Orig 1 S 000 Med R

CENTER FOR DRUG EVALUATION AND
RESEARCH
APPLICATION NUMBER:
761055Orig1s000
MEDICAL REVIEW(S)
Clinical Review
Brenda Carr, MD
BLA 761055
Dupixent (dupilumab)
CLINICAL REVIEW
Application Type BLA
Application Number(s) 761055
Priority or Standard Priority
Submit Date(s) July 28, 2016

Received Date(s) July 29, 2016
PDUFA Goal Date March 29, 2016
Division/Office DDDP/ODE III
Reviewer Name(s) Brenda Carr, MD

Review Completion Date March 15, 2017
Established Name Dupilumab

(Proposed) Trade Name Dupixent
Applicant Regeneron Pharmaceuticals, Inc.
Formulation(s) Solution
Dosing Regimen an initial dose of 600 mg (two 300 mg injections), followed by
300 mg given every other week
Proposed Indication(s) treatment of adult patients with moderate-to-severe atopic
dermatitis whose disease is not adequately controlled with
topical prescription therapies or when those therapies are not
advisable
Intended Population(s) Adults
Recommendation on Approval
Regulatory Action
Recommended treatment of adult patients with moderate-to-severe atopic
Indication(s) (if applicable) dermatitis whose disease is not adequately controlled with
topical prescription therapies or when those therapies are not
advisable
CDER Clinical Review Template 2015 Edition 1

Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
Reference ID: 4075125
Clinical Review
Brenda Carr, MD
BLA 761055
Table of Contents
Glossary ........................................................................................................................................12
1 Executive Summary ...............................................................................................................14

1.1. Product Introduction......................................................................................................14
1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................14
1.3. Benefit-Risk Assessment ................................................................................................15
2 Therapeutic Context..............................................................................................................23
2.1. Analysis of Condition......................................................................................................23
2.2. Analysis of Current Treatment Options .........................................................................25
3 Regulatory Background .........................................................................................................26

3.1. U.S. Regulatory Actions and Marketing History.............................................................27
3.2. Summary of Presubmission/Submission Regulatory Activity ........................................27
3.3. Foreign Regulatory Actions and Marketing History .......................................................29
4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on

Efficacy and Safety ................................................................................................................29
4.1. Office of Scientific Investigations (OSI) ..........................................................................29
4.2. Product Quality ..............................................................................................................29
4.3. Clinical Microbiology......................................................................................................32
4.4. Nonclinical Pharmacology/Toxicology ...........................................................................32
4.5. Clinical Pharmacology ....................................................................................................34
4.5.1. Mechanism of Action..............................................................................................36
4.5.2. Pharmacodynamics.................................................................................................37
4.5.3. Pharmacokinetics....................................................................................................38
4.6. Devices and Companion Diagnostic Issues ....................................................................38
4.7. Consumer Study Reviews...............................................................................................40
5 Sources of Clinical Data and Review Strategy .......................................................................40

5.1. Table of Clinical Studies .................................................................................................40
5.2. Review Strategy .............................................................................................................47
6 Review of Relevant Individual Trials Used to Support Efficacy .............................................47

Clinical Review
Brenda Carr, MD
BLA 761055
6.1. R668-AD-1334 (1334); SOLO 1 .......................................................................................47

“A Phase 3 Confirmatory Study Investigating the Efficacy and Safety of Dupilumab
Monotherapy Administered to Adult Patients with Moderate-to-Severe Atopic Dermatitis”.47
6.1.1. Study Design ...........................................................................................................47
6.1.2. Study Results ..........................................................................................................60
6.2. R668-AD-1416 (1416); SOLO 2 .......................................................................................73
Monotherapy Administered to Adult Patients with Moderate to Severe Atopic Dermatitis” .73
6.2.1. Study Design ...........................................................................................................73
6.2.2. Study Results ..........................................................................................................73
6.3. R668-AD-1224 (1224); CHRONOS .................................................................................83
6.3.1. Study Design ...........................................................................................................83
6.3.2. Study Results ..........................................................................................................94
7 Integrated Review of Effectiveness.....................................................................................110

7.1. Assessment of Efficacy Across Trials ............................................................................110
7.1.1. Primary Endpoints ................................................................................................110
7.1.2. Secondary and Other Endpoints ...........................................................................111
7.1.3. Subpopulations .....................................................................................................113
7.1.4. Dose and Dose-Response .....................................................................................114
7.1.5. Onset, Duration, and Durability of Efficacy Effects...............................................115
7.2. Additional Efficacy Considerations...............................................................................115
7.2.1. Considerations on Benefit in the Postmarket Setting...........................................115
7.2.2. Other Relevant Benefits........................................................................................115
7.3. Integrated Assessment of Effectiveness ......................................................................116
8 Review of Safety..................................................................................................................120
8.1. Safety Review Approach ..............................................................................................120
8.2. Review of the Safety Database ....................................................................................122
8.2.1. Overall Exposure...................................................................................................122
8.2.2. Relevant characteristics of the safety population: ...............................................128
8.2.3. Adequacy of the safety database: ........................................................................128
8.3. Adequacy of Applicant’s Clinical Safety Assessments..................................................129

Clinical Review
Brenda Carr, MD
BLA 761055
8.3.1. Issues Regarding Data Integrity and Submission Quality......................................129

8.3.2. Categorization of Adverse Events .........................................................................129
8.3.3. Routine Clinical Tests............................................................................................129
8.4. Safety Results...............................................................................................................129
8.4.1. Deaths...................................................................................................................129
8.4.2. Serious Adverse Events.........................................................................................131
8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects..................................140
8.4.4. Significant Adverse Events....................................................................................144
8.4.5. Treatment Emergent Adverse Events and Adverse Reactions .............................169
8.4.6. Laboratory Findings ..............................................................................................176
8.4.7. Vital Signs..............................................................................................................183
8.4.8. Electrocardiograms (ECGs) ...................................................................................187
8.4.9. QT .........................................................................................................................189
8.4.10. Immunogenicity.............................................................................................189
8.5. Analysis of Submission-Specific Safety Issues ..............................................................192
8.5.1. Eye Disorders ........................................................................................................192
8.5.2. Herpes Virus Infections.........................................................................................199
8.6. Specific Safety Studies/Clinical Trials ...........................................................................201
8.7. Additional Safety Explorations .....................................................................................202
8.7.1. Human Carcinogenicity or Tumor Development ..................................................202
8.7.2. Human Reproduction and Pregnancy...................................................................203
8.7.3. Pediatrics and Assessment of Effects on Growth .................................................205
8.7.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound ..............................206
8.8. Safety in the Postmarket Setting .................................................................................206
8.8.1. Safety Concerns Identified Through Postmarket Experience ...............................206
8.8.2. Expectations on Safety in the Postmarket Setting................................................207
8.9. Additional Safety Issues From Other Disciplines..........................................................207
8.10. Integrated Assessment of Safety..............................................................................207
9 Advisory Committee Meeting and Other External Consultations .......................................209
10 Labeling Recommendations ................................................................................................209

Clinical Review
Brenda Carr, MD
BLA 761055
10.1. Prescribing Information............................................................................................209

10.2. Patient Labeling........................................................................................................210
10.3. Non-Prescription Labeling ........................................................................................210
11 Risk Evaluation and Mitigation Strategies (REMS) ..............................................................210
12 Postmarketing Requirements and Commitments...............................................................210
13 Appendices..........................................................................................................................211
13.1. References................................................................................................................211
13.2. Financial Disclosure ..................................................................................................211

Clinical Review
Brenda Carr, MD
BLA 761055
Table of Tables
Table 1. Effect of body weight on IGA 0/1 response rates at Week 16 in Phase 3 studies* ........36
Table 2. Listing of Clinical Trials Relevant to this BLA...................................................................41
Table 3. Features to be considered in the diagnosis of patients with atopic dermatitis*...........52
Table 4. Table of Schedule of Events ............................................................................................53
Table 5. Table of Schedule of Events ...........................................................................................55
Table 6. Investigator’s Global Assessment (IGA) Scale ................................................................57
Table 7. Initial Treatment Period Subject Disposition for Trials 1334* ........................................61
Table 8. Summary of Protocol Deviations – All Randomized Subjects* .......................................62
Table 9. Summary of Baseline Demographic Characteristics* ......................................................63
Table 10. Baseline Disease Characteristics* .................................................................................64
Table 11. Medical History Findings (≥10% of Patients in Any Treatment Group) by Primary
System Organ Class and Preferred Term – SAF: ...........................................................................64
Table 12. Atopic/Allergic Disease History – SAF* .........................................................................66
Table 13. Compliance with Background Moisturizer (Emollient)* ...............................................66
Table 14. Number (%) of Patients Taking Rescue Treatment During the 16-Week Treatment
Period – FAS*................................................................................................................................68
Table 15.Table Proportion of Subjects Achieving Treatment Success at Week 16 for Trial 1334*
......................................................................................................................................................69
Table 16. Proportion of subjects with EASI75 (≥75% improvement from baseline) at Week 16*71
Table 17. Proportion of subjects with improvement (reduction) of weekly average of peak daily
pruritus ≥4 from baseline to Week 16..........................................................................................71
Table 18. Proportion of Subjects with at least 4-point change from baseline Weeks 2, 4, 16 for
Trials 1334* ..................................................................................................................................71
Table 19. IGA Responders by Baseline IGA Severity for Trial 1334*.............................................72
Table 20. Initial Treatment Period Subject Disposition for Trials 1416* .....................................74
Table 21. Summary of Protocol Deviations – All Randomized Patients*......................................75
Table 22. Summary of Baseline Demographic Characteristics* ....................................................75
Table 23. Baseline Disease Characteristics for Study 1416*........................................................76
Table 24. Medical History Findings (≥10% of Patients in Any Treatment Group) by Primary
System Organ Class and Preferred Term – SAF* ..........................................................................77
Table 25. Table 10: Atopic/Allergic Disease History – SAF* .........................................................78
Table 26. Compliance with Background Moisturizer (Emollient)* ...............................................79
Table 27. Proportion of Subjects Achieving Treatment Success at Week 16 for Trial 1416* .......80
Table 28. Proportion of subjects with EASI75 (≥75% improvement from baseline) at Week 16*81
pruritus ≥4 from baseline to Week 16*........................................................................................81
Trials 1334* ..................................................................................................................................82
Table 31. IGA Responder by Baseline IGA Severity for Trial 1416* ..............................................82

Clinical Review
Brenda Carr, MD
BLA 761055
Table 32. Schedule of Events - Screening, Baseline, and Treatment Period – Visits 1 through 14*
......................................................................................................................................................87
Table 33. Schedule of Events - Treatment Period Cont. – Visits 15 through 27* .........................89
Table 34. Schedule of Events – Follow-up, Unscheduled Visit, and Early Termination* ..............91
Table 35. Initial (16-week) Treatment Period Subject Disposition for Trial 1224*.......................95
Table 36. Summary of Subject Accountability and Study Disposition – All Randomized Subjects*
......................................................................................................................................................96
Table 37. Summary of Major Protocol Deviations – All Randomized Patients* ...........................98
Table 38. Baseline Demographics for Trial 1224* ........................................................................99
Table 39. Baseline Disease Severity for Trial 1224* ...................................................................100
Table 40. Medical History Findings (≥5% of Patients in Any Treatment Group) by Primary System
Organ Class and Preferred Term– SAF*......................................................................................101
Table 41. Atopic/Allergic Disease History – SAF* .......................................................................102
Table 42. Compliance with Background Moisturizer (Emollient)* .............................................103
Table 43. Rescue Medication Taken during the 16-Week Period – SAF* ...................................105
Table 44. Rescue Medication Taken during the 52-Week Period*.............................................106
Table 45. Proportion of Subjects Achieving Treatment Success at Week 16 for Combination Trial
1224*..........................................................................................................................................106
Table 46. Proportion of subjects with EASI75 (≥75% improvement from baseline) at Week 16*
....................................................................................................................................................108
pruritus ≥4 from baseline to Week 16*......................................................................................108
Trial 1224*..................................................................................................................................109
Table 49. Proportion of Subjects with IGA success(1) at Week 52 among those that were IGA
responders(1) at Week 16 for Trial 1224*..................................................................................109
Table 50. Success on the IGA at Week 16 by Baseline IGA Severity for Trial 1224*...................110
Table 51. Proportion of Subjects Achieving Treatment Success at Week 16 for Monotherapy
Studies 1334, 1416* ...................................................................................................................111
Table 52. Proportion of Subjects Achieving Treatment Success at Week 16 for Combination
Study 1224*................................................................................................................................111
Table 53. Proportion of Subjects Achieving Treatment Success at Week 16 for Monotherapy
Studies 1334, 1416* ...................................................................................................................112
Table 54. Proportion of Subjects Achieving Treatment Success at Week 16 for Study 1224*...112
Table 55. Efficacy (IGA 0 or 1) by Baseline Demographics for Studies 1334 and 1416*.............113
Table 56. Efficacy (IGA 0 or 1) by Baseline Demographics for Trial 1224* .................................113
Table 57. IGA Responder by Baseline IGA Severity for Studie 1334 and 1416* .........................114
Table 58. Success on the IGA at Week 16 by Baseline IGA Severity for Study 1224*.................114
Table 59. Efficacy Results of DUPIXENT Monotherapy at Week 16 (FAS) ..................................119
Table 60. Efficacy Results of DUPIXENT with Concomitant TCSa at Week 16 .............................120
Table 61. Sample Size by Study Number – Primary Safety Pool - (All Enrolled Subjects)* .........123

