CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
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`213871Orig1s000
`
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`NDA 213871 abrocitinib tablets
`
`Multi-disciplinary Review and Evaluation
`
`NDA Multi-Disciplinary Review and Evaluation
`
`NDA
`Application Type
`213871
`Application Number(s)
`Priority or Standard
`Priority
`August 25, 2020
`Submit Date(s)
`Received Date(s)
`August 25, 2020
`July 25, 2021
`PDUFA Goal Date
`Division/Office
`DDD/OIl
`January 13, 2022
`Review Completion Date
`Established/Proper Name
`abrocitinib
`(Proposed) Trade Name
`CIBINQO
`NME
`Pharmacologic Class
`Code name
`Applicant Pfizer Inc.
`Dosage form
`Applicant proposed Dosing
`Regimen
`Applicant Proposed
`Indication(s)/Population(s)
`
`100mg or 200mgoncedaily
`
`®¢
`
`
`
`Applicant Proposed
`SNOMEDCT Indication
`
`Disease Term for each
`
`ProposedIndication
`
`Recommendation on
`Regulatory Action
`
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`Recommended SNOMED
`
`CT Indication Disease
`
`
`
` Tablets
` CIBINQOis indicated for the treatmentof adult patients with
`
`refractory, moderate to severe atopic dermatitis whose disease
`is not adequately controlled with other systemic drug products,
`biologics or whenuseof thosetherapiesis inadvisable.
`Recommendedpopulation are adults, 18 years and older
`oa
`
`O@|
`
`Moderateto severe atopic dermatitis,
`
`a
`
`Term for each Indication
`(if applicable)
`©®if an
`100 mg PO QD
`Recommended Dosing
`adequate responseis not achieved with CIBINQO 100 mgorally
`Regimen
`daily after 12 weeks, consider increasing doseage to 200 mg
`
`Version date: October 12, 2018
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`Reference ID: 4920256
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`orally once daily. Discontinue therapy if inadequate response is
`seen after dosage increase to 200 mg once daily.
`
`Table of Contents
`
`Table of Tables...........................................................................................................................................................5
`Table of Figures.......................................................................................................................................................10
`Reviewers of Multi-Disciplinary Review and Evaluation.....................................................................12
`Glossary......................................................................................................................................................................17
`1
`Executive Summary......................................................................................................................................20
`1.1. Product Introduction..........................................................................................................................20
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness.................................................21
`1.3. Benefit-Risk Assessment...................................................................................................................23
`1.4. Patient Experience Data....................................................................................................................28
`2
`Therapeutic Context.....................................................................................................................................29
`2.1. Analysis of Condition..........................................................................................................................29
`2.2. Analysis of Current Treatment Options......................................................................................30
`Regulatory Background..............................................................................................................................33
`3
`3.1. U.S. Regulatory Actions and Marketing History......................................................................33
`3.2.
`Summary of Presubmission/Submission Regulatory Activity.........................................33
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`4
`Efficacy and Safety........................................................................................................................................34
`4.1. Office of Scientific Investigations (OSI)......................................................................................34
`4.2. Product Quality.....................................................................................................................................34
`4.3.
`Clinical Microbiology..........................................................................................................................37
`4.4. Devices and Companion Diagnostic Issues...............................................................................37
`5 Nonclinical Pharmacology/Toxicology................................................................................................38
`5.1. Executive Summary.............................................................................................................................38
`5.2. Referenced NDAs, BLAs, DMFs.......................................................................................................40
`5.3. Pharmacology........................................................................................................................................40
`5.4. ADME/PK.................................................................................................................................................42
`5.5. Toxicology...............................................................................................................................................45
`5.5.1.General Toxicology.....................................................................................................................45
`5.5.2.Genetic Toxicology......................................................................................................................47
`5.5.3.Carcinogenicity.............................................................................................................................48
`5.5.4.Reproductive and Developmental Toxicology................................................................49
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`5.5.5.Other Toxicology Studies.........................................................................................................56
`Clinical Pharmacology.................................................................................................................................58
`6.1. Executive Summary.............................................................................................................................58
`6.1.1.Recommendations......................................................................................................................59
`Summary of Clinical Pharmacology Assessment....................................................................60
`6.2.
`6.2.1.Pharmacology and Clinical Pharmacokinetics................................................................60
`6.2.2.General Dosing and Therapeutic Individualization......................................................62
`6.3.
