................................................................. 279
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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`Reference ID: 4494441Reference ID: 4497378
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` 6
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`

`
` Clinical Review
`
` Andreea Ondina Lungu
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` NDA 213051
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`
` Oral Semaglutide
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` Table of Tables
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` Table 1 Background Therapies...................................................................................................... 32
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` Table 2 Listing of Clinical Trials ..................................................................................................... 32
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` Table 3 Dose Escalation and Treatment Periods .......................................................................... 37
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` Table 4 Statistical Testing Hierarchy............................................................................................. 39
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` Table 5 Patient Disposition PIONEER 1......................................................................................... 41
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` Table 6 Summary of Important Site-Level and Patient-Level Protocol Deviations PIONEER 1 .... 42
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` Table 7 Demographics and Baseline Characteristics ̌ Continuous Variables, PIONEER 1........... 43
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` Table 8 Demographics and Baseline Characteristics for Categorical Variables ̌ PIONEER 1 ...... 44
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` Table 9 Additional Anti-Diabetic Medication and Rescue Medication PIONEER 1 ...................... 45
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` Table 10 Primary and Confirmatory Secondary Endpoints ̌ Primary Statistical Analyses ̌
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` Treatment Policy Estimand, PIONEER 1........................................................................................ 46
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` Table 11 Patient Disposition PIONEER 2....................................................................................... 54
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` Table 12 Important Site and Patient-Level Protocol Deviations, PIONEER 2 ............................... 55
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` Table 13 Baseline Characteristics and Demographics ̌ Continuous Variables PIONEER 2.......... 56
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` Table 14 Baseline Characteristics and Demographics ̌ Categorical Variables ̌ PIONEER 2 ....... 57
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` Table 15 Additional Anti-Diabetic Medication and Rescue Medication at week 26 and 52 ̌
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` PIONEER 2 ..................................................................................................................................... 59
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` Table 16 Primary and Confirmatory Secondary Endpoints ̌ PIONEER 2 ..................................... 60
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` Table 17 Amendments to the Protocol PIONEER 3 ...................................................................... 66
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` Table 18 Patient Disposition Summary PIONEER 3....................................................................... 68
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` Table 19 Summary of Important Site and Patient-Level Protocol Deviations PIONEER 3............ 70
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` Table 20 Demographics and Baseline Characteristics for Continuous Variables ̌ PIONEER 3 .... 71
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` Table 21 Demographics and Baseline Characteristics for Categorical Variables ̌ PIONEER 3 .... 72
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` Table 22 Additional Concomitant Anti-Diabetic Medication and Rescue Medication at Weeks 26,
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` 52 and 78 ...................................................................................................................................... 74
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` Table 23 Primary and confirmatory secondary endpoints ̌ PIONEER 3 ...................................... 75
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` Table 24 Patients Disposition PIONEER 4 ..................................................................................... 83
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` Table 25 Summary of Important Site-Level and Patient-Level Protocol Deviations .................... 85
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` Table 26 Baseline Characteristics and Demographics ̌ Continuous Variables ̌ PIONEER 4....... 86
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` Table 27 Demographics and Baseline Characteristics for Categorical Variables ̌ PIONEER 4 .... 87
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` Table 28 Additional Anti-Diabetic Medication and Rescue Medication PIONEER 4 .................... 89
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` Table 29 HbA1c ̌ Primary Statistical Analysis ̌ FAS ̌ PIONEER 4 ............................................... 90
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` Table 30 Amendments to the Protocol PIONEER 5 ...................................................................... 95
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` Table 31 Patient Disposition PIONEER 5....................................................................................... 98
