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`
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`CENTER FOR DRUG EVALUATION AND
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`
`RESEARCH
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` APPLICATION NUMBER:
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`212028Orig1s000
`
`
` MULTI-DISCIPLINE REVIEW
`
`Summary Review
`
`Office Director
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`
`Cross Discipline Team Leader Review
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`Clinical Review
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`Non-Clinical Review
`
`Statistical Review
`
`Clinical Pharmacology Review
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`Page 1 of 386
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`EISAI EXHIBIT 1038
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`

`

` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
`
`
`
`
`
` NDA/BLA Multi-Disciplinary Review and Evaluation
`
`
`
` Application Type NDA
`
`
` Application Number(s) 212028
`
`
` Priority or Standard Standard
`
`
`
` Submit Date(s) 12/27/2018
`
`
` Received Date(s) 12/27/2018
`
`
` PDUFA Goal Date 12/27/2019
`
`
` Division/Office DP/ODE-I
`
`
` Review Completion Date 12/20/2019
`
`
` Established/Proper Name Lemborexant
`
`
` (Proposed) Trade Name DAYVIGO
`
`
`
` Pharmacologic Class Orexin receptor antagonist
`
`
`
` Chemical Name
`
`(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3­
`
` fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide
`
` Applicant Eisai Inc.
`
`
` Dosage Form Tablet
`
`
` Applicant proposed Dosing
`
` 5 to 10 mg by mouth nightly before bedtime
`
`
` Regimen
`
` Applicant Proposed
`
`
` Indication(s)/Population(s)
`
`
`
`
`
`
`
`
` Treatment of insomnia, characterized by difficulties with sleep
`
`
` onset and/or sleep maintenance,
` Population: Adults
`
` 193462001 | Insomnia (disorder) |
`
`
`
`
`
`
` Approval
`
`
`
` Treatment of insomnia, characterized by difficulties with sleep
`
` onset and/or sleep maintenance
`
`
`
`
`
` 193462001 | Insomnia (disorder) |
`
`Applicant Proposed
` SNOMED CT Indication
`
`
` Disease Term for each
`
` Proposed Indication
`
` Recommendation on
`
` Regulatory Action
`
` Recommended
`
` Indication(s)/Population(s)
`
`(if applicable)
`
` Recommended SNOMED
`
` CT Indication Disease
`
`
` Term for Each Indication
`
`
` (if applicable)
`
` Recommended Dosing
`
` Regimen
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5 to 10 mg by mouth nightly before bedtime
`
`
`
`
`Version date: October 12, 2018
`
`
`
`
`1
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`
`Reference ID: 4538004
`
`
`(b) (4)
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`Page 2 of 386
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`

`

` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
`
`
`
` Table of Contents
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`
`
` Table of Tables ................................................................................................................................ 5
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`
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`Table of Figures............................................................................................................................. 10
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`Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 14
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`Glossary......................................................................................................................................... 18
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`1. Executive Summary ............................................................................................................... 20
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`Product Introduction...................................................................................................... 20
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`Conclusions on the Substantial Evidence of Effectiveness ............................................ 20
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`Benefit-Risk Assessment ................................................................................................ 22
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`Patient Experience Data................................................................................................. 31
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` 2. Therapeutic Context .............................................................................................................. 32
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` Analysis of Condition...................................................................................................... 32
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`Analysis of Current Treatment Options ......................................................................... 34
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` 3. Regulatory Background ......................................................................................................... 41
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` U.S. Regulatory Actions and Marketing History............................................................. 41
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`Summary of Presubmission/Submission Regulatory Activity ........................................ 41
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`
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` Foreign Regulatory Actions and Marketing History....................................................... 42
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`4. Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on
`
`
`
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`Efficacy and Safety................................................................................................................. 43
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`Office of Scientific Investigations (OSI) .......................................................................... 43
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`
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` Product Quality .............................................................................................................. 44
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`Clinical Microbiology ...................................................................................................... 44
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`
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`Devices and Companion Diagnostic Issues .................................................................... 44
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` 5. Nonclinical Pharmacology/Toxicology................................................................................... 45
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`
`
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`Executive Summary........................................................................................................ 45
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`Referenced NDAs, BLAs, DMFs....................................................................................... 48
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`Pharmacology................................................................................................................. 49
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`ADME/PK........................................................................................................................ 55
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`Toxicology....................................................................................................................... 61
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`General Toxicology.................................................................................................. 61
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`Genetic Toxicology.................................................................................................. 70
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`2
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`Version date: October 12, 2018
`
`Reference ID: 4538004
`
`Page 3 of 386
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`