Clinical Review
Brenda Carr, MD
BLA 761055
Table 62. Primary Reason for Withdrawal from Study - Primary Safety Pool – SAF*.................123
Table 63. Summary of Patient Accountability and Study Disposition – R668-AD-1224 - All
Randomized Subjects*................................................................................................................124
Table 64. Treatment Exposure and Duration of Observation Period – R668-AD-1224 -SAF* ....125
Table 65. Summary of Treatment Exposure Study 1225– SAF* .................................................125
Table 66. Study R668-AD-1224: Summary of Patient Accountability and Study Disposition during
the Study Period, Cumulative until 31 August 2016 - All Randomized Patients*.......................126
Table 67. Study R668-AD-1225: Summary of Patient Accountability and Study Disposition –
Cumulative until 23 August 2016 (SAF)* ....................................................................................127
Table 68. Number of Patients with Serious Treatment-Emergent Adverse Events by Primary
System Organ Class and Preferred Term – 16-Week Period - Primary Safety Pool – SAF* ........132
Table 69. Number of Subjects with Serious Treatment-Emergent Adverse Events by Primary
System Organ Class and Preferred Term - 52-Week Period – R668-AD-1224 – SAF* ................136
Table 70. Number of Subjects with Serious Treatment-Emergent Adverse Events (TEAE) per 100
Subject-years during 52-Week Period by Primary System Organ Class and Preferred Term-Study
1224 (Safety Analysis Set)*.........................................................................................................137
Table 71. Summary of Treatment-Emergent Adverse Events Leading to Permanent
Discontinuation of Study Drug by SOC and PT – Primary Safety Pool - Entire Study Period – SAF*
....................................................................................................................................................140
Table 72. Number of Subjects with Treatment-Emergent Adverse Events Leading to Permanent
Study Drug Discontinuation During the 52-Week Period by Primary System Organ Class and
Preferred Term-Study 1224 – SAF* ............................................................................................141
Table 73. Summary of Treatment-Emergent Adverse Events Leading to Permanent Study Drug
Discontinuation in Dupilumab-naïve and Re-treated Patients by System Organ Class and
Preferred Term- 1225 – SAF* .....................................................................................................142
Table 74. Severe Treatment-Emergent Adverse Events by SOC and PT – 16-Week Treatment
Period – Primary Safety Pool – SAF (next page)* ......................................................................145
Table 75. Number of Patients with Severe Treatment-Emergent Adverse Events During the 16-
Week Period by Primary System Organ Class and Preferred Term-Study 1224 – SAF* .............147
Table 76. Number of Subjects with Severe Treatment-Emergent Adverse Events (TEAE) per 100
Subject-Years during 52-Week Period by Primary System Organ Class and Preferred Term
(Safety Analysis Set)*..................................................................................................................148
Table 77. Search Criteria for Treatment-Emergent Adverse Event of Special Interest* ............152
Table 78. Overall Summary of Number of Patients with Treatment-Emergent Adverse Events of
Special Interest – Treatment Period and Follow-Up Period -Primary Safety Pool*....................153
Table 79. Overall Summary of Number of Subjects with Serious Treatment-Emergent Adverse
Events of Special Interest – Treatment Period and Follow-Up Period - Primary Safety Pool* ...154
Table 80. Number of Subjects with Treatment-Emergent Adverse Events of Special Interest
during the 16-Week Period by AESI Category, High Level Term, and Preferred Term-Study 1224–
SAF* ............................................................................................................................................155

Clinical Review
Brenda Carr, MD
BLA 761055
Table 81. Number of Subjects with Treatment-Emergent Adverse Events of Special Interest
during the 52-Week Treatment Period by AESI Category, High Level Term, and Preferred Term-
Study 1224 – SAF* ......................................................................................................................157
Table 82. Table 32: Summary of Treatment-Emergent Adverse Events of Special Interest – SAF
....................................................................................................................................................159
Table 83.p. 149Table 53: Summary of Treatment-Emergent Adverse Events of Special Interest
Opportunistic Infection by HLT and PT – Treatment Period and Follow-Up Period - Primary
Safety Pool*................................................................................................................................160
Table 84. Number of Patients with Treatment-Emergent Adverse Events of Special Interest
Study 1224 – SAF* ......................................................................................................................160
during the 52-Week Treatment Period by AESI Category, High Level Term, and Preferred Term –
SAF* ............................................................................................................................................161
Table 86. Summary of Treatment-Emergent Adverse Events of Special Interest Any Severe
Infection by HLT and PT – 16-Week Treatment Period - Primary Safety Pool*..........................162
during the 52-Week Treatment Period by AESI Category, High Level Term, and Preferred Term –
SAF* ............................................................................................................................................163
Study 1224 – SAF* ......................................................................................................................164
Table 89. Summary of Treatment-Emergent Adverse Events of Special Interest Acute Allergic
Reactions Requiring Treatment by HLT and PT – Treatment Period - Primary Safety Pool*......166
Table 90. Summary of Treatment-Emergent Adverse Events of Special Interest Suicidal Behavior
by HLT and PT – 16-Week Treatment Period - Primary Safety Pool* .........................................168
Table 91. Number of Subjects with Treatment-Emergent Adverse Events ≥1% in any Treatment
Group by Primary System Organ Class and Preferred Term – 16-Week Treatment Period -
Primary Safety Pool – SAF*.........................................................................................................170
Table 92. Number of Subjects with Treatment-Emergent Adverse Events ≥1% in any Treatment
Group by Primary System Organ Class and Preferred Term – 16-Week Data - R668-AD-1224 –
SAF* ............................................................................................................................................172
Table 93. Number of Patients with Treatment-Emergent Adverse Events ≥2% in any Treatment
Group by Primary .......................................................................................................................174
Table 94. Summary statistics for Hematology (Red Blood Cells and Platelets) values and changes
from baseline by visit platelets*.................................................................................................176
Table 95. Summary statistics for Hematology (White Blood Cells) values and changes from
baseline by visit (Safety Analysis Set)* .......................................................................................178
baseline by visit Eosinophils (Safety Analysis Set)* ...................................................................179

Clinical Review
Brenda Carr, MD
BLA 761055
Table 97. Summary statistics for Hematology (Red Blood Cells and Platelets) values and changes
from baseline by visit platelets*.................................................................................................181
baseline by visit (Safety Analysis Set)* .......................................................................................182
Table 99. Summary of Treatment Emergent potentially clinical significant value (PCSV) for vital
sign and weight (Safety Analysis Set)* .......................................................................................183
Table 100. Summary of Treatment Emergent potentially clinical significant value (PCSV)*......184
Table 101. Shift Table for Electrocardiogram (ECG) status by Visit(Safety Analysis Set)*..........187
Table 102. Shift Table for Electrocardiogram (ECG) status by Visit (Safety Analysis Set)*.........188
Table 103. Summary of incidences of anti-drug antibodies (ADA), treatment-emergent ADA
(TEADA) and neutralizing ADA (NAb) in AD Phase 3 studies.* ...................................................189
Table 104. Table 3: Search Criteria for Conjunctivitis Events* ...................................................191
Table 105. Number of Subjects with Narrow Conjunctivitis CMQ by PT Primary Safety Pool – 16-
Week...........................................................................................................................................193
Table 106. Number of Subjects with Narrow Conjunctivitis Events Per 100 Patient-Years by
Preferred Term during the 52-Week Treatment Period (Safety Analysis Set)............................194
Table 107. Number of Patients with Broad Conjunctivitis CMQ by PT Primary Safety Pool-
Treatment Period - SAF Dupilumab* ..........................................................................................195
Table 108. Number of Patients with Broad Conjunctivitis Events per 100 Patient-Years by
Preferred Term during the 52-week Treatment Period (Safety Analysis Set)* ..........................196
Table 109. Number of patients with treatment-emergent adverse events (TEAE) during the
treatment period by high level term and preferred term (Safety Analysis Set)* .......................196
Table 110. Number of patients with treatment-emergent adverse events (TEAE) during the 16-
week period by primary system organ class, high level term and preferred term (Safety Analysis
Set)*............................................................................................................................................197
Set)*............................................................................................................................................197
Table 112. Number of patients with Treatment Emergent Adverse Events per 100 Patient-years
during 52-week period by primary System Organ Class and Preferred Term (Safety Analysis
Set)*............................................................................................................................................198
Table 113. Number of subjects with treatment-emergent adverse events (TEAE) during the
treatment period by preferred term (Safety Analysis Set)* .......................................................199
Set)*............................................................................................................................................199
Table 115. Number of patients with Treatment Emergent Adverse Events per 100 Patient-years
during 52-week period by primary System Organ Class and Preferred Term (Safety Analysis
Set)*............................................................................................................................................200

Clinical Review
Brenda Carr, MD
BLA 761055
Table of Figures
Figure 1. Study Flow Diagram .......................................................................................................50

Figure 2. Peak Pruritus NRS* .......................................................................................................58
Figure 3. Success on the IGA(1) for the initial treatment period for Trial 1334* .........................70
Figure 4. Success on the IGA(1) for the initial treatment period for Trial 1416*.........................80
Figure 5. Study Flow Diagram* .....................................................................................................85
Figure 6. Success on the IGA(1) for the initial treatment period for Trial 1224* .........................107
Figure 7. Mean Change (+/-SE) of Hematology (Red Blood Cells and Platelets) From Baseline.177
Figure 8. Mean Change (+/-SE) of Hematology (White Blood Cells) From Baseline (Safety
Analysis Set)(Safety Analysis Set)* .............................................................................................178
Figure 9. Mean Change (+/-SE) of Hematology (White Blood Cells) From Baseline (Safety
Analysis Set)*..............................................................................................................................179
Figure 10. Mean Change (SE) in Sitting Systolic Blood Pressure (mmHg) from Baseline through
Week 52 TreatmentPeriod – SAF*..............................................................................................185
Figure 11. Mean Change (+/-SE) of sitting systolic blood Pressure (mmHg) From Baseline(Safety
Analysis Set)*..............................................................................................................................186

Clinical Review
Brenda Carr, MD
BLA 761055
Glossary
AC advisory committee
AE adverse event
AAD American Academy of Dermatology
ADA anti-drug antibodies
BLA biologics license application
BPCA Best Pharmaceuticals for Children Act
BRF Benefit Risk Framework
BSA body surface area
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CDRH Center for Devices and Radiological Health
CDTL Cross-Discipline Team Leader
CFR Code of Federal Regulations
CMC chemistry, manufacturing, and controls
COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms
CRF case report form
CRO contract research organization
CRT clinical review template
CSR clinical study report
CSS Controlled Substance Staff
DMC data monitoring committee
EASI eczema area and severity index
ECG electrocardiogram
eCTD electronic common technical document
ETASU elements to assure safe use
FDA Food and Drug Administration
FDAAA Food and Drug Administration Amendments Act of 2007
FDASIA Food and Drug Administration Safety and Innovation Act
GCP good clinical practice
GRMP good review management practice
ICH International Conference on Harmonization
IND Investigational New Drug
IGA Investigator Global Assessment
ISE integrated summary of effectiveness
ISS integrated summary of safety
ITT intent to treat
Clinical Review
Brenda Carr, MD
BLA 761055
IVRS interactive voice response system

IWRS interactive web responses system
LTT long-term treatment
MedDRA Medical Dictionary for Regulatory Activities
mITT modified intent to treat
NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event
NDA new drug application
NME new molecular entity
NRS numeric rating scale
OCS Office of Computational Science
OLE open label extension
OPQ Office of Pharmaceutical Quality
OSE Office of Surveillance and Epidemiology
OSI Office of Scientific Investigation
PBRER Periodic Benefit-Risk Evaluation Report
PD pharmacodynamics
PFS pre-filled syringe
PI prescribing information
PK pharmacokinetics
PMC postmarketing commitment
PMR postmarketing requirement
PP per protocol
PPI patient package insert
PREA Pediatric Research Equity Act
PRO patient reported outcome
PSUR Periodic Safety Update report
REMS risk evaluation and mitigation strategy
SAE serious adverse event
SAP statistical analysis plan
SEALD Study Endpoints and Labeling Development
SGE special government employee
SOC standard of care
SUR safety update report
TCI topical calcineurin inhibitors
TCS topical corticosteroids
TEAE treatment emergent adverse event