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` Table 32 Summary of important site-level and patient-level protocol deviations ...................... 99
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` Table 33 Selected Demographics and Baseline Characteristics for Continuous Variables ­
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` PIONEER 5 ................................................................................................................................... 100
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` Table 34 Selected Demographics and Baseline Characteristics for Categorical Variables ­
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` PIONEER 5 ................................................................................................................................... 101
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` Table 35 Additional Anti-Diabetic Medication and Rescue Medication PIONEER 5 .................. 103
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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`Reference ID: 4494441Reference ID: 4497378
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` 7
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`

`

`
`
`
` Clinical Review
`
` Andreea Ondina Lungu
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`
` NDA 213051
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`
` Oral Semaglutide
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`
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` Table 36 Primary and Confirmatory Secondary Endpoints ̌ PIONEER 5 ................................... 103
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` Table 37 Amendments to the Protocol PIONEER 7 .................................................................... 109
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` Table 38 Patient Disposition PIONEER 7..................................................................................... 111
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` Table 39 Site- and Patient-Level PDs ̌ PIONEER 7 ..................................................................... 113
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` Table 40 Baseline Characteristics and Demographics ̌ Continuous Variables ̌ FAS ................ 114
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` Table 41 Baseline Characteristics and Demographics ̌ Categorical Variables ̌PIONEER 7 ...... 114
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` Table 42 Additional Anti-Diabetic Medication and Rescue Medication PIONEER 7 .................. 117
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` Table 43 Primary and Confirmatory Secondary Endpoints ̌PIONEER 7 .................................... 117
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` Table 44 Concomitant Non-Insulin Anti-Diabetic Medication Ongoing at Screening and
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` Randomization PIONEER 8.......................................................................................................... 121
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` Table 45 Increase in Insulin Dose Guidelines.............................................................................. 122
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` Table 46 Decrease in Insulin Dose Guidelines ............................................................................ 123
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` Table 47 Protocol Amendments PIONEER 8 ............................................................................... 125
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` Table 48 Patient Disposition ̌ PIONEER 8 .................................................................................. 127
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` Table 49 Site and Patient-Level Protocol Deviations PIONEER 8................................................ 129
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` Table 50 Selected Demographics and Baseline Characteristics for Continuous Variables ̌ FAS ̌
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` PIONEER 8 ................................................................................................................................... 130
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` Table 51 Selected Demographics and Baseline Characteristics for Categorical Variables ̌ FAS ̌
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` PIONEER 8 ................................................................................................................................... 131
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` Table 52 Concomitant Non-Insulin Anti-Diabetic Medication Ongoing at Screening and
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` Randomization ̌ PIONEER 8 ....................................................................................................... 133
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` Table 53 Concomitant Insulin at Screening and Randomization ̌ PIONEER 8........................... 133
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` Table 54 Insulin Dose at Screening by Insulin Treatment ̌ PIONEER 8 ..................................... 134
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` Table 55 Additional Anti-Diabetic Medication and Rescue Medication Initiated Prior to Week 26
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` ̌ PIONEER 8 ................................................................................................................................ 135
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` Table 56 Additional Anti-Diabetic Medication and Rescue Medication Initiated Prior to Week 52
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` ̌ PIONEER 8 ................................................................................................................................ 136
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` Table 57 Primary and Confirmatory Secondary Endpoints ̌ PIONEER 8 ................................... 136
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` Table 58 Confirmatory Analyses of Change from Baseline in HbA1c (%) ̌ PIONEER 1-5 and 8 140