`Comprehensive Clinical Pharmacology Review......................................................................63
`6.3.1.General Pharmacology and Pharmacokinetic Characteristics.................................63
`6.3.2.Clinical Pharmacology Questions.........................................................................................66
`Sources of Clinical Data and Review Strategy...................................................................................73
`7.1. Table of Clinical Studies.....................................................................................................................73
`7.2. Review Strategy....................................................................................................................................78
`Statistical and Clinical and Evaluation.................................................................................................79
`8.1. Review of Relevant Individual Trials Used to Support Efficacy.......................................79
`8.1.1.Trial Design....................................................................................................................................79
`8.1.2.Efficacy Endpoints.......................................................................................................................82
`8.1.3.Statistical Methodologies.........................................................................................................83
`8.1.4.Subject Disposition, Demographics, and Baseline Disease Characteristics.......87
`8.1.5.Results for the Co-Primary Efficacy Endpoints..............................................................91
`8.1.6.Results for the Key Secondary Efficacy Endpoints.......................................................95
`8.1.7.Efficacy Over Time......................................................................................................................99
`8.1.8.Patient Reported Outcomes.................................................................................................101
`8.1.9.Efficacy Results by Prior Use of Systemic Therapy....................................................102
`8.1.10.
`Efficacy Results for Adult Subjects (Monotherapy Trials).............................104
`8.1.11.
`Additional Analyses for Itching.................................................................................105
`8.1.12.
`Findings in Additional Subgroup Populations....................................................108
`8.2. Review of Safety.................................................................................................................................109
`8.2.1.Safety Review Approach........................................................................................................113
`8.2.2.Review of the Safety Database............................................................................................109
`8.2.3.Adequacy of Applicant’s Clinical Safety Assessments...............................................111
`8.2.4.Safety Results.............................................................................................................................113
`8.2.5.Analysis of Submission-Specific Safety Issues.............................................................123
`8.2.5.1.
`Severe Infections/Opportunistic Infections.........................................................127
`8.2.5.2.
`Retinal Detachment........................................................................................................128
`8.2.5.3. Malignancy..........................................................................................................................135
`8.2.5.4.
`Thrombosis/MACE..........................................................................................................136
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`8.2.6.Safety Analyses by Demographic Subgroups................................................................140
`8.2.7.Long-Term Safety.....................................................................................................................144
`8.2.8.Specific Safety Studies/Clinical Trials.............................................................................146
`8.2.9.Additional Safety Explorations...........................................................................................146
`8.2.10.
`Safety in the Postmarket Setting...............................................................................149
`8.2.11.
`Integrated Assessment of Safety...............................................................................149
`8.3.
`Summary and Conclusions............................................................................................................150
`8.3.1.Statistical Issues........................................................................................................................150
`8.3.2.Conclusions and Recommendations.................................................................................151
`9
`Advisory Committee Meeting and Other External Consultations..........................................152
`10 Pediatrics........................................................................................................................................................153
`11 Labeling Recommendations...................................................................................................................155
`11.1.
`Prescription Drug Labeling.......................................................................................................155
`12 Risk Evaluation and Mitigation Strategies (REMS)......................................................................184
`13 Postmarketing Requirements and Commitment..........................................................................185
`14 Division Director (Clinical) Comments.............................................................................................188
`15 Office Director Comments.......................................................................................................................189
`16 Appendices....................................................................................................................................................191
`16.1.
`References........................................................................................................................................191
`16.2.
`Financial Disclosure.....................................................................................................................191
`16.3.
`Clinical/Biostatistics....................................................................................................................193
`16.4.
`Nonclinical Pharmacology/Toxicology................................................................................209
`16.4.1.
`Calculations for multiples of exposures.................................................................209
`16.4.2.
`Nonclinical labeling.........................................................................................................210
`16.4.3.
`Review of Carcinogenicity Studies Conducted with Abrocitinib.................217
`16.5.
`OCP Appendices.............................................................................................................................224
`16.5.1.
`Clinical Pharmacology Studies...................................................................................224
`16.5.2.
`Population PK and PK/PD Studies...........................................................................247
`16.5.3.
`In Vitro Studies Using Human Biomaterials.........................................................272
`16.5.4.
`Pharmacogenomics.........................................................................................................276
`16.5.5.