Clinical Review
Brenda Carr, MD
BLA 761055
1 Executive Summary
1.1. Product Introduction
Dupilumab is a recombinant human immunoglobulin-G4 (IgG4) monoclonal antibody (mAb) that

inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4
receptor alpha (IL-4Rα) sub-unit shared by the IL-4 and IL-13 receptor complexes. Dupilumab
inhibits IL-4 signaling via the Type I receptor, and both IL-4 and IL-13 signaling through the Type
II receptor.
Dupilumab belongs to the pharmacological class of immunomodulators, interleukin inhibitors. It

is a new molecular entity (NME), and the proposed proprietary name is “Dupixent.”
The proposed indication for dupilumab is for the treatment of adult patients with
moderate-to-severe atopic dermatitis (AD) whose disease is not adequately controlled with
topical prescription therapies or when those therapies are not advisable.
The recommended dose of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg
injections), followed by 300 mg given every other week (Q2W). It is administered by
subcutaneous injection.
Dupilumab can be used with or without topical corticosteroids and topical calcineurin inhibitors,
which should be reserved for problem areas only, such as the face, neck, intertriginous and
genital areas.
1.2. Conclusions on the Substantial Evidence of Effectiveness
The Applicant provided substantial evidence of effectiveness from 3 adequate and well-
controlled studies that evaluated dupilumab for treatment of adult subjects with moderate-to-
severe atopic dermatitis whose disease was not adequately controlled with topical prescription
therapies or when those therapies were not advisable. Two replicate studies evaluated
dupilumab as monotherapy, and the third study evaluated dupilumab with protocol-specified,
concomitant use of topical corticosteroids TCS. Dupilumab was statistically superior to placebo
in all 3 studies in the target AD population for the primary endpoint, the proportion of subjects
with both Investigator’s Global Assessment (IGA) 0 to 1 (on a 5-point scale) and a reduction
from baseline of ≥2 points at Week 16. The treatment response was generally similar across the

Clinical Review
Brenda Carr, MD
BLA 761055
3 studies.
1.3. Benefit-Risk Assessment
Appears this way on original

Clinical Review
Brenda Carr, MD
BLA 761055
Benefit-Risk Summary and Assessment
Dupilumab is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signaling by specifically
binding to the IL-4 receptor alpha sub-unit shared by the IL-4 and IL-13 receptor complexes. It is a new molecular entity, proposed for the
treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription
therapies or when those therapies are not advisable.
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory cutaneous disorder, which is characterized by intensely pruritic, xerotic skin. Other
clinical features may include erythema, edema, erosions, oozing, and lichenification. Although it may affect all age groups, AD is most common
in children. Onset is typically between the ages of 3 and 6 months, with approximately 60% of patients developing the disease during the first
year of life and 90% by the age of 5 years. For 10-30% of individuals, AD persists into adulthood. The prevalence is estimated to be
approximately 3% in adults.
The Applicant provided substantial evidence of effectiveness from 3 adequate and well-controlled studies that evaluated dupilumab in the
target population. Two replicate studies evaluated dupilumab as monotherapy, and the third study evaluated dupilumab with protocol-
specified, concomitant use of topical corticosteroids (TCS) (with allowance for use of topical calcineurin inhibitors). Dupilumab was statistically
superior to placebo in all 3 studies in the target AD population for the primary endpoint, the proportion of subjects with both Investigator’s
Global Assessment (IGA) 0 to 1 (on a 5-point scale) and a reduction from baseline of ≥2 points at Week 16. The proportion of IGA responders, in
the 300 mg Q2W regimen recommended for approval, was 38% and 36% in the monotherapy studies and 39% in concomitant TCS study. The
treatment response was generally similar across the 3 studies.
The Applicant adequately characterized the safety profile of dupilumab through analyses of data from the safety database of 2,526 subjects.
The numbers of subjects with dupilumab exposures at relevant doses exceeded those recommended in the ICH E1A guideline. The safety
profiles were similar whether dupilumab was administered as monotherapy or whether with concomitant topical corticosteroids. Dupilumab
was generally well tolerated under both treatment regimens. No deaths were considered to be treatment related. The highest incidence rates
of treatment-emergent adverse events (TEAEs) were reported in the Infections and Infestations category. The most common adverse events
(AEs) in that category for dupilumab and placebo groups included Nasopharyngitis, Upper respiratory tract infection, Conjunctivitis, and Oral
Herpes. The safety analyses identified signals for AEs relating to the eye, and those AEs included conjunctivitis (most commonly), blepharitis
and dry eye. These events were generally mild to moderate in severity and did not lead to discontinuation of treatment. The Applicant

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BLA 761055
performed comprehensive, post hoc analyses of the Phase 3 safety database to further evaluate the signal for eye disorders. Additionally, the
Applicant has amended the protocol for an ongoing open-label extension (OLE) study to incorporate scheduled assessments of a subset of
subjects by ophthalmologists. The Applicant also identified a signal for herpes virus infections (oral herpes and Herpes simplex, not otherwise
specified), which can also be further evaluated in the OLE study. Information from this study along with product labeling and routine
pharmacovigilance activities should serve as adequate risk mitigation strategies. I conclude that the Applicant has established that the benefits
of dupilumab for treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with
topical prescription therapies or when those therapies are not advisable outweigh its risks.
Dimension Evidence and Uncertainties Conclusions and Reasons
• Atopic dermatitis (AD) is a chronic, relapsing, inflammatory cutaneous While AD may not be a life-threatening
disorder, which is characterized by intensely pruritic, xerotic skin. condition, it can be serious. It may significantly
Other clinical features may include erythema, edema, erosions, impact the quality of life not only of the
oozing, and lichenification. It is clinically diagnosed and relies patient, but also of family members. The
principally on disease pattern (morphology and distribution), intense pruritus may disrupt sleep, which can
disease history, and medical history (e.g., personal and/or family have carryover effects of tiredness during the
history of atopy). day. The dysfunctional skin barrier, further
• Although it may affect all age groups, AD is most common in children. compromised from scratching, may predispose
Analysis of
Onset is typically between the ages of 3 and 6 months, with patients to secondary infections. The primary
Condition
approximately 60% of patients developing the disease during the and secondary disease-related skin changes
first year of life and 90% by the age of 5 years. For most patients, may distort the appearance of the skin. The
the disease resolves by adulthood. However, for 10-30% of disease may also have impact on the mood,
individuals, AD persists into the adult years, and, for a smaller and affected individuals may experience
proportion of subjects, the disease initially presents in adulthood. depression and feelings of social isolation.
The prevalence in adults in the United States may be approximately
3%.
• Co-morbidities may include asthma, allergic rhinoconjunctivitis, and

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BLA 761055

food allergies.
• For the Applicant’s target population, the only available FDA- The medical need of the patient population
approved systemic treatment is corticosteroids. The American with moderate-to-severe AD is not currently
Academy of Dermatology (AAD) recommends that systemic being adequately met by currently available
corticosteroids generally be avoided because of the potential for therapies. Approval of dupilumab would
short- and long-term adverse reactions. Phototherapy is an option for represent an important addition to the
this population, but its drawbacks include a potentially time-intensive, treatment options for patients with moderate-
in-office treatment schedule. Risks from phototherapy may vary to-severe AD that is not manageable by topical
according to the type of phototherapy and may include actinic therapies, a population for whom approved
damage, sunburn-like reactions, skin cancer (nonmelanoma and treatment options are extremely limited. In
Current melanoma), and cataracts. Systemic products that are used off-label my opinion, dupilumab would considerably
Treatment to treat moderate-to-severe AD include cyclosporine, azathioprine, advance the state of the treatment
Options methotrexate, and mycophenolate mofetil. armamentarium for this population. It would
be the first systemic product approved for AD
since corticosteroids.
It would represent a safe and effective
alternative to corticosteroids, the only
approved systemic treatment for this
indication and a treatment that is generally not
recommended for treatment of AD.

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• The Applicant provided substantial evidence of effectiveness from 3 I conclude that the submitted evidence has
adequate and well-controlled studies that evaluated dupilumab for met the evidentiary standard for providing
treatment of adult subjects with moderate-to-severe atopic substantial evidence of effectiveness. The
dermatitis whose disease was not adequately controlled with Applicant has established that dupilumab is
topical prescription therapies or when those therapies were not effective for treatment of the target AD
advisable. Two replicate studies evaluated dupilumab as population.
monotherapy, and the third study evaluated dupilumab with
protocol-specified, concomitant use of TCS. Dupilumab was
statistically superior to placebo in all 3 studies in the target AD
Benefit population for the primary endpoint, the proportion of subjects
with both Investigator’s Global Assessment (IGA) 0 to 1 (on a 5-
point scale) and a reduction from baseline of ≥2 points at Week 16.
The treatment response was generally similar across the 3 studies.
The proportions of IGA responders in the 300 mg Q2W regimen
recommended for approval were 38% and 36% in the monotherapy
studies and 39% in concomitant TCS study. Dupilumab was also
statistically superior to placebo for the key secondary endpoints of
≥ 4-point reduction in pruritus and ≥ 75% reduction in Eczema Area
and Severity Index (EASI-75) score.
• The Applicant comprehensively assessed the safety of dupilumab in The size of the safety database and the scope
the target population. The safety database consisted of 2,526 of the safety analyses were sufficient to
subjects exposed to dupilumab in 11 studies in the clinical characterize the safety profile of dupilumab.
Risk development program. The numbers of subjects at relevant The safety analyses revealed adverse reactions
exposures exceeded those recommended for the time points that might be considered foreseeable with SC
outlined in the ICH E1A guideline. The types and frequency of the administration of a biologic (injection site
safety evaluations identified local and systemic treatment-emergent reactions, hypersensitivity reactions). The

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adverse events (TEAEs) that might be expected from subcutaneous safety analyses also revealed unexpected
injection of a biologic product, including injection site reactions and adverse reactions in the form of signals for eye
hypersensitivity. The Applicant identified a signal for eye disorders disorders and herpes virus infections.
(conjunctivitis, blepharitis, and dry eye) on analyses of the Phase 3 However, the safety analyses generally did not
data and conducted extensive analyses of their Phase 3 database to reveal any worrisome types or patterns of
evaluate the signal. Most events were mild to moderate in severity, events. Dupilumab was generally well-
did not lead to discontinuation of treatment, and resolved or were tolerated.
resolving during treatment. The Applicant also amended the
protocol for an ongoing open-label extension study to formally
incorporate ophthalmological examination at specified time points
at select centers for certain subjects. These efforts may be helpful in
further evaluating the signal and, along with routine
pharmacovigilance, may be helpful in further defining and
identifying the nature of this risk.
• The Applicant also identified a signal for herpes virus infections
(oral herpes and “Herpes simplex” not otherwise specified). The
incidence rates of eczema herpeticum and herpes zoster were
either similar between placebo and dupilumab groups or higher in
the placebo group relative to the dupilumab groups. Eczema
herpeticum was considered to be an SAE for one subject in the
safety database, and that subject was in the placebo group.
Subjects who developed eczema herpeticum or herpes zoster while
receiving dupilumab either had the study treatment temporarily
held until resolution of the infection or continued study treatment
according to schedule; all ultimately completed dupilumab
treatment. The generalizability of this approach (holding or
continuing dupilumab) is unclear, as there were too few subjects
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who experienced these events. However, this may be a
management consideration for patients who develop either of
these events.
The signals for eye disorders and herpes virus infections have not
been observed in other dupilumab clinical development programs.
• No serious safety concerns were identified that might require risk Risks associated with dupilumab can be
management beyond labeling and routine pharmacovigilance. No adequately managed by product labeling and
serious safety concerns were identified that warranted consideration routine pharmacovigilance. The risks of eye
of a Risk Evaluation and Mitigation Strategy (REMS). disorders can be further managed by
• Atopic dermatitis (AD) occurs most commonly in children, and the continued assessment in the ongoing open-
safety and efficacy of dupilumab for AD in children have not been label study, which includes ophthamological
established. The Applicant has an Agreed initial Pediatric Study Plan study procedures. The signal for herpes virus
(iPSP) which covers cohorts down to 6 months of age. These infections can also continue to be assessed in
Risk pediatric studies are deferred because the adult studies are ready this study.
Management for approval. Studies are waived for subjects younger than 6 Labeling will reflect that dupilumab is indicated
months because study of these subjects would be impossible or for adult patients. The pediatric studies
highly impractical as dupilumab is being developed for the outlined in the iPSP will be listed as Pediatric
treatment of moderate-to-severe atopic dermatitis in patients who Research Equity Act (PREA) postmarketing
are not adequately controlled with, or who are intolerant to topical requirements (PMRs). The Applicant will
medications, and it would be impractical to make this evaluate the safety and efficacy of dupilumab
determination in patients younger than 6 months of age. in pediatric subjects in a comprehensive
• Pregnant and breastfeeding women, and women planning to become clinical program.
pregnant and breastfeed during the study were excluded from

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participation in the studies. Therefore, evaluations of patients in
these categories will be conducted as postmarketing requirements.