`

` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
`
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`
`
` Carcinogenicity........................................................................................................ 71
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` Reproductive and Developmental Toxicology........................................................ 72
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` Other Toxicology Studies ........................................................................................ 84
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`
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` 6. Clinical Pharmacology............................................................................................................ 85
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`Executive Summary........................................................................................................ 85
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`Summary of Clinical Pharmacology Assessment............................................................ 87
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`Pharmacology and Clinical Pharmacokinetics ........................................................ 87
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`
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`Comprehensive Clinical Pharmacology Review ............................................................. 91
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`General Pharmacology and Pharmacokinetic Characteristics................................ 91
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`Clinical Pharmacology Questions............................................................................ 92
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` 7. Sources of Clinical Data and Review Strategy ..................................................................... 118
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` Table of Clinical Studies................................................................................................ 118
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` Review Strategy............................................................................................................ 125
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` 8. Statistical and Clinical and Evaluation ................................................................................. 126
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`Review of Relevant Individual Trials Used to Support Efficacy.................................... 126
`
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`
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`E2006-G000-303 ................................................................................................... 126
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`E2006-G000-304 ................................................................................................... 159
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`
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`Integrated Review of Effectiveness ...................................................................... 191
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`Review of Safety........................................................................................................... 198
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`Safety Review Approach ....................................................................................... 198
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`
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`Review of the Safety Database ............................................................................. 198
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`Adequacy of Applicant’s Clinical Safety Assessments .......................................... 210
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`Safety Results........................................................................................................ 214
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`
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`
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`Analysis of Submission-Specific Safety Issues....................................................... 231
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`Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability...... 251
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`Safety Analyses by Demographic Subgroups........................................................ 251
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`
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`Specific Safety Studies/Clinical Trials.................................................................... 254
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`Additional Safety Explorations.............................................................................. 256
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`Safety in the Postmarket Setting................................................................... 256
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`Integrated Assessment of Safety................................................................... 257
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`Statistical Issues ........................................................................................................... 258
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`3
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`Version date: October 12, 2018
`
`Reference ID: 4538004
`
`Page 4 of 386
`
`

`

`NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
`DAYVIGO (lemborexant)
`
`
`
` Conclusions and Recommendations ............................................................................ 258
`
`
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`
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` 9. Advisory Committee Meeting and Other External Consultations....................................... 260
`
`
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` 10. Pediatrics ............................................................................................................................. 261
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` 11. Labeling Recommendations ................................................................................................ 261
`
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`Prescription Drug Labeling ....................................................................................... 261
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` 12. Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 267
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` 13. Postmarketing Requirements and Commitment ................................................................ 268
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` Postmarketing Requirements................................................................................... 268
`
`
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`
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`Maternal, Fetal, and Infant Outcomes of Women Exposed to Lemborexant268
`
`
`
` Clinical PMR to Assess Respiratory Safety..................................................... 269
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` Clinical Pharmacology PMCs.......................................................................... 269
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` 14. Appendices .......................................................................................................................... 271
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` References ................................................................................................................ 271
`
`
`
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` Financial Disclosure .................................................................................................. 274
`
`
`
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`Nonclinical Pharmacology/Toxicology...................................................................... 277
`
`
`
`
`OCP Appendices (Technical Documents Supporting OCP Recommendations)........ 277
`
`
`
`
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`Population Pharmacokinetic Analysis ........................................................... 277
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`Physiologically based Pharmacokinetic (PBPK) Analyses .............................. 285
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`
`
`
`
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`Driving Study Review..................................................................................... 297
`
`
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`Summary of Bioanalytical Method Validation and Performance.................. 309
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`Version date: October 12, 2018
`
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`4
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`Reference ID: 4538004
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`Page 5 of 386
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`