`Summary of Bioanalytical Method Validation and Performance................282
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`Version date: October 12, 2018
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`Reference ID: 4920256
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`Table of Tables
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`Table 1: Summary of Clinical Pharmacology Review ....................................................................58
`Table 2: Summary of Clinical Pharmacology, Pharmacokinetics and Pharmacodynamics of
`Abrocitinib ....................................................................................................................................64
`Table 3: Proportion of Subjects Achieving Investigator’s Global Assessment (IGA) of Clear or
`Almost Clear and ≥2 Points Improvement by Abrocitinib from Baseline at Week 12 (Study
`B7451006) ....................................................................................................................................67
`Table 4:Effect of Renal and Hepatic Impairment on the Combined Exposure of Abrocitinib and
`Its Two Active Metabolites ...........................................................................................................68
`Table 5: Effect of Abrocitinib on the Exposure of Other Drugs ....................................................71
`Table 6: Summary Table of Clinical Studies ..................................................................................73
`Table 7: Tabular Listing of Clinical Studies Pertinent to Clinical Review.......................................74
`Table 8: Key Secondary Endpoints................................................................................................83
`Table 9: Disposition of Subjects through Week 12 – Trials B7451012 and B7451013 .................87
`Table 10: Disposition of Subjects through Week 12 – Trial B7451029.........................................87
`Table 11: Demographics - Trials B7451012, B7451013 and B7451029 (FAS1)..............................89
`Table 12: Baseline Disease Severity - Trials B7451012, B7451013 and B7451029 (FAS1) ............90
`Table 13: Results for the Co-Primary Endpoints at Week 12 - Trials B7451012 and B7451013
`(FAS; NRI1) ....................................................................................................................................91
`Table 14: Results for the Co-Primary Endpoints at Week 12 – Trial B7451029 (FAS; NRI1)..........92
`Table 15: Missing Data for the Co-Primary Endpoints through Week 12 - Trials B7451012 and
`B7451013 (FAS1) ...........................................................................................................................92
`Table 16: Missing Data for the Co-Primary Endpoints through Week 12 - Trial B7451029 (FAS1)
`......................................................................................................................................................92
`Table 17: Results for Co-Primary Efficacy Endpoints at Week 12 with Different Approaches for
`Handling Missing Data - Trial B7451012 (FAS1) ............................................................................93
`Table 18: Results for Co-Primary Efficacy Endpoints at Week 12 with Different Approaches for
`Handling Missing Data - Trial B7451013 (FAS1) ............................................................................93
`Table 19: Results for Co-Primary Efficacy Endpoints at Week 12 with Different Approaches for
`Handling Missing Data - Trial B7451029 (FAS1) ............................................................................94
`Table 20: Missing Data for Pruritus NRS by Visit - Trials B7451012 and B7451013 (FAS1)...........96
`Table 21: Missing Data for Pruritus NRS by Visit – Trial B7451029 (FAS1)....................................96
`Table 22: Results for the Key Secondary Efficacy Endpoints - Trials B7451012 and B7451013
`(FAS; Hybrid Method1)..................................................................................................................97
`Table 23: Results for the Key Secondary Efficacy Endpoints - Trials B7451012 and B7451013
`(FAS; NRI1) ....................................................................................................................................97
`Table 24: Results for the Key Secondary Efficacy Endpoints for Several Methods of Handling the
`Missing Data - Trial B7451012 (FAS1) ...........................................................................................98
`Table 25: Results for the Key Secondary Efficacy Endpoints for Several Methods of Handling the
`Missing Data - Trial B7451013 (FAS1) ...........................................................................................98
`Table 26: Results for the Key Secondary Efficacy Endpoints – Trial B7451029 (FAS; NRI1) ..........99
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`Version date: October 12, 2018
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`Reference ID: 4920256
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`Table 27: IGA 0/1 Response Rate at Week 12 in Subgroups by Prior Systemic Therapy for AD -
`Trials B7451012, B7451013 and B7451029 (FAS; NRI1)..............................................................103
`Table 28: EASI-75 Response Rate at Week 12 in Subgroups by Prior Systemic Therapy for AD -
`Trials B7451012, B7451013 and B7451029 (FAS; NRI1)..............................................................103
`Table 29: IGA 0/1 and EASI-75 Response Rates at Week 12 in Subgroup who had Treatment
`Failure or Intolerance to Prior Systemic Therapy for AD- Trials B7451012, B7451013 and
`B7451029 (FAS; NRI1) .................................................................................................................104
`Table 30: Itching Results at Week 12 in Monotherapy Trials for Abrocitinib and Dupilumab (FAS;