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BLA 761055
2 Therapeutic Context
2.1. Analysis of Condition
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory cutaneous disorder, which is

characterized by intensely pruritic, xerotic skin. Other clinical features may include erythema,
edema, erosions, oozing, and lichenification. Although it may affect all age groups, AD is most
common in children. Onset is typically between the ages of 3 and 6 months, with approximately
60% of patients developing the disease during the first year of life and 90% by the age of 5
years.1 For most patients, the disease resolves by adulthood. However, for 10-30% of
individuals, AD persists into the adult years, and, for a smaller proportion of subjects, the
disease initially presents in adulthood.1 A population–based study found a prevalence of 3.2%
for AD in adults in the United States.2
AD is clinically diagnosed and relies principally on disease pattern (morphology and

distribution), disease history, and medical history (e.g., personal and/or family history of atopy).
However, biopsy may be appropriate to exclude other diagnoses, e.g. cutaneous T-cell
lymphoma, in some clinical settings. Common comorbidities include asthma, allergic rhinitis/
rhinoconjunctivitis, and food allergies.1 Patients with AD often experience sleep disturbance,
largely attributable to the associated pruritus. During disease flares, approximately 80% of
patients may experience disturbed sleep. Sleep disturbance in the AD patient may also disrupt
the sleep of family members.1 The disease may also have impact on mood, and affected
individuals may experience depression.1,3 A longitudinal cohort study found that patients with
AD may be at increased risk for major depression, any depressive disorder and anxiety
disorders.4
Patients with AD are predisposed to colonization or infection by microbes, particularly

Staphylococcus aureus and herpes simplex virus. The susceptibility to S. aureus is related to
1 Eichenfield LF et al. Guidelines of care for the management of atopic dermatitis Section 1. Diagnosis and
assessment of atopic dermatitis. J Am Acad Dermatol 2014;70:338-51.
2 Silverberg JI and Hanifin JM. Adult eczema prevalence and associations with asthma and other health and
demographic factors: A US population–based study. J Allergy Clin Immunol 2013;132:1132-8.

3 Drucker AM et al. The Burden of Atopic Dermatitis: Summary of a Report for the National Eczema Association. J
Invest Dermatol (2017) 137, 26-30.

4 Weston WL and Howe W. Pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis (eczema).
UpToDate


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BLA 761055
multiple factors, including the abnormal skin barrier function and the production of serine
proteases that degrade the skin barrier.5
The most common laboratory finding is an elevated IgE.1 Approximately 80% of the
AD population has elevated IgE and/or shows immediate skin test positivity to allergens.
However, 20% of patients show no IgE to tested food or inhalant allergens.5 Some patients with
severe AD have normal IgE levels. Additionally, increased allergen-specific IgE is found in 55% of
the general population in the United States. Thus, this finding is nonspecific.1
The pathogenesis involves a complex interplay of genetic, immunological and environmental

factors that result in abnormal skin barrier function and immune system dysfunction.
Irregularities in the terminal differentiation of the epidermal epithelium lead to a faulty stratum
corneum which permits the penetration of environmental allergens. The exposure to allergens
may ultimately result in systemic sensitization and may predispose AD patients to other
conditions, such as asthma and food allergies.5
Acute AD is associated with cytokines produced by T helper 2 type (Th2) cells (as well as other
T-cell subsets and immune elements).5 These cytokines are thought to play an important role in
the inflammatory response of the skin, and IL-4 and IL-13 may have distinct functional roles in
Th2 inflammation.6 IL-4 has been shown to stimulate IgE production from B cells.7 IL-13
expression correlates with disease severity and flares.7 IL-4 mediates its biological activity via
binding to IL-4Rα. IL-13 receptor alpha 1 (IL-13Rα1) may then be recruited to form a signaling
complex. IL-13 mediates its biological activity via binding to IL-13Rα1 and subsequent
recruitment of IL-4Rα, forming a signaling complex.7 IL-4 and IL-13 reside on chromosome
5q23-31, among a grouping of genes related to development of allergic diseases.7 Dupilumab
inhibits downstream effects of IL-4 and IL-13 by blocking the shared IL-4 receptor alpha (IL-4Rα)
subunit.8
2.2. Analysis of Current Treatment Options
5 Leung DYM, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: Shifting paradigms in
treatment approaches. J Allergy Clin Immunol 2014;134:769-79.
6 Bao K and Reinhardt RL. The differential expression of IL-4 and IL-13 and its impact on type-2 Immunity.Cytokine
75 (2015) 25-37.
7 May RD, Fung M. Strategies targeting the IL-4/IL-13 axes in disease. Cytokine 2015;75:89-116.
8 Applicant’s BLA. Clinical Pharmacology Overview.


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Food and Drug Administration (FDA)-approved treatments for AD fall in the categories of
corticosteroids (topical and systemic), calcineurin inhibitors (topical), and phosphodiesterase-4
(PDE-4) inhibitors (topical). Corticosteroids are available for treatment of AD by various routes
of administration, including topical, oral, and intramuscular. Corticosteroids are the only
systemically-administered products that are FDA-approved for treatment of AD. Although their
use may result in rapid disease improvement, the AD commonly recurs with worse severity on
discontinuation of the systemic corticosteroids. Because of this and because of the potential for
adverse effects, the American Academy of Dermatology (AAD) recommends that systemic
steroids generally be avoided in the treatment of AD.9 Thus, FDA-approved treatment options
for the Applicant’s target population are extremely limited. Phototherapy may also be an
option for patients who are candidates for systemic therapy. However, phototherapy may
require frequent in-office visits (e.g. several times a week). Risks from phototherapy may vary
according to the type of phototherapy and may include actinic damage, sunburn-like reactions
(erythema, tenderness, pruritus), skin cancer (nonmelanoma and melanoma), and cataracts.9
Systemic products that are used off-label to treat AD include cyclosporine, azathioprine,
methotrexate, and mycophenolate mofetil.9
Topical corticosteroids (TCS) are the most commonly used medications and are first-line
pharmacologic treatment for AD. TCS are recommended for AD-affected individuals who have
failed to respond to good skin care and regular use of emollients alone or to active skin
lesions.10,11 Topical corticosteroids are available in a wide range of potencies (low to super-
high). As listed in product labels, local adverse reactions from TCS may include atrophy, striae,
telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions,
hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and
miliaria. These may be more likely to occur with occlusive use, prolonged use, or use of higher
potency corticosteroids. Some local adverse reactions may be irreversible.
Irrespective of the route of administration, corticosteroids carry the risk of hypothalamic

pituitary- adrenal (HPA) axis suppression, with the potential for glucocorticosteroid
insufficiency. As discussed in labels for TCS, factors that predispose to HPA axis suppression
from TCS include use of more potent corticosteroids, use over large surface areas, prolonged
use, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-
containing products, liver failure, and young age. Per product labels, recovery of HPA axis
function is generally prompt and complete upon discontinuation of TCS.
Labels describe that systemic effects of TCS may also include Cushing's syndrome,
9 Sidbury et al. Guidelines of care for the management of atopic dermatitis. Section 3. Management and treatment
with phototherapy and systemic agents. J Am Acad Dermatol 2014;71:327-49.
10 Eichenfield et al. Guidelines of care for the management of atopic dermatitis. Section 2. Management and
treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol 2014;71:116-32.Ar

11 Arndt KA. Chapter 9. Dermatitis. In: Manual of Dermatologic Therapeutics, 8e.Wolters Kluwer.2014


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hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the
same time may increase the total systemic exposure to topical corticosteroids.
Calcineurin inhibitors are approved for treatment of AD only by topical administration, and the
approved products are tacrolimus ointment and pimecrolimus cream. The labels specify that
these products are second-line therapy for AD and are for “short-term and non-continuous
chronic treatment…in non-immunocompromised adults and children who have failed to
respond adequately to other topical prescription treatments for atopic dermatitis, or when
those treatments are not advisable.”12 The calcineurin inhibitors carry boxed warnings advising
that the safety of their long-term use has not been established. More specifically, the boxed
warnings describes that rare cases of malignancy (e.g., skin and lymphoma) have been reported
in patients treated with topical calcineurin inhibitors; a causal relationship has not been
established. “Burning” is listed as an adverse reaction for topical calcineurin inhibitors.
The newest approved topical treatment for AD (approved 12/14/2016) is crisaborole ointment,
2%. Crisaborole ointment is the first topical PD-4 inhibitor, and provides a new, non-steroid
option for treatment of AD. “Application site pain” is the only event reported in the Adverse
Reactions section of the label.
Nonpharmcologic Care
Nonpharmacologic care is critical to good management of AD and includes the regular use of
moisturizers, which are available in several delivery systems, such as creams, ointments, oils,
lotions.10 Moisturizers are directed at the xerosis and transpeidermal water loss that are central
elements of the disease. They may also relieve pruritus, lessen erythema and fissurring, and
improve lichenification. Moisturizers themselves may be the principle treatment for mild
disease. Although, there are no standardized or universal recommendations regarding the use
of moisturizers, repeated application of generous amounts is thought to be important and
required, irrespective of the severity of disease.10 The use of moisturizers during maintenance
may stave off flares and may lessen the amount of pharmacologic agents needed to control
disease.10
3 Regulatory Background
3.1. U.S. Regulatory Actions and Marketing History

(b) (4)
Dupilumab is an NME.
12 Package inserts for tacrolimus ointment and pimecrolimus cream.


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3.2. Summary of Presubmission/Submission Regulatory Activity
The Applicant developed dupilumab for the AD indication under IND 107969. The Applicant had
extensive presubmission interactions and communications with the FDA, in the form of face-to-
face meetings, teleconferences, and advice letters. Presubmission regulatory activities and
advice included the following:
Pre-IND Meeting (05/26/2010):

In the confirmatory Phase 3 trials the primary efficacy endpoint should be based an Investigator
Global Assessment (IGA). Customarily, success using an IGA has been defined as “clear” or
“almost clear,” with a two-grade improvement on the scale.
The FDA advised the Applicant that they would need to establish safety and activity of
dupilumab in adults (18 and older) before beginning investigations in a pediatric population.
The Applicant opened the IND on 06/30/2010, with a protocol for a safety and
pharmacokinetics study (R668-AD-0914) in subjects 18 years or older with moderate-to-severe
AD.
End-of-Phase 2 Meeting (05/21/2014):

(b) (4)
The Applicant could consider a sequential clinical development program in which they
conducted two adequate and well-controlled Phase 3 trials for one treatment paradigms (either
monotherapy or adjunctive therapy); following establishment of an efficacy claim in one
paradigm, it is possible that a single adequate and well-controlled Phase 3 trial would be
sufficient to support an additional claim for the other paradigm. The Applicant was referred to
the guidance for industry, Providing Clinical Evidence of Effectiveness for Human Drug and
Biological Products.
The FDA reminded the Applicant of the recommended primary endpoint (see discussion of pre-
IND meeting above). Change in the eczema area and severity index (EASI) score could be
included as a key secondary endpoint. If the Applicant were to include EASI as a co-primary
endpoint, subjects should win on both IGA and EASI to be considered a success.
EASI 50 may not represent a sufficient degree of improvement to be considered a success in

subjects with significant disease at baseline. If a change in EASI were to be incorporated as part


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of the primary endpoint, the Applicant was requested to propose a threshold which would
translate to clinically meaningful improvement consistent with success on the IGA. The meeting
discussion reflects that the FDA found the Applicant’s proposal for one primary endpoint (IGA
0-1) and EASI75 as a key secondary endpoint to be reasonable.
The Applicant also proposed a numeric rating scale (NRS) for measurement of pruritus as a key
secondary endpoint. The FDA agreed that assessment of pruritus was important.
To determine the optimal management strategy for subjects who achieve an adequate
treatment response with 16 weeks treatment with dupilumab, the FDA recommended that the
Applicant explore different doses and dosing regimens, as well as duration of effect (such as
with randomized withdrawal), to inform future trial design.
Guidance Meeting (08/04/2014):
The Applicant indicated that subjects who achieved either IGA of 0 or 1 or EASI 75 at Week 16
would be eligible to enroll in a maintenance trial. The FDA advised that enrollment criteria
might create issues in interpreting study findings for maintenance if subjects achieved EASI 75,
but not IGA of 0 or 1. Therefore, if the Applicant desired to include EASI 75 for the maintenance
trial, the FDA recommended that the enrollment criteria include those subjects who meet the
two criteria jointly (i.e., IGA 0 or 1 and EASI 75).
Pre-BLA meeting
The pre-BLA meeting was scheduled for 12/16/2015. However, the Applicant cancelled the
meeting following receipt of the preliminary comments from the FDA, which included
discussion of the content and format of the marketing application.
Additional Regulatory Activities:

• The FDA sent a letter of agreement with the Applicant’s Agreed Initial
Pediatric Study Plan (Agreed iPSP) on 11/10/2015. See Section 8.7.3 of this review for
discussion of the Applicant’s pediatric plan.
• The Applicant was granted Breakthrough Therapy designation on 11/18/2014.
• Rolling review was granted on 11/18/2015.
• Priority review was granted following BLA submission on (submission date:
07/29/2016).
3.3. Foreign Regulatory Actions and Marketing History
Dupilumab was not being marketed in any jurisdiction, at the time of this review.