`

` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
` Table of Tables
`
`
`
`
`
` Table 1: DSM-5 Diagnostic Criteria for Insomnia Disorder........................................................... 32
`
`
`
`
`
` Table 2: Summary of Treatment Armamentarium Relevant to Insomnia Disorders ................... 34
`
`
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`
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` Table 3: In Vitro Properties of Lemborexant at Human OX1R and OX2R Compared to Suvorexant
`
` ............................................................................................................................................... 50
`
`
`
`
`Table 4: Lemborexant Pharmacokinetic Parameters After Single Intravenous and Oral
`
`
`
`
`Administration to Male Rats ................................................................................................. 55
`
`
`
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`Table 5: Lemborexant Pharmacokinetic Parameters After Single Intravenous and Oral
`
`
`
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`Administration to Male Monkeys.......................................................................................... 55
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`Table 6: In Vitro Plasma Protein Binding of Lemborexant and Its Metabolites ........................... 56
`
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` Table 7: Excretion of Radioactivity After a Single Oral Administration of [14C]Lemborexant to
`
`
`
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` Male Rats and Monkeys ........................................................................................................ 58
`
`
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` Table 8: Radioactivity In Plasma and Milk of Pregnant Lactating Rats......................................... 58
`
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` Table 9: TK of Lemborexant in Rats on Day 183 ........................................................................... 59
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` Table 10: TK of Lemborexant in Monkeys on Day 269 ................................................................. 59
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`Table 11: TK of Lemborexant In Pregnant Rats ............................................................................ 60
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`Table 12: TK of Lemborexant in Pregnant Rabbits ....................................................................... 60
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`Table 13: TK of Lemborexant in Pregnant Rats ............................................................................ 60
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`Table 14: TK of Lemborexant in Rats on Day 178 of Carcinogenicity Study................................. 60
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`Table 15: Observations and Results: Changes From Control........................................................ 62
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`Table 16: Observations and Results: Changes From Control........................................................ 64
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`Table 17: Observations and Results.............................................................................................. 73
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`Table 18: Observations and Results.............................................................................................. 75
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`Table 19: Observations and Results.............................................................................................. 76
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`Table 20: Incidence of Abnormal Lung Lobation in Rabbit Fetuses Compared With Historical
`
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`Controls ................................................................................................................................. 77
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`Table 21: Observations and Results.............................................................................................. 79
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`Table 22: Observations and Results.............................................................................................. 83
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`Table 23: Acceptability of Specific Drug Information to Support Approval of Lemborexant....... 86
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`Table 24: General Pharmacology and Pharmacokinetic Characteristics...................................... 91
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`Version date: October 12, 2018
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`5
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`Reference ID: 4538004
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`Page 6 of 386
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`

`

`
`
` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
`
`
`Table 25: Itraconazole (ITZ) and Hydroxy-Itraconazole (OH-ITZ) PK Parameters Following a Single
`
`Oral Dose of Itraconazole Capsules or Solution Administered Under Fasting or Fed
`
`
`Conditions............................................................................................................................ 101
`
`
` Table 26: Listing of Clinical Trials Relevant to NDA 212028 ....................................................... 119
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`Table 27: Definition of Sleep Parameters for Study E2006-G000-303 ....................................... 133
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`Table 28: Applicant Schedule of Procedures/Assessments in Study E2006-G000-303.............. 134
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`Table 29: Revisions and Amendments to the E2006-G000-303 Protocol .................................. 138
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`Table 30: Applicant’s Description of Analysis Sets Used in E2006-G000-303 ............................ 140
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`Table 31: Subject Disposition and Reason for Discontinuation From Study 303 Period 1......... 142
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`Table 32: Applicant Summary of Major Protocol Deviations Study 303, Full Analysis Set......... 143
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`Table 33: Demographic Characteristics of the Full Analysis Set for E2006-G000-303 ............... 145
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`Table 34: Other Baseline Characteristics (Height, Weight, BMI), Full Analysis Set for E2006­
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`
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`G000-303 ............................................................................................................................. 146
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`Table 35: Baseline Scores for Primary and Key Secondary Endpoints in E2006-G000-303 ....... 147
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`Table 36: Study Medication Compliance During Study E2006-G000-303 Period 1, Safety Analysis
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`Set........................................................................................................................................ 148
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`Table 37: Primary Efficacy Results on sSOL (Minutes), Study E2006-G000-303 ........................ 149
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`Table 38: Sensitivity Analysis: MMRM Without Imputation Analysis Results on sSOL (Minutes),
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`
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`Study E2006-G000-303........................................................................................................ 151
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`Table 39: Sensitivity Analysis: Jump to Placebo Analysis Results on sSOL (Minutes), Study E2006­
`
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`G000-303 ............................................................................................................................. 152
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`Table 40: Efficacy Results on Key Secondary Endpoint sSE (%), Study E2006-G000-303........... 154
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`Table 41: Efficacy Results on Key Secondary Endpoint sWASO (Minutes), Study E2006-G000-303
`
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`............................................................................................................................................. 155
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`Table 42: Exploratory Analysis: Persistence vs. Loss of Effect from Month 1 During Phase 1,
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`E2006-G000-303.................................................................................................................. 157
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`Table 43: Applicant’s Definition of Sleep Parameters for Study E2006-G000-304 .................... 165
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`Table 44: Applicant’s Schedule of Procedures/Assessments in Study E2006-G000-304 ........... 166
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`Table 45: Applicant Reported Revisions/Amendments to the Protocol for Study E2006-G000-304
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`............................................................................................................................................. 170
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`Table 46: Subject Disposition and Reasons for Discontinuation from Study 304 ...................... 172
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`Table 47: Major Protocol Deviations for Study E2006-G000-304, Full Analysis Set................... 173
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`Table 48: Demographic Characteristics of the Primary Efficacy Analysis for Study 304............ 175
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`Version date: October 12, 2018
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`6
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`Reference ID: 4538004
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`Page 7 of 386
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`