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` Table 59 Confirmatory Analyses of Change from Baseline in Body Weight (kg) ̌ PIONEER 1-5, 7,
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` and 8 ........................................................................................................................................... 143
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` Table 60 Key Trial Designs for the Phase 3 Trials........................................................................ 148
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` Table 61 Phase 3 trials Contributing to Different Pools ............................................................. 151
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` Table 62 Total Exposure ̌ Phase 3a Trials and Pools ................................................................. 152
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` Table 63 Duration of Exposure ̌ PIONEER 6 ̌ FAS .................................................................... 153
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` Table 64 Patient Disposition ̌ Phase 3a Trials and Pools........................................................... 154
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` Table 65 Patient Disposition Overview Phase 3 Pool SAS .......................................................... 155
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` Table 66 Patient Disposition Placebo Pool SAS .......................................................................... 156
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` Table 67 Patient Disposition PIONEER 6..................................................................................... 156
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` Table 68 AEs with Additional Data Collection and/or in Scope for Event Adjudication............. 158
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` Table 69 Hypoglycemia Definition .............................................................................................. 161
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` Table 70 Clinical Laboratories ..................................................................................................... 161
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` CDER Clinical Review Template
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` Version date: September 6, 2017 for all NDAs and BLAs
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` 8
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`Reference ID: 4494441Reference ID: 4497378
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`

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` Clinical Review
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` Andreea Ondina Lungu
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` NDA 213051
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` Oral Semaglutide
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` Table 71 Deaths by Trial ̌ Phase 3a Pool ................................................................................... 163
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` Table 72 Total Deaths and EAC-Confirmed Deaths in the Phase 3a Pool and Placebo Pool...... 164
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` Table 73 Deaths in the Phase 3a Pool by SOC and PT ̌ In-Trial ................................................. 165
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` Table 74 EAC-Confirmed Deaths ̌ Phase 3a Pool ̌ In-Trial ....................................................... 166
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` Table 75 Deaths by SOC and PT ̌ PIONEER 6 ............................................................................. 166
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` Table 76 EAC-Confirmed Deaths ̌ PIONEER 6............................................................................ 168
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` Table 77 Total SAEs ̌ Phase 3a Pool, Placebo Pool and PIONEER 6 ̌ On-Treatment................ 169
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` ϼΚΧ̇ζ ϳϴ ϶!Ę Rζ̡̤̲̕ζβ Χ͟ ш΄ϰϮ% ̕π PΚ̲ϵζ̨̲̎ Χ͟ ϶O Κ̎β Pϼ ̌ Phase 3a Pool ̌ On-Treatment
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` ϼΚΧ̇ζ ϳϵ ϶!Ę Rζ̡̤̲̕ζβ Χ͟ ш΄ϰϱ% ̕π PΚ̲ϵζ̨̲̎ Χ͟ ϶O Κ̎β Pϼ - PIONEER 6 ̌ On-Treatment .... 171
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` Table 80 Overview of AEs Leading to Permanent Premature Trial Product Discontinuation ̌
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` Phase 3a Pool, Placebo Pool and PIONEER 6 ̌ On-Treatment................................................... 173
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` ϼΚΧ̇ζ ϴϭ !Ę ̖ш΄ϰϮ %̗ щζΚβϵ̎Ϩ ̲̕ Pζ̤̍Κ̎ζ̲̎ ϼ̤ϵΚ̇ P̤̕β͍Ψ̲ Dϵ̨Ψ̲̎̕ϵ͍̎Κ̲ϵ̎̕ Χ͟ ϶O Κ̎β Pϼ ̌
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` Phase 3a Pool ̌ On-Treatment................................................................................................... 174
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` ϼΚΧ̇ζ ϴϮ !Ę ̖ш΄ϰϮ %̗ щζΚβϵ̎Ϩ ̲̕ Pζ̤̍Κ̎ζ̲̎ ϼ̤ϵΚ̇ P̤̕β͍Ψ̲ Dϵ̨Ψ̲̎̕ϵ͍̎Κ̲ϵ̎̕ by SOC and PT ̌
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` PIONEER 6 ̌ On-Treatment ........................................................................................................ 175
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` Table 83 Overview of AEs Leading to Premature Treatment Discontinuation by Dose ̌ PIONEER
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` 3 and Placebo Dose Pool ̌ On-Treatment.................................................................................. 176
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` Table 84 Adverse Events by Severity and Outcome ̌ Phase 3a Pool......................................... 177
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` Table 85 Adverse Events by Severity and Outcome ̌ Placebo Pool .......................................... 178
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` Table 86 SAEs by Severity and Outcome ̌ PIONEER 6 ............................................