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BLA 761055
4 Significant Issues from Other Review Disciplines Pertinent to Clinical

Conclusions on Efficacy and Safety
4.1. Office of Scientific Investigations (OSI)
Three clinical sites underwent OSI audit, one site from each of the 3 pivotal trials. The selected
sites along with the rationale for their selection are presented below:
1. Trial 1334: Site 840004; Howard Sofen (Los Angeles, CA)

This site was selected because of high enrollment (28 subjects) and high efficacy results (71% in
(b) (5)
the QW arm and 42% in the Q2W arm).
2. Trial 1416: Site 276007; Harald Brüning (Germany)

This site had relatively high enrollment (13 subjects) and high efficacy results (100% in the QW
arm and 50% in the Q2W arm).
3. Trial 1224: Site 616025; Tomasz Kolodziej (Poland)

This site had relatively high enrollment (14 subjects) and high efficacy results (100% in the QW
arm and none in the Q2W arm).
The Applicant, i.e. Regeneron Pharmaceuticals, Inc., was also inspected.
The final classification of the inspections of Dr. Sofen, Dr. Kolodziej, and Regeneron was No
Action Indicated (NAI).
The final classification of the inspection of Dr. Brüning was Voluntary Action Indicated (VAI). Dr.
Brüning received a Form 483 for issues relating to missing and back-dated informed consent
forms (ICFs). In his response to the Form 483, Dr. Brüning committed to implementing new
procedures to ensure that ICFs were handled properly. Aside from the deficiencies relating to
the ICFs, the study appeared to have been adequately conducted, and the data generated
appeared to be acceptable to support the BLA. I agree with OSI that the ICF issues “would not
appear to significantly affect either subject safety or efficacy considerations.”
4.2. Product Quality
The following information represents excerpts from the draft Office of Product Quality (OPQ)
Executive Summary:
Drug Substance: Dupilumab Quality Summary


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Description
Dupilumab is human IgG4 κ antibody. The heavy chains contain 452 amino acids each,
the light chains contain 219 amino acids and the hinge region has a serine to proline
mutation at amino acid 233 to stabilize the interaction between heavy chains. The
average molecular mass is 147 kDa. Each heavy chain contains a single N-linked
glycosylation site at asparagine 302.
Potency Assay
The biological function of dupilumab was characterized for its ability to bind to IL-4Rα by
surface plasm on resonance-based Biacore and by in vitro cell based bioassays. These
bioassays show that dupilumab is able to inhibit IL-4-mediated CD23 up-regulation in
primary human B lymphocytes and in human Ramos Burkitt lymphoma cell line and also
to inhibit IL-4-induced up-regulation of thymus and activation regulated chemokine in
human embryonic kidney (HEK293) cell line. The function of the Fc domain was analyzed
for its ability to promote complement-dependent cytotoxicity (CDC) and antibody
dependent cell-mediated cytotoxicity (ADCC). Fc function is not detected.
Dupilumab binds to soluble IL-4rα with high affinity… Dupilumab does not induce Fc
mediated cytotoxicity (ADCC or CDC).
Manufacturing process summary

(b) (4)
The manufacture of dupilumab drug substance
Drug Product: Dupilumab Quality Summary
Potency and Strength

Dupilumab is supplied as a 300 mg/2 mL solution in a single-dose pre-filled syringe (PFS)

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with or without a safety system.
Summary of Product Design

Dupilumab is a sterile, preservative free, clear to slightly opalescent, colorless to pale
yellow solution. Dupilumab is supplied in two presentations: a single-use prefilled
syringe assembled with a safety system (PFS-S) and a single-use prefilled syringe without
the safety system. Both syringes contain 2 mL of 150 mg/mL dupilumab.
List of Excipients: L-arginine hydrochloride (25 mM), L-histidine (20 mM), polysorbate
80 (0.2% (w/v)), sodium acetate (12.5 mM), sucrose (5% (w/v))
Manufacturing Process
(b) (4)
The manufacturing process of drug product consists of
The control strategy is appropriate to ensure aseptic processing, consistently accurate

fill and adequate critical quality attributes.
Container Closure
Dupilumab is supplied in two presentations. The bulk PFS is stored in a 2.25 mL clear
glass syringe barrel with a 27 gauge stainless steel needle, protected by a rigid needle
(b) (4) (b) (4)
shield and an plunger stopper with
In the PFS presentation the bulk PFS is assembled with a plunger rod and a finger flange.
In the PFS-S presentation the bulk PFS is assembled with a plunger rod and inserted in a
safety system preassembled with a finger flange.
Appropriate compatibility studies were performed for the container closure system.
Le Trait Manufacturing Site
The information below reflects my understanding of issues relating to the Le Trait site which
could impact approvability of the dupilumab BLA:
Regeneron and Sanofi Winthrop Industrie are collaborating on the development of dupilumab.
(b) (4)
. Significant good manufacturing practice (GMP) deficiencies

(b) (4)
were identified during inspection of the Le Trait filling facility
. The Sanofi Le Trait manufacturing

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BLA 761055
(b) (4)
The deficiencies at the filling

site have reportedly been addressed, and the Facility Compliance Status for Sanofi Winthrop
Industrie has been changed to “compliant.” Pre-approval inspection for the dupilumab BLA was
scheduled for February 6-14, 2017.
4.3. Clinical Microbiology
Not applicable.
4.4. Nonclinical Pharmacology/Toxicology
The information in this section is from the review by Renqin Duan, Ph.D. Dr. Duan considered
the application to be approvable from the from a pharmacology/toxicology perspective. From
Dr. Duan’s review:
Dupilumab binds specifically to the human IL-4Rα and does not bind to IL-4Rα in any
animal species. The sponsor submitted three pivotal repeat dose toxicity studies and an
enhanced pre- and postnatal developmental toxicity study (ePPND) in cynomolgus
monkey with REGN646 which is a fully human homologous antibody specific for
cynomolgus monkey IL4Rα, and a subcutaneous fertility study in mice with REGN1103, a
mouse homologous antibody that binds to IL4Rα.
No REGN646-related adverse effects (including effects on the immune system except

decreased IgE levels in 13-week study) were observed in these repeat dose toxicology
studies in cynomolgus monkeys up to 100 mg/kg/week, the highest dose tested. No
target organs of toxicity were identified in these studies. There were no neoplastic or
test article-related non-neoplastic proliferative lesions in these studies. The serum
concentrations of REGN646 at the NOAEL in the 5-week, 13-week, and 6-month monkey
toxicology studies exceeded the concentration required to block IL-4Rα signaling in the
in vitro and ex vivo assays.
In an ePPND study, weekly subcutaneous administration of REGN646 to pregnant adult

female cynomolgus monkeys at doses of 25 mg/kg/week and 100 mg/kg/week from
approximately GD20 and every week thereafter until parturition was well tolerated.
There were no neoplastic or test article-related non-neoplastic proliferative lesions.
There were no test article related effects on maternal, fetal, or infant parameters during
the study. There were no test article related effects on immune system parameters. No
test article related macroscopic or microscopic findings were noted for the infants. The
postnatal growth and development of the offspring was monitored for a period of 6
months postpartum. Overall, the concentrations of REGN646 in the offsprings were
comparable to those in the corresponding dams, indicating that the monkey fetuses do

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BLA 761055
have adequate systemic exposure to REGN646 from in utero exposure. The NOAEL for
maternal and developmental toxicity was 100 mg/kg/week based on the results of this
study, which is 10 times the maximum recommended human dose (MRHD) on a mg/kg
basis.
In a subcutaneous fertility study in young sexually mature male and female mice, no
REGN1103-related changes in any of the evaluated fertility, early embryonic
development and implantation parameters were observed at doses up to 200
mg/kg/week.
Labeling Recommendations
HIGHLIGHTS OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE
DUPIXENT is an interleukin-4 receptor alpha antagonist

indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis
whose disease is not adequately controlled with topical prescription therapies or when
those therapies are not advisable. DUPIXENT can be used with or without topical
corticosteroids.
8.1 Pregnancy
Risk Summary
There are no available data on DUPIXENT use in pregnant women to inform any drug
associated risk. Human IgG antibodies are known to cross the placental barrier;
therefore, DUPIXENT may be transmitted from the mother to the developing fetus. In an
enhanced pre- and post-natal developmental study, no adverse developmental effects
were observed in offspring born to pregnant monkeys after subcutaneous
administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα)
during organogenesis through parturitionat doses up to 10 times the maximum
recommended human dose (MRHD) [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss or
other adverse outcomes. In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and
15 to 20%, respectively.
Data
Animal Data
In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus

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monkeys were administered weekly subcutaneous doses a homologous antibody

against IL-4Rα up to10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the
beginning of organogenesis to parturition. No treatment-related adverse
effects on embryofetal toxicity or malformations or on morphological, functional or
immunological development were observed in the infants from birth through 6 months
of age.
12.1 Mechanism of Action

(b) (4) (b) (4)
Dupilumab is a human monoclonal IgG4 antibody
that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically
binding to the IL-4Rα sub-unit shared by the IL-4 and IL-13 receptor complexes.
Dupilumab inhibits IL-4 signaling via the Type I receptor, and both IL-4 and IL-13
signaling through the Type II receptor.
Blocking IL-4Rα inhibits IL-4 and IL-13 cytokine-induced responses, including the
release of proinflammatory cytokines and chemokines.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic
(b) (4)
potential of dupilumab.
4.5. Clinical Pharmacology
The Office of Clinical Pharmacology review team (Divisions of Clinical Pharmacology 3 and
Pharmacometrics) recommended approval of this BLA from a clinical pharmacology
perspective. The information in this section reflects findings and conclusions from the clinical
pharmacology team.
Proposed Dosing Regimens

The Applicant proposed the following language for the Dosage and Administration instructions
for the label:
The recommended dose of DUPIXENT for adult patients is an initial dose of 600 mg (two
(b) (4)
300 mg injections), followed by 300 mg given every other week.


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BLA 761055
See Table 1.
• The EASI-75 response rate was similar across body weight quartiles for both 300
mg Q2W and 300 mg QW dosing regimens in the two monotherapy Phase 3 studies.
Table 1. Effect of body weight on IGA 0/1 response rates at Week 16 in Phase 3 studies*
Study Body weight IGA 0/1 response at Week 16, % (n)

Placebo Dupilumab
300 mg Q2W 300 mg QW
AD-1334 <70 kg 9% (100) 36.5% (85) 42.3% (71)
≥70 kg to <100 kg 10.9% (101) 38.0% (121) 36.6% (123)
≥100 kg 13.6% (22) 44.4% (18) 27.6% (29)
AD-1416 <70 kg 10.6% (85) 36.2% (94) 39.6% (91)
≥70 kg to <100 kg 6.4% (125) 37.5% (104) 31.4% (121)
≥100 kg 11.5% (26) 31.4% (35) 48.1% (27)
AD-1224 <70 kg 10.6% (141) 32.7% (49) 40.8% (147)
≥70 kg to <100 kg 15% (147) 45.1% (51) 38.6% (140)
≥100 kg 7.4% (27) 33.3% (6) 34.4% (32)
*Source: from Table 3.3.3 a of the clinical pharmacology review.
Clinical Pharmacology Postmarketing Commitment (PMC):
Patients with AD are thought to have elevated proinflammatory cytokines, and dupilumab
could modulate cytokine levels. Thus, the potential exists for disease-drug-drug interaction in
patients with AD treated with dupilumab. The team recommends a PMC for the Applicant to
conduct a clinical trial to determine the potential for dupilumab to alter the pharmacokinetics
of CYP substrates in AD patients.
The Applicant is currently conducting a clinical drug interaction study (1433) to evaluate the
potential effects of dupilumab on the PK of CYP450 substrates in adult patients with moderate-
to-severe AD. The PMC recommendation will request that the Applicant complete this ongoing
drug interaction study.
4.5.1. Mechanism of Action
From the clinical pharmacology review:
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and
interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the
IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I
receptor and both IL-4 and IL-13 signaling through the Type II receptor. Blocking IL-4Rα

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BLA 761055
inhibits IL-4 and IL-13 cytokine-induced responses, including the release of

proinflammatory cytokines and chemokines.
4.5.2. Pharmacodynamics
From the clinical pharmacology review:
Results from a small exploratory study showed that serum levels of IL-4 and IL-13 were
increased following dupilumab treatment. The relationship between the
pharmacodynamic (PD) activity and the mechanism(s) by which dupilumab exerts its
clinical effects is unknown.
The clinical pharmacology team recommended the following language for Section 12.2 of the
label:
Serum levels of IL-4 and IL-13 were increased following dupilumab treatment. The
relationship between the pharmacodynamic activity and the mechanism(s) by which
dupilumab exerts its clinical effects is unknown.
The following information is from the clinical pharmacology review:
Plasma concentrations of IL-4 and IL-13 following dupilumab treatment were assessed in
Study R668-AD-1307. In the study, subjects with moderate-to-severe AD were treated
with SC dupilumab 200 mg QW for 16 weeks (with an initial 400 mg loading dose).
The time courses of plasma IL-4 and IL-13 levels… showed the following:
• Baseline median IL-4 level was 0 pg/mL. The plasma IL-4 level was increased by
~ 1 pg/mL from baseline during the entire dupilumab treatment period (i.e.,
from Week 2 through Week 16) and returned to the baseline level at the next
assessment timepoint (Week 32) after the dupilumab treatment was stopped at
Week 16.
• Baseline median IL-13 level was 2 pg/mL. The plasma IL-13 levels were increased
at Weeks 2 and 4 following dupilumab treatment and returned to the baseline
level by Week 8 while the subjects were still receiving the dupilumab treatment.
The increased plasma IL-4 and IL-13 levels could be a result of the blockade of
the IL-4Rα by dupilumab leading to a decrease in clearance of both cytokines.
The increased plasma IL-13 level occurred only at Weeks 2 and 4 for the
dupilumab 200 mg QW dosing regimen. The transient increase in IL-13 may be
resulting from the interaction of IL- 13 with IL-13Rα2 which dupilumab does not
block. The PD effect on IL-13 levels for the 300 mg QW or 300 mg Q2W dosing
regimens are unknown.