`

`
`
` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
`
`
`
`
`Table 49: Other Baseline Characteristics in Study E2006-G000-304, Full Analysis Set .............. 176
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` Table 50: Primary Efficacy Results on LPS (Minutes), Study E2006-G000-304........................... 179
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` Table 51: Efficacy Results on Key Secondary Endpoint SE (%), Study E2006-G000-304 ............ 184
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` Table 52: Efficacy Results on Key Secondary Endpoint WASO (Minutes), Study E2006-G000-304
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` ............................................................................................................................................. 186
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`Table 53: Efficacy Results on Key Secondary Endpoint WASO2H (Minutes), Study E2006-G000­
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`304....................................................................................................................................... 188
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`Table 54: Secondary Endpoints, PSG Assessments of Sleep Parameters in Study 304.............. 190
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`Table 55: Efficacy Parameters Evaluated in the Phase 3 Program by Dose ............................... 191
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`Table 56: Results for the Primary Endpoint (Studies 303 and 304)............................................ 192
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`Table 57: Studies Included in the Applicant’s Summary of Clinical Safety (SCS), Grouped by
`
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`Subject Population .............................................................................................................. 199
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`Table 58: Extent of Lemborexant Exposure by Time in the Phase 3 Pool .................................. 203
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`Table 59: Demography - Combined Phase 2 and 3 Database..................................................... 205
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`Table 60: Lemborexant Studies Included in the Phase 3 Pool, by Treatment Arm.................... 206
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`Table 61: Demography – Phase 3 Pool, by Treatment Arm........................................................ 207
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`Table 62: Lemborexant Studies Included in the Phase 3 30-Day Pool, by Treatment Arm........ 207
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`Table 63: Demography – Phase 3 Safety Pool ............................................................................ 208
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`Table 64: Examples of Review Team Updates to Preferred Terms for Safety Review............... 211
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`Table 65: Grouping Terms and Related Preferred Terms........................................................... 211
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`Table 66: Applicant Rules for Coding AEs as TEAEs .................................................................... 212
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`Table 67: Treatment-Emergent Serious Adverse Events Occurring in ≥2 Subjects Receiving
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`Lemborexant in Phase 3 Pool – Events per 100 Patient-years............................................ 214
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`Table 68: TEAE Leading to Discontinuation From Study Drug Within 14 Days of Last Dose by
`
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`Increasing Frequency, Phase 3 Pool.................................................................................... 217
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`Table 69: Summary of Subjects with Intentional Overdose in All Studies ................................. 218
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`Table 70: Adverse Events ≥2% and Greater Than Placebo, First 30 Days Combined Studies 303
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`and 304................................................................................................................................ 219
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`Table 71: Adverse Events per 100 Patient-years: Study 303, Treatment Periods 1 and 2 (6
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`Months Each) and Study 304 (30 days); Risk Difference > 2 per 100 Patient-years........... 220
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`Table 72: Study 303 - Incidence of Markedly Abnormal Chemistry Laboratory Parameters..... 222
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`Table 73: Study 304 - Incidence of Markedly Abnormal Chemistry Laboratory Parameters..... 222
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`Table 74: ALT Shift Tables, Studies 303 and 304 ........................................................................ 223
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`7
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`Version date: October 12, 2018
`
`
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`Reference ID: 4538004
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`Page 8 of 386
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`