`NRI1)............................................................................................................................................105
`Table 31: Itching Results at Week 12 in Trials with Concomitant Therapy for Abrocitinib and
`Dupilumab (FAS; NRI1)................................................................................................................106
`Table 32: Results for Peak Pruritus NRS at Week 2 - Trials B7451012 and B7451013 (FAS; NRI1)
`....................................................................................................................................................107
`Table 33: Results for Peak Pruritus NRS at Week 2 – Trial B7451029 (FAS; NRI1) ......................107
`Table 34: Overview of Exposure Duration in the Abrocitinib clinical Development Program....109
`Table 35: Treatment Exposure – Placebo-Controlled Safety Pool..............................................110
`Table 36: Summary of Discontinuations from Study – Placebo-Controlled Safety Pool ............110
`Table 37: Abrocitinib Summary of Clinical Safety (Atopic Dermatitis) Incidence of Treatment-
`Emergent Serious Adverse Events by System Organ Class and Preferred Terms (All Causalities) –
`Placebo-Controlled Safety Pool ..................................................................................................115
`Table 38: Adverse Reactions Reported in ≥1% of TRADENAME Treated-Patients with Moderate
`to Severe Atopic Dermatitis and at Higher Rate than Placebo for up to 16 Weeks – Placebo-
`Controlled Safety Pool................................................................................................................117
`Table 39: Treatment-Emergent Adverse Events (All Causalities) Excluding Events of Atopic
`Dermatitis – Placebo-Controlled Safety Pool .............................................................................118
`Table 40: Proportion, Incidence Rates and Risk Difference for Adverse Events of Special Interest
`(AESI) – Placebo-Controlled Pool (Weeks 0-16) .........................................................................123
`Table 41: Incidence of Severe Treatment Emergent Adverse Events for Infection and Infestation
`– Placebo-Controlled Safety Pool ...............................................................................................127
`Table 42: Abrocitinib Summary of Clinical Safety (Atopic Dermatitis) Proportion and Incidence
`Rates for Adjudicated MACE, Non-MACE, and Non-Fatal VTE (CMQ) – All Exposure Cumulative
`Pool (Excluding Subjects from Study B7451014)........................................................................137
`Table 43: Proportion of Subjects with Prior Systemic Treatment for Atopic Dermatitis –
`Combination Therapy Trial and Monotherapy Pool ...................................................................142
`Table 44: Abrocitinib Summary of Clinical Safety TEAE for Non-Responder and Responders to
`Dupilumab – All Exposure Pool Subanalyses ..............................................................................142
`Table 45: Proportion and Incidence Rates for AESI – All Exposure Cumulative Pool (Excluding
`B7451014) ..................................................................................................................................144
`Table 46: Proportion and Incidence Rates for Additional AESI – All Exposure Cumulative Pool
`(Excluding B7451014) .................................................................................................................145
`Table 47: Summary of Standard Deviation Scores (SDS) for Height Measurement and Its Change
`from Baseline Overtime for Adolescent Subjects – All Exposure Pool .......................................148
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`Version date: October 12, 2018
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`Reference ID: 4920256
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`Table 48: Summary of Standard Deviation Scores (SDS) for Height Measurement and Its Change
`from Baseline Overtime for Adolescent Subjects – All Exposure Pool .......................................154
`Table 49: Investigator’s Global Assessment (IGA) Scale.............................................................193
`Table 50: Results for the Co-Primary Endpoints at Week 12 - Trials B7451012 and B7451013
`(PPAS; NRI1) ................................................................................................................................195
`Table 51: Results for the Co-Primary Endpoints at Week 12 – Trial B7451029 (PPAS; NRI1) .....195
`Table 52: Absolute Change from Baseline to Week 12 in PSAAD Total Score - Trials B7451012
`and B7451013 (FAS1) ..................................................................................................................196
`Table 53: Proportion of Subjects with PSAAD Total Score of 0 at Week 12 – Trials B7451012,
`B7451013 and B7451029 (FAS; NRI1) .........................................................................................196
`Table 54: Missing PSAAD Itching Item Data from Baseline through Week 12 – Trials B7451012,
`B7451013 and B7451029 (FAS; NRI1) .........................................................................................197
`Table 55: Responder Analysis for PSAAD Itching Item at Week 12 – Trials B7451012, B7451013
`and B7451029 (FAS; NRI1) ..........................................................................................................197
`Table 56: Responder Analysis for PSAAD Items 2-10 at Week 12 – Trials B7451012 and
`B7451013 (FAS; NRI1) .................................................................................................................198
`Table 57: Responder Analysis for PSAAD Items at Week 12 – Trial B7451029 (FAS; NRI1) ........199
`Table 58: Results for the Co-Primary Endpoints at Week 12 in Adult Subjects - Trial B7451012