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BLA 761055
4.5.3. Pharmacokinetics
The clinical pharmacology review provides for the following summary of the clinical
pharmacokinetics of dupilumab:
The PK of dupilumab was described by a 2-compartment model with parallel linear and
nonlinear elimination and first order absorption following subcutaneous administration.
Dupilumab exposure increased in a greater than dose-proportional manner; the
systemic exposure increased by 30-fold when the dose increased 8-fold from 75 mg to
600 mg.
Absorption: Following a single subcutaneous (SC) dose of 300 mg, dupilumab reached
peak mean±SD concentrations (Cmax) of 34.8±17.5 mcg/mL by approximately 1 week
post-dose. Steady-state concentrations were achieved by Week 16 following the
administration of 600 mg starting dose and 300 mg dose either weekly or every 2
weeks. Across clinical trials, the mean±SD steady-state trough concentrations ranged
from 73.3±40.0 mcg/mL to 79.9 ±41.4 mcg/mL for 300 mg administered every 2 weeks
and from 173±75.9 mcg/mL to 193 ±77.0 mcg/mL for 300 mg administered weekly.
Dupilumab trough concentrtions were lower in subjects with higher body weight.
The bioavailability of dupilumab following an SC dose was estimated to be 64%.
Distribution: The estimated total volume of distribution was approximately 4.6 L.
Elimination: The metabolic pathway of dupilumab has not been characterized. As a

human monoclonal IgG4 antibody dupilumab is expected to be degraded into small
peptides and amino acids via catabolic pathways in the same manner as endogenous
IgG. The mean systemic clearance for the linear elimination pathway was 0.13 L/day.
The clearance for the nonlinear elimination pathway is concentration-dependent and
plays a role in the studied SC dose range of 75 mg to 300 mg.
4.6. Devices and Companion Diagnostic Issues
The Center for Devices and Radiological Health (CDRH) considered the application to be
approvable from the perspective of the applicable Quality System Requirements.
The CDRH consult review provided the following product description:

(b) (4)
Dupilumab drug substance (DS) contains
.
The Dupilumab combination product is provided in a single-use prefilled syringe (PFS)
that contains 150 mg/mL in a 2mL solution for subcutaneous (SC) injection. An entire
PFS of the combination product delivers a 300 mg dose of Dupilumab and is intended

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BLA 761055
Regeneron has the ultimate responsibility for the overall combination product in the United
(b) (4)
States, which include auditing and other oversight activities
The documentation review of the application for compliance with the Quality System
Requirements showed no deficiencies.
4.7. Consumer Study Reviews
Carlos M. Mena-Grillasca, RPh of the Division of Medication Error Prevention and Analysis
(DMEPA) evaluated the human factors (HF) validation study report. The study was conducted to
evaluate the use of a standard, single dose, 2-mL prefilled syringe (PFS) and a 2-mL pre-filled
syringe with needle shield (PFS-S), associated labeling, packaging, and Instructions for Use (IFU)
for Dupixent. The observed critical task errors were 1) failure to pinch the skin and insert the
needle at 45° angle and 2) failure to depress the plunger and inject a full dose. Mr. Mena-
Grillasca agreed with the Applicant that neither of these errors would result in patient harm,
although the latter could compromise efficacy. DMEPA recommended revisions to the IFUs to
address the failure-to-pinch issue. The errors relating to failure to full depress the plunger were
observed to decrease over time in one study, and DMEPA expects that a similar pattern of
decrease will be observed with real-world use, given the chronicity of AD. I agree with DMEPA’s
conclusions.
5 Sources of Clinical Data and Review Strategy
5.1. Table of Clinical Studies
The table provides for those studies relied on to establish efficacy and safety of dupilumab in
this BLA.
In this review, studies will generally be referenced by the last 4 digits of the full study name,
e.g. “R668-AD-1334” will be referenced as “1334.”


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BLA 761055
Table 2. Listing of Clinical Trials Relevant to this BLA

Trial Trial Design Regimen/ Study Endpoints Treatment No. of Study Population No. of Centers and
Identity schedule/ route Duration/ patients Countries
Follow Up enrolled
Controlled Studies to Support Efficacy and Safety
R668-AD- Randomized double-blind, parallel Placebo, 300 mg Primary: Treatment 224 in Males / Females with 131 global sites;
1334 group, placebo-controlled, QW with a 600- Proportion of duration 16 the placebo moderate-to-severe United States,
(1334) parallel group, dose-ranging mg loading dose, patients with weeks group, AD Germany, Japan,
or 300 mg Q2W both an IGA 0 to 224 in the Age: ≥18 years Estonia, Spain,
with a 600-mg 1 and a 12 weeks follow- Dupilumab Canada, Denmark,
loading dose, SC reduction from up Q2W, Bulgaria,
baseline of 223 in the Singapore, Finland
≥2 points at Dupilumab
Week 16 QW
Secondary
(partial list):
Proportion of
patient with
EASI-75 at Week
16
Proportion of
patients with
an improvement
in pruritus NRS
of ≥4 points from
baseline to Week
16
R668-AD- Randomized double-blind, Placebo, 300 mg Primary: Treatment 236 Males / Females with 143 global sites;
1416 parallel group, QW with a 600- Proportion of duration 16 patients in moderate-to-severe United States,
(1416) placebo-controlled, mg loading dose, patients with weeks the placebo AD Canada, Poland
parallel group, or 300 mg Q2W both an IGA 0 to group, 233 Age: ≥18 years Germany,
dose-ranging with a 600-mg 1 and a 12 weeks follow- patients in Republic of Korea,
Monotherapy loading dose, SC reduction from up the France, Italy,
baseline of dupilumab United Kingdom,
≥2 points at 300 mg Lithuania,
Week 16 Q2W Hong Kong
group, and


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BLA 761055
Secondary 239
(partial list): patients in
Proportion of the
patient with 300 mg QW
EASI-75 at Week group
16,
Proportion of
patients with
an improvement
in pruritus
NRS of ≥4 points
from
baseline to Week
16
R668-AD- Randomized double-blind, Placebo, 300 mg Primary: Treatment 315 Males / Females with 174 global study
1224 parallel group, QW with a 600- Proportion of duration 52 patients in moderate-to severe sites:
(1224) placebo-controlled, mg loading dose, patients with weeks placebo + AD Australia,Canada,
parallel group, or 300 mg Q2W both an IGA 0 to TCS, Age: ≥18 years Czech Republic
dose-ranging with a 600-mg 1 and a 12 weeks follow- 106 Hungary, Italy,
Monotherapy loading dose, SC reduction from up patients in Japan,
baseline of 300 mg q2w Netherlands New
≥2 points at +TCS, Zealand, Poland
Week 16 319 Republic of Korea,
Key Secondary patients Romania, Spain,
(partial list): mg qw + United Kingdom,
Proportion of TCS United States
patient with
EASI-75 at Week
16,
Proportion of
patients with
improvement of
pruritus NRS of
≥4 points from
baseline to Week
16
Proportion of
patients with IGA


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BLA 761055
0 or 1 and a
reduction from
baseline of ≥2
points at
week 52
Dose-Ranging Study; Supports Safety
R668-AD- Randomized double-blind, Placebo, 300 mg Primary: Treatment Dupilumab: Males / Females ~80 global study
1021 parallel group, QW with a 600- % change in EASI duration 16 316 Patients moderate-to sites; Japan was
(1021) placebo-controlled, mg score weeks Placebo: 63 severe the only country
parallel group, loading dose, from baseline to AD specified in the
dose-ranging 300 mg Q2W Week 16 16 weeks follow- Age: ≥18 years study report
Monotherapy with a Secondary up
600-mg loading (partial list):
dose, 300 mg Proportion of
Q4W patients
with a 600-mg achieving IGA 0
loading dose, or 1 at
200 mg Week 16
Q2W with a 400 Proportion of
mg-loading dose, patients
or achieving IGA
100 mg Q4W score
with a 400-mg reduction of ≥2
loading at Week 16
dose, SC
PD and PK PD Studies; Support Safety
R668-AD- Randomized double-blind Placebo or 200 Primary: Treatment Dupilumab: Males / Females with 10 study sites in
1307 placebo-controlled mg QW with a % change in EASI duration 16 27 moderate-to-severe AD the United States
(1307) sequential ascending, 400-mg loading score from weeks Placebo:27 Age: ≥18 years and Canada
repeated-dose dose, SC baseline to Week
Monotherapy 16 16 weeks follow-
Secondary up
(partial list):
Proportion of
patients
achieving IGA 0
or 1 at
Week 16


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BLA 761055
Proportion of
patients
achieving IGA
score
reduction of ≥2
at Week 16
Proportion of
patients
achieving EASI-
90,-75,-50 and
SCORAD-50,-75,
-90 at Week 16
R668-AD- Randomized double-blind Placebo or 300 Primary: Treatment Dupilumab: Males / Females with ~ 50 clinical sites in
1314 placebo-controlled mg QW with a Proportion of duration, 16 97 moderate-to-severe the United States
(1314) sequential ascending, 600-mg loading patients with weeks Placebo: 97 AD
repeated-dose dose, SC a positive Age: ≥18 years
Monotherapy response to 16 weeks follow-
tetanus toxoid at up
Week 16
(4 weeks after
immunization)
Secondary
(partial list):
Proportion of
with Positive
response at
Week 16 in anti-
tetanus IgG
Menomune
response: an
SBA titer of ≥8
for serogroup C
Proportion of
patients
achieving IGA 0
or 1 at Week 16
Proportion of
patients


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BLA 761055
achieving at least
50%,
75% reduction in
EASI score at
Week 16
R668-AD- Randomized double-blind, placebo- Placebo or 300 Primary: Treatment Dupilumab: Males / Females ~25 study
1117 controlled, repeated-dose mg QW, SC The % change in duration 12 55 Patients moderate- sites in Europe
Monotherapy EASI weeks Placebo: 54 tosevere
score from AD
baseline to 16 weeks follow- Age: ≥18 years
Week 12 up
Secondary
(partial list):
Proportion of
patient who
achieve an IGA
score of 0
or 1 at Week 12
Proportion of
patients who
achieve ≥50%
overall
improvement in
EASI score
from baseline to
Week 12
Uncontrolled Clinical Study

R668-AD- Open-label extension 300 mg qw with Primary: Treatment 1492 Males / Females ~500 global sites
1225 a 600-mg loading Incidence and duration ~ 3 with moderate-to-severe
(1225) dose, SC rate of years AD who participated in
TEAEs through previous dupilumab
the last 16 weeks follow- clinical studies or were
study visit up eligible to participate in
Key Secondary: 1334 and 1416
Incidence and
rate of SAE Age: ≥18 years
and AEs of


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BLA 761055
special interest
Proportion of
patients with
IGA 0-1 at each
visit
Proportion of
patients with
EASI-75 at each
visit
Secondary /
Other:
PK and ADA


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BLA 761055
5.2. Review Strategy
The efficacy review will focus on the 3 pivotal Phase 3 studies, which are intended to establish
(b) (4)
efficacy and support proposed labeling of use of dupilumab “with and without topical .”
The Applicant conducted 2 replicate, randomized, placebo-controlled, parallel-group Phase 3
studies (1334 and 1416) that evaluated use of dupilumab as monotherapy. The Applicant
conducted one study (1224) that required protocol-specified use of concomitant TCS and
allowed for use of topical calcineurin inhibitors (TCI). Carin Kim, PhD was the statistical reviewer
for this application, and my review will present her analyses and include tables and figures from
her review.
The safety review will focus on the Primary Safety Pool in which the Applicant combined data
from 3 studies with 16-week treatment durations and dosing arms of dupilumab 300 mg QW,
300 mg Q2W and placebo. For long-term safety, the review will primarily focus on the 52-week,
long-term treatment (LTT) study that included concomitant TCS (1224) because this study was
placebo-controlled for the duration of the 52-week treatment period. This review will also
include discussion of the Supportive Safety Pool and from an open-label (OLE) extension study,
1225. See Section 8.1 for a more detailed description of the safety database.
6 Review of Relevant Individual Trials Used to Support Efficacy
6.1. R668-AD-1334 (1334); SOLO 1

Monotherapy Administered to Adult Patients with Moderate-to-Severe Atopic
Dermatitis”
6.1.1. Study Design
Overview and Objective
This was a randomized, double-blind, placebo-controlled, parallel-group study to confirm the

efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe AD.
Trial Design
The study was either 16 weeks (16-week treatment period) or 28-weeks (16-week treatment
period and 12-week follow-up), depending on whether or not subjects continued in a
maintenance or extension study (see below). AD treatments were washed out during a 35-day
screening period.