`

`
`
` NDA 212028 Multi-disciplinary Review and Evaluation
`
`
`
` DAYVIGO (lemborexant)
`
`
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`
`
`Table 75: AST Shift Tables, Studies 303 and 304 ........................................................................ 223
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`Table 76: Total Cholesterol and Triglyceride Shift Tables, Study 303 ........................................ 224
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`Table 77: Abnormal Vital Signs, Phase 3 Pool............................................................................. 227
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`Table 78: Abnormal QTc, PR, and QRS Results, Phase 3 Pool (Studies 303 and 304) ................ 229
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`Table 79: Occurrences of Rash, Allergy/Allergic, or Hypersensitivity in the Phase 2 and 3
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`Database.............................................................................................................................. 230
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`Table 80: Incidence of Somnolence by Age in the Phase 3 Pools, First 30-Days and Up to 12
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`Months ................................................................................................................................ 234
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`Table 81: Results From Middle of the Night Safety Testing of Cognition (Attention and Memory)
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`in Study 108......................................................................................................................... 239
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`Table 82: C-SSRS Endorsed Items, Result from the All Insomnia Pool ....................................... 240
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`Table 83: Summary of C-SSRS by Month of Treatment, Treatment Period 1; Study 303 .......... 241
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`Table 84
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`Table 85
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`Table 86
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`Table 87: Narrative Summary for Fractures Categorized at Serious Adverse Events, Phase 3
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`Studies ................................................................................................................................. 246
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`Table 88: The Incidence of “Fall” in Study 303-Core, Phase 3 Pool, and the All Insomnia Pool 248
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`Table 89: Treatment-emergent Somnolence by Subgroup in Studies 303 and 304 .................. 252
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`Table 90: Treatment-emergent Parasomnia by Subgroup in Studies 303 and 304 ................... 253
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`Table 91: Incidence of Somnolence by Group in Study 104 ....................................................... 256
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`Table 92: Exposure Ratios of M10 in Animals Compared to Humans........................................ 277
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`Table 93: Summary of Baseline Covariates................................................................................. 279
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`Table 94: Final Population PK Parameter Estimates of Lemborexant – All Data ....................... 280
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` Table 95: Summary of Statistical Analysis Comparison of Lemborexant AUCss Following
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` Lemborexant 5 mg/Nightly in Adult and Elderly Subjects .................................................. 282
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` Table 96: Summary of Statistical Analysis Comparison of Lemborexant AUCss Following
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` Lemborexant 5 mg/Nightly in Each BMI Category .............................................................. 282
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`Table 97: Lemborexant Studies in Special Safety Populations ................................................... 283
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`Table 98: Clinical DDI Effects of Lemborexant as a CYP3A Substrate or As an Inducer for CYP3A
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`or CYP2B6 Pathway ............................................................................................................. 287
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`Version date: October 12, 2018
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`Reference ID: 4538004
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`Page 9 of 386
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`NDA 212028 Multi-disciplinary Review and Evaluation
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`DAYVIGO (lemborexant)
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` Table 99: PBPK Simulations and Study Design Used for Lemborexant Model........................... 289
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` Table 100: Comparison of PBPK Predicted and Observed Mean Cmax and AUC Values of
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` Table 101: Observed and PBPK Predicted Cmax and AUC Ratios for Lemborexant in the Presence
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` of CYP3A4 Modulators ........................................................................................................ 291
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`Table 102: fa and ka Values Used in the IQ-WG ITZ PBPK Model for Different Formulations... 292
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`Table 103: Comparison of the Simulated PK Parameters of Itraconazole and OH-ITZ at Steady
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`State (on Day 20) Using Simcyp’s and the Applicant’s Itraconazole Model ....................... 292
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`Table 104: Verification of IQ-WG ITZ PBPK Model With Sensitive or Moderate Sensitive CYP3A
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`Substrates in the Fasted Condition ..................................................................................... 294
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`Table 105:Primary Analysis Results on SDLP (cm) ...................................................................... 301
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`Table 106: Symmetry Analysis Results for SDLP......................................................................... 302
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` Table 107: Summary Review of Bioanalytical Method Measuring Plasma Lemborexant and its
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` Metabolites by
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` Table 108: Summary Review of Bioanalytical Method Measuring Urine Lemborexant by
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` Table 109: Summary Review of Bioanalytical Method Measuring Plasma Lemborexant and Its
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` Metabolites by
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`Version date: October 12, 2018
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`Reference ID: 4538004
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` NDA 212028 Multi-disciplinary Review and Evaluation
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` DAYVIGO (lemborexant)
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` Table of Figures
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` Figure 1: Effects of Lemborexant on Cataplexy in Wild-Type and Orexin Knock-Out Mice......... 52
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` Figure 2: Relationship Between Lemborexant Dose and Benefit-Risk ......................................... 93
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` Figure 3: Mean Dose-Normalized Lemborexant Concentrations by Age and BMI ...................... 94
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`Figure 4: Mean Dose-Normalized Lemborexant Concentrations by Race and Sex...................... 95
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`Figure 5: Pharmacokinetic Profiles of Lemborexant in Subjects With Normal, Mild and Moderate
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`Hepatic Impairment............................................................................................................... 97
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`Figure 6: Mean Plasma Concentration-Time Curve of Lemborexant Over 0 to 24 Hours by
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`Treatment.............................................................................................................................. 98
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`Figure 7: Effects of Other Drugs on the Pharmacokinetics of Lemborexant.............................. 105
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`Figure 8: Measurement of Postural S