`(FAS; NRI1) ..................................................................................................................................200
`Table 59: Results for the Co-Primary Endpoints at Week 12 in Adult Subjects – Trial B7451013
`(FAS; NRI1) ..................................................................................................................................200
`Table 60: Results for the Key Secondary Efficacy Endpoints in Adult Subjects – Trial B7451012
`(FAS; NRI1) ..................................................................................................................................200
`Table 61: Results for the Key Secondary Efficacy Endpoints in Adult Subjects – Trial B7451013
`(FAS; NRI1) ..................................................................................................................................201
`Table 62: Responder Analysis for PSAAD Itching Item at Week 12 in Adult Subjects – Trial
`B7451012 (FAS; NRI1) .................................................................................................................201
`Table 63: Responder Analysis for PSAAD Itching Item at Week 12 in Adult Subjects – Trial
`B7451013 (FAS; NRI1) .................................................................................................................202
`Table 64: IGA 0/1 Response at Week 12 by Age, Sex, Race, Weight, Baseline IGA Score and Prior
`Use of Systemic Therapy for AD – Trial B7451012 (FAS; NRI1) ...................................................203
`Table 65: EASI-75 Response at Week 12 by Age, Sex, Race, Weight, Baseline IGA Score and Prior
`Use of Systemic Therapy for AD – Trial B7451012 (FAS; NRI1) ...................................................203
`Table 66: IGA 0/1 Response at Week 12 by Age, Sex, Race, Weight, Baseline IGA Score and Prior
`Use of Systemic Therapy for AD – Trial B7451013 (FAS; NRI1) ...................................................204
`Table 67: EASI-75 Response at Week 12 by Age, Sex, Race, Weight, Baseline IGA Score and Prior
`Use of Systemic Therapy for AD – Trial B7451013 (FAS; NRI1) ...................................................204
`Table 68: IGA 0/1 Response at Week 12 by Age, Sex, Race, Weight, Baseline IGA Score and Prior
`Use of Systemic Therapy for AD – Trial B7451029 (FAS; NRI1) ...................................................205
`Table 69: EASI-75 Response at Week 12 by Age, Sex, Race, Weight, Baseline IGA Score and Prior
`Use of Systemic Therapy for AD – Trial B7451029 (FAS; NRI1) ...................................................206
`Table 70: IGA 0/1 and EASI-75 Response at Week 12 by Country – Trial B7451012 (FAS; NRI1)207
`Table 71: IGA 0/1 and EASI-75 Response at Week 12 by Country – Trial B7451013 (FAS; NRI1)207
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`Version date: October 12, 2018
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`Reference ID: 4920256
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`NDA 213871 abrocitinib tablets
`Multi-disciplinary Review and Evaluation
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`Table 72: IGA 0/1 and EASI 75 Response Rates at Week 12 by Country – Trial B7451029 (FAS;
`NRI1)............................................................................................................................................208
`Table 73. Summary of Plasma Abrocitinib PK Parameters Following Single Oral Doses in the
`Study B7451001..........................................................................................................................227
`Table 74. Summary of Plasma Abrocitinib PK Parameters in Western and Japanese Subjects
`Following a Single 800 mg Oral Dose in Study B7451001...........................................................228
`Table 75. Summary of Plasma Abrocitinib PK Parameters Following Multiple Oral Doses in the
`Study B7451001..........................................................................................................................229
`Table 76. Statistical Analysis for Absolute Oral Bioavailability (F)..............................................230
`Table 77. Geometric Mean Ratio for Fraction Absorbed (Fa) .....................................................231
`Table 78. Investigational Product Description............................................................................232
`Table 79. Descriptive Summary of Plasma Abrocitinib Pharmacokinetic Parameters in the Study
`B7451032....................................................................................................................................233
`Table 80. Randomized Treatment Sequences of Part B .............................................................233
`Table 81. Summary of Statistical Analysis for Bioequivalence Following Single Dose of To-be-
`marketed Tablet 200 mg (Test, T) and Phase 3 Tablet 2x100 mg (Reference, R).......................234
`Table 82. Statistical Summary of Combined Exposure of Abrocitinib and Its Two Active
`Metabolites and the Exposure of Abrocitinib in the Study B7451020 .......................................235
`Table 83. Statistical Summary of Combined Exposure of Abrocitinib and Its Two Active
`Metabolites and the Exposure of Abrocitinib in the Study B7451021 .......................................235
`Table 84. Predicted Combined Exposure of Abrocitinib and Its Two Active Metabolites (AUCinf,u)
`Ratio for Subjects with Mild Renal Impairment and Normal Renal Function Based on Linear
`Regression Analysis of AUCinf,u vs. Estimated Glomerular Filtration Rate (eGFR), Protocol
`B7451021....................................................................................................................................237
`Table 85. Descriptive and Statistical Summary of Combined Exposure of Abrocitinib and Its Two
`Active Metabolites and the Exposure of Abrocitinib, Study B7451017......................................238
`Table 86. Descriptive and Statistical Summary of Combined Exposure of Abrocitinib