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BLA 761055
Subjects were required to apply moisturizers (emollients) twice daily for at least the 7
consecutive days immediately before randomization and continue throughout the study. To
allow adequate assessment of skin dryness, moisturizers were not to have been applied on non-
lesional skin designated for such assessments for at least 8 hours before each clinic visit.
Subjects were randomized in a 1:1:1 ratio to receive:

• once weekly (QW) subcutaneous (SC) injections of 300 mg dupilumab following a
loading dose of 600 mg on Day 1,
• every two weeks (Q2W) SC injections of 300 mg dupilumab following a loading dose of
600 mg on Day 1 (subjects received placebo on alternate weeks), or
• matching placebo.
Randomization was stratified by baseline disease severity (moderate [Investigator’s Global

Assessment (IGA) = 3] vs. severe [IGA = 4] AD) and by region. Subjects were randomized to a
treatment group according to a central randomization scheme provided by an interactive voice
response system/interactive voice response system (IVRS/IWS).
Following the initial dose, study treatment was administered weekly for 15 weeks. Following
training, subjects and/or caregivers had the option to administer study drug outside the study
site.
Study visits were weekly during the 16-week treatment period. Monitoring included laboratory
tests, samples for dupilumab concentrations and anti-drug antibodies (ADA). The end of
treatment visit occurred at Week 16 (one week after last dose), and the primary endpoint was
assessed at Week 16.
Rescue Treatment
If needed to control intolerable AD symptoms, rescue treatment for AD could be provided at

the discretion of the investigator. Subjects who received rescue treatment during the study
treatment period were considered treatment failures, but were to continue study treatment if
rescue consisted of topical medications. TCI could be used for rescue, but were to be “reserved
for problem areas only, eg, face, neck, intertriginous and genital areas, etc.” Investigators were
to attempt to limit the first step of rescue therapy to topical medications, and escalate to
systemic medications only for subjects who did not respond adequately after at least 7 days of
topical treatment. If a subject received rescue treatment with systemic corticosteroids or non-
steroidal systemic immunosuppressive drugs (cyclosporine, methotrexate, mycophenolate-
mofetil, azathioprine, etc.) study treatment was to be immediately discontinued. After the
systemic treatment was completed, study treatment could be resumed, but not sooner than 5
half-lives after the last dose of rescue medication. All subjects were to complete the schedule of

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BLA 761055
study visits and assessments whether or not they completed study treatment or received
rescue treatment for AD.
However, per the statistical review, the Applicant submitted an amended statistical analysis
plan (SAP), dated 02/06/2016 that provided for a “rescue medication algorithm” that specified
that subjects who used TCS during the first 14 days would not be considered as having used
rescue treatment. Therefore, the Applicant would not consider these subjects as non-
responders in the efficacy analyses. The monotherapy studies 1334 and 1416 were completed
on 2/12/2016 and 1/21/2016, respectively.
Prohibited Medications and Procedures
The following concomitant medications were prohibited during the study:

• live (attenuated) vaccine
• immunomodulating biologics
• other investigational drug
• TCS or TCI
• systemic corticosteroids or non-steroidal systemic immunosuppressive drugs
Subjects with IGA 0 to 1 (0/1) or eczema area severity index (EASI)-75 at Week 16 were eligible
for further study participation:
• Those who had not received rescue treatment were eligible to participate in a
maintenance study.
• Those who chose not to participate in the maintenance study were eligible to
participate in an open-label extension (OLE) study, but no sooner than 36 weeks after
completing the Week 16 visit in the current study.
Subjects who did not meet eligibility criteria for the maintenance study underwent at least 4
weeks of follow-up (through week 20). At Week 20:
• Subjects with IGA 3 to 4 were eligible to enroll in the OLE study.
• Subjects with IGA <3 continued follow-up to Week 28 or until their IGA became 3 to 4
(whichever came first).
Subjects who declined to participate in the OLE or maintenance study were followed every 4
weeks from Week 20 through Week 28. This 12-week follow-up period was based on the time
expected for drug levels to reach zero (below the lower limit of quantification) in most subjects
after the last dose of dupilumab. The end of study visit was at Week 28.
Subjects with an ADA titer of ≥240 at their last study visit and some subjects who were negative
for ADA at their last study visit were asked to return to have additional ADA samples collected
for analysis.

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BLA 761055
Figure 1. Study Flow Diagram
1 Subjects received a loading dose of study drug on day 1 and then received dupilumab weekly or every two weeks or matching
placebo during the subsequent 15 weeks. Subjects in the Q2W group received matching placebo in the weeks that dupilumab
was not administered.
2 Subjects remained at the study site for ≥ 30 minutes after each of the first 3 doses of study drug from day 1 through week 2.
3 The follow-up period was for those subjects who declined to enter the open-label extension or the maintenance study; for
these subjects, the end of treatment was week 16.
Study Population
Key Inclusion Criteria:
1. Male or female, 18 years or older

2. Chronic AD, (according to American Academy of Dermatology Consensus Criteria
[Eichenfield 2014]; see Table 3 below), present for at least 3 years before the screening
visit
3. EASI score ≥ 16 at the screening and baseline visits
4. Investigator’s Global Assessment (IGA) score ≥3 (on the 0 to 4 IGA scale, in which 3 was
moderate and 4 was severe) at the screening and baseline visits; see IGA scale below
5. ≥ 10% body surface area (BSA) of AD involvement at the screening and baseline visits
6. Baseline Pruritus Numerical Rating Scale (NRS) average score for maximum itch
intensity ≥3
NOTE: Baseline Pruritus NRS average score was based on the average of daily NRS scores for
maximum itch intensity (the daily score: 0 to 10) during the 7 days immediately preceding
randomization.
7. Documented recent history (within 6 months before the screening visit) of inadequate
response to treatment with topical medications or for whom topical treatments are
otherwise medically inadvisable (e.g., because of important side effects or safety risks
• Inadequate response was defined as failure to achieve and maintain remission or a

low disease activity state (comparable to IGA 0=clear to 2=mild) despite treatment
with a daily regimen of TCS of medium to higher potency (±TCI as appropriate),

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BLA 761055
applied for at least 28 days or for the maximum duration recommended by the
product prescribing information (e.g., 14 days for super-potent TCS), whichever was
shorter.
• Subjects with documented systemic treatment for AD in the past 6 months were also
considered as inadequate responders to topical treatments and were potentially
eligible for treatment with dupilumab after appropriate washout.
• Important side effects or safety risks were those that outweighed the potential
treatment benefits and included intolerance to treatment, hypersensitivity reactions,
significant skin atrophy, and systemic effects.
8. Had applied a stable dose of topical emollient (moisturizer) twice daily for at least the
7 consecutive days immediately before the baseline visit
Exclusion Criteria included:
1. Participation in a prior dupilumab clinical study

2. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known),
whichever was longer, before the baseline visit
3. Having used any of the following treatments within 4 weeks before the baseline visit, or
any condition that, in the opinion of the investigator, was likely to require such
treatment(s) during the first 4 weeks of study treatment:
• Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids,
cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine,
methotrexate, etc.)
• Phototherapy for AD
4. Treatment with TCS or TCI within 1 week before the baseline visit
5. Treatment with biologics as follows:
• Any cell-depleting agents (e.g.,rituximab): within 6 months before the baseline visit,
or until lymphocyte count returns to normal, whichever is longer
• Other biologics: within 5 half-lives (if known) or 16 weeks prior to baseline visit,
whichever is longer
6. Treatment with a live (attenuated) vaccine within 12 weeks of the baseline visit
7. Active chronic or acute infection requiring treatment with systemic treatment (e.g.
antibiotics, antivirals, antiparasitics, etc.) within 2 weeks of the baseline visit, or
superficial skin infections within 1 week of the baseline visit. NOTE: patients may be
rescreened after infection resolves
8. Known or suspected history of immunosuppression, including history of invasive
opportunistic infections (e.g., tuberculosis [TB], histoplasmosis,
9. History of human immunodeficiency virus (HIV) infection or positive HIV serology at
Screening
10. Positive with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or
hepatitis C antibody at the screening visit

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BLA 761055
11. History of malignancy within 5 years before the screening visit, except completely
treated in situ carcinoma of the cervix, treated and non-metastatic squamous or basal
cell carcinoma of the skin
12. Active endoparasitic infections; suspected or high risk of endoparasitic
infection, unless active infection ruled out before randomization
Table 3. Features to be considered in the diagnosis of patients with atopic dermatitis*
*Eichenfeld et al.


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BLA 761055
Table 4. Table of Schedule of Events
1 The site will contact the patient by telephone to conduct these visits. The patient/caregiver may administer study drug on these
days. Patients who receive study drug outside the study center will complete a dosing diary to document compliance with study drug


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BLA 761055
administration and to document any related issues.

2 For patients who decide to participate and provide a specific written informed consent for the optional genomics sub-study (DNA
and RNA sample collection). DNA sample should be collected at the day 1 visit, but can be collected at any visit during the study.
RNA sample must be collected before the administration of the first dose of study drug.
3 Patients will be trained at the screening visit on using the appropriate diary system to report pruritus and provide other
information as required.
4 Patients will be monitored at the study site at visits 2, 3, and 4 for a minimum of 30 minutes after study drug administration. Vital
signs (blood pressure and heart rate) and AE assessments will be done at 30 minutes (+/- 10 minutes) post-injection.
5 For patients who choose to self-administer study drug during some weeks, counsel patient on proper dosing diary
completion/reporting of each dose of study drug that is administered outside of the clinic.
6 Starting at visit 4, study drug will be dispensed to the patient for the dose that will be administered before the next clinic visit.
Patients will return the original kit box for the prefilled syringe at each clinic visit.
7 To be collected before the injection of study drug.


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BLA 761055
Table 5. Table of Schedule of Events
1 The follow-up period will be for those patients who decline to enter the open-label extension or the maintenance study; for these patients,
the end of treatment will be week 16.
2 During an unscheduled visit, any of the study procedures noted may be performed, but not all are required.
3 The site will contact the patient by telephone to conduct these visits. The patient/caregiver may administer study drug on these days.
Patients who receive study drug outside the study center will complete a dosing diary to document compliance with study drug administration
and to document any related issues.
4 For patients who choose to self-administer study drug during some weeks, counsel patient on proper dosing diary completion/reporting of
each dose of study drug that is administered outside of the clinic.
5 Starting at visit 4, study drug will be dispensed to the patient for the dose that will be administered before the next clinic visit. Patients will
return the original kit box for the prefilled syringe at each clinic visit.


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BLA 761055
7 Assessments/procedures should be conducted in the following order: patient reported outcomes, investigator assessments, safety and
laboratory assessments, administration of study drug.
8 Patients will be trained at the screening visit on using the appropriate diary system to report pruritus and provide other information as
required.
9 The questionnaires will be administered only to the subset of patients who speak fluently the language in which the questionnaire is
presented (based on availability of validated translations in participating countries). ACQ-5 will be administered only to patients with a
medical history of asthma. SNOT-22 will be administered only to patients with chronic inflammatory conditions of the nasal mucosa and/or
paranasal sinuses (eg, chronic rhinitis/rhinosinusitis, nasal polyps, allergic rhinitis). All questionnaires will be administered before any invasive
procedures (blood draws, study drug injection, etc.).
10 Select sites only - photograph AD area
11 Includes: antigen-specific IgE (region-specific allergen panels).
12 Non-invasive skin swabs; this is a sub-study that may be conducted at selected sites
13 Patients with an ADA titer of ≥240 at the last study visit will be asked to return to the clinic to have additional samples collected for analysis
(see section 6.3.4.2 for details and time points).
Study Endpoints
Primary: Proportion of subjects with both IGA 0 to 1 (on a 5-point scale) and a reduction from
baseline of ≥2 points at Week 16
Secondary:
• Proportion of subjects with EASI-75 (≥75% improvement from baseline) at Week 16
• Proportion of patients with improvement (reduction) of weekly average of peak daily
pruritus NRS ≥4 from baseline to week 16
• Percent change from baseline to week 16 in weekly average of peak daily pruritus NRS
Investigator’s Global Assessment (IGA) Scale
The IGA was described in the protocol as “a static 5-point scale assessment instrument to rate
AD disease severity globally in clinical studies. The ratings (0 = clear, 1 = almost clear, 2 = mild, 3
= moderate, 4 = severe) are an overall assessment of AD skin lesions based on erythema and
papulation/infiltration.”


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Brenda Carr, MD
BLA 761055
Table 6. Investigator’s Global Assessment (IGA) Scale
Eczema Area and Severity Index (EASI)
The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics
(erythema, thickness [induration, papulation, edema], scratching [excoriation], and
lichenification) are assessed for severity by the investigator or designee on a scale of “0”
(absent) through “3” (severe). In addition, the area of AD involvement is assessed as a
percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score
of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30%
to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
Different regulatory bodies requested different primary endpoints for the Applicant’s global
development program. The EASI is a co-primary endpoint (along with the IGA) in the European
Union (EU), EU reference market countries, and Japan. The EASI is a mathematically-derived
assessment and is difficult to translate into readily, clinically-interpretable labeling.
Subject Assessment of Pruritus
The Peak Pruritus Numerical Rating Scale (NRS) was an assessment tool that subjects used to
report the intensity of their pruritus during a daily recall period using an IVRS. Subjects were
asked the following questions:
• For average itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the
‘worst itch imaginable’, how would you rate your itch overall (on average) during the
previous 24 hours?”
• For maximum itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being
the ‘worst itch imaginable’, how would you rate your itch at the worst moment during


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Brenda Carr, MD
BLA 761055
the previous 24 hours?”
Figure 2. Peak Pruritus NRS*
*Source: Patient Reported Outcome (PRO) Dossier for the Peak Pruritus NRS
Subjects completed the rating scale daily through Week 16 and weekly thereafter through the
last study visit. Clinical sites received alerts when subjects did not complete IVRS items. Sites
were to contact subjects who had missed 2 consecutive IVRS entries to encourage subject
compliance.
The Clinical Outcome Assessment (COA) team concluded that the Peak Pruritus NRS
appropriately measured patient-reported pruritus intensity and appeared to be fit-for purpose
for the Applicant’s clinical development program.
Statistical Analysis Plan

The following discussion of statistical methods is from the statistical review by Carin Kim, PhD:
The primary efficacy analyses were based on the Full Analysis Set (FAS) defined as all
randomized subjects. The protocols defined the Per Protocol Set (PPS) as all FAS
subjects except those with major efficacy-related protocol violations, and the protocol
specified a major protocol violation as the one that may affect the interpretation
of study results and listed the following criteria of major protocol violations:
• A patient who did not receive treatment as randomized
• Patients who were randomized more than once
• Any major violations of efficacy-related entry criteria
• Patients who received <80% or >120% of the scheduled doses during the study
treatment period.


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Brenda Carr, MD
BLA 761055
For efficacy analyses, the protocols for both trials specified the following hypotheses for
each dupilumab dose regimen:
H0: No treatment difference between dupilumab vs. placebo.
H1: There is a treatment difference between dupilumab vs. placebo.
The protocols specified that a hierarchical testing procedure would be used for the
multiple endpoints at α=0.025 for each dose regimen independently. The sponsor used
“a serial gatekeeping procedure” for the multiplicity adjustment for the secondary
endpoints, and tested the endpoints in a pre-specified order.
For analysis of the binary endpoints, the CMH test adjusted by randomization strata
(baseline disease severity and region) was used.
For handling missing data, the protocols for both trials specified that if a patient
withdrew from the study, then this patient would be counted as non-responder for
endpoints after withdrawal. In addition, if a patient received rescue medication, then
the patient was specified as a non-responder from the time the rescue was used. As
sensitivity analyses for handling missing data, the sponsor used the last observation
carried forward (LOCF), and used all observed data analyses as a sensitivity analysis.
While the sponsor originally defined rescue treatment as having used any TCS during the
trials, in an amended SAP submitted to the Agency (dated: 2/6/2016), the sponsor
included a “rescue medication algorithm” that specified that subjects who used TCS
during the first 14 days would not be considered using rescue treatment, and
consequently, these subjects were not considered as non-responders for the efficacy
analyses. It should be noted that the monotherapy trials were completed on 2/12/2016
and 1/21/2016 for Trials 1334 and 1416, respectively. Further, the protocols still specify
TCS as prohibited medications, therefore, this reviewer considered those subjects that
used TCS within the first 14 days as having used rescue treatment, and consequently,
considered them as non-responders in the efficacy analyses.
Protocol Amendments
The above study description reflects the protocol as revised under Amendment 2 (issued
02/05/2016).
Data Quality and Integrity: Sponsor’s Assurance
The protocol detailed the procedures for study monitoring, audits and inspections, as described
below:
Monitoring of Study Sites/Source Document Requirements


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BLA 761055
The study monitor and/or designee were to visit each site prior to enrollment of the first
subject and periodically during the study. In accordance with International Conference on
Harmonisation (ICH) guidelines, the monitor was to compare the case report form (CRF) entries
with the source documents. Investigators were required to keep all source documents on file
with the CRF. Review of other documentation and data collection procedures was also possible.
A copy of the drug dispensing log was required to be provided to the Applicant upon request.
Case Report Form Requirements
Study data obtained in the course of the clinical study was to be recorded on electronic CRFs by
trained site personnel. A CRF was to be completed for every subject enrolled in the study and
electronically signed by the investigator after review of the clinical data. A copy of each CRF
page was to be retained by the investigator as part of the study record and had to be available
at all times for inspection by authorized representatives of the Applicant and regulatory
authorities.
Corrections to the CRF were to be entered by the investigator or an authorized designee. All
changes, including date and person performing corrections, were to be available via the audit
trail. For corrections made via data queries, a reason for any alteration was required to be
provided.
Audits and Inspections
The study was subject to a quality assurance audit or inspection by the Applicant or regulatory
authorities. Documents subject to audit or inspection included but were not limited to all
source documents, CRFs, medical records, correspondence, Institutional Review Board/Ethics
Committee files, and documentation of certification and quality control of supporting
laboratories. Conditions of study material storage were subject to inspection. Representatives
of the Applicant could observe the conduct of any aspect of the clinical study or its supporting
activities both within and outside of the investigator's institution.
I consider the Applicant’s efforts and procedures for ensuring data quality to have been
comprehensive and acceptable.
6.1.2. Study Results
Compliance with Good Clinical Practices
The Applicant attested that this study was conducted in accordance with the ethical principles
that are consistent with the International Conference on Harmonisation (ICH) guidelines for
Good Clinical Practice (GCP). One site was closed due to unspecified GCP-related issues,

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BLA 761055
involving a total of 11 subjects. Subjects from these sites were included in the full analysis set
but were excluded from the per protocol analysis set.
I consider this to be an acceptable handling of this issue.
Financial Disclosure
The Applicant adequately disclosed financial interests with clinical investigators. For study 1334,
(b) (6)
the Applicant disclosed financial interests for one clinical investigator: , who
(b) (6) (b) (6)
was a principal investigator at Site in . He received $33,678 for “consulting
(b) (6)
services and steering committee member from Regeneron from .” Dr.
(b) (6) (b) (6)
was also a principal investigator in the covered .
The Applicant implemented the following measures to protect the covered studies from
potential bias:
• All of the covered studies employed double-blind masking for the collection of pivotal
safety and efficacy data.
• Subjects were randomly assigned to treatment arms via an IVRS system.
• A recruitment threshold was set up for each study site and further recruitment was
authorized upon careful review of the quality of data.
• The quality of data reported by investigators and adherence to the protocol were
followed during the course of the studies by a central clinical team blinded to the
treatment arm.
The measures taken by the Applicant were adequate to minimize bias. The financial disclosure
by this investigator does not affect my review or conclusions.
Patient Disposition
Disposition of subjects for the 16-week treatment period is presented in Table 7.
Table 7. Initial Treatment Period Subject Disposition for Trials 1334*
Study 1334
Dupilumab Dupilumab Placebo
300 mg QW 300 mg Q2W
Randomized 223 224 224
Discontinued 17 (8%) 11 (5%) 23 (10%)
Reasons for discontinuation
Adverse events 4 2 3
Lack of efficacy 4 1 2
Lost to follow-up 0 0 0


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Physician decision 0 0 1
Protocol violation 2 1 0
Withdrawal by subject 5 6 14
Death 0 0 0
Other 1 1 1
Subjects who used at least one topical corticosteroids (TCS; dermatological preparations)(1)
TCS 27 (12%) 24 (11%) 51 (23%)
Source: statistical review Table 6
1 Subjects who used topical corticosteroids within the initial treatment period were considered as nonresponders for the
efficacy analyses.
Protocol Violations/Deviations
Protocol deviations were reported as follows:

• 7.6% (17/224) of subjects in the placebo group,
• 3.1% (7/224) in the dupilumab 300 mg Q2W group, and
• 7.2% (16/223) of patients in the dupilumab 300 mg QW group.
“Inadequate informed consent administration” was the most common major protocol violation.
“Procedure not performed” was the second most common violation. The remaining types of
violations were generally reported in similar proportions of subjects across treatment groups
(≤ 1% of subjects).
Table 8. Summary of Protocol Deviations – All Randomized Subjects*
*Source: study report Table 5
The Applicant excluded 25 randomized subjects from the per protocol set because of major


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BLA 761055
violations: efficacy-related entry criteria (6 subjects), closed site (7 subjects), received <80% or
>120% of scheduled doses (10 subjects) or were randomized but not treated (2 subjects).
I consider the number of protocol violations to be low, generally similar between treatment
groups, and not likely to have impacted efficacy results.
Table of Demographic Characteristics
Baseline demographic characteristics are presented in the following table. Most subjects were
white, male and the mean age was approximately 39.5 years. Demographic and baseline
characteristics were similar among the treatment groups.
Table 9. Summary of Baseline Demographic Characteristics*
Trial 1334
Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo
Gender
Male 142 (64%) 130 (58%) 118 (53%)
Female 81 (36%) 94 (42%) 106 (47%)
Age
Mean 39.3 39.8 39.5
SD 14.4 14.7 13.9
Range 18-76 18-85 18-84
Median 39 38 39
<65 215 (96%) 208 (93%) 216 (96%)
≥65 8 (4%) 16 (7%) 8 (4%)
Race
White 149 (67%) 155 (69%) 146 (65%)
Black 20 (9%) 10 (5%) 16 (7%)
Asian 51 (23%) 54 (24%) 56 (25%)
Other 3 (1%) 5 (2%) 6 (3%)
*Source: Table 8 of statistical review
Other Baseline Characteristics
Baseline severity and extent of AD were similar between the placebo and dupilumab treatment
groups. The proportion of subjects with moderate (IGA of 3) and severe (IGA of 4) disease was
similar across treatment groups, with a slightly higher proportion of subjects having moderate
disease in the dupilumab groups. The mean EASI score was 34.5±14.5 for the placebo group,
33.0±13.6 for the dupilumab 300 mg Q2W group, and 33.2±14.0 for the dupilumab 300 mg QW
group. Mean BSA involvement was ~ 55 to 58% across treatment groups. The mean peak
weekly averaged pruritus NRS was 7.4±1.8 for the placebo group, 7.2±1.9 for the dupilumab
300 mg Q2W group, and 7.2±2.1 for the dupilumab 300 mg QW group. The summary of

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baseline disease characteristics is presented in Table 10.
Table 10. Baseline Disease Characteristics*
Trial 1334
IGA
Moderate=3 117 (53%) 116 (52%) 113 (50%)
Severe=4 106 (47%) 108 (48%) 111 (50%)
EASI score
Mean 33.2 33.0 34.5
SD 14.0 13.6 14.5
Median 29.8 30.4 31.8
Range 16-72 16-71 16-72
Weekly Average Peak Pruritus NRS score
Mean 7.2 7.2 7.4
SD 2.1 1.9 1.8
Median 7.7 7.6 7.7
Range 1-10 0-10 2-10
≥3 211 (95%) 220 (98%) 221 (99%)
≥4 201 (90%) 213 (95%) 212 (95%)
BSA
Mean 56.1 54.7 57.5
SD 23.0 23.2 23.4
Median 54.5 53.4 57.0
Range 12-100 11-100 12-100
The Applicant collected the medical history by using a general questionnaire. However, the
Applicant collected history pertaining to atopy by using a targeted questionnaire. Therefore,
there may be disparities in the reports of some events because of the differing methods of
information collection.
In collection of the general medical history, the following MedDRA PTs were reported in ≥10%
of subjects in any treatment group: Dermatitis Atopic, Asthma, Rhinitis Allergic, Seasonal
Allergy, Food Allergy, Allergy to Animal, House Dust Allergy, Conjunctivitis Allergic, Depression,
and Hypertension.
Table 11. Medical History Findings (≥10% of Patients in Any Treatment Group) by Primary System Organ Class
and Preferred Term – SAF:


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Brenda Carr, MD
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*Source: Table 9 of study report
From the collection of history using the targeted questionnaire for atopic disease, the most
common comorbidity reported in this category was allergic rhinitis, with approximately 60% of
subjects reporting this condition in each treatment group. Approximately 37 % of subjects had a
history of asthma, with the lowest proportion of subjects being in the placebo group (33%).
Approximately 26% of subjects had a history of allergic conjunctivitis. An additional 5% of
subjects in each treatment group reported a history of atopic keratoconjunctivitis.


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Brenda Carr, MD
BLA 761055
Table 12. Atopic/Allergic Disease History – SAF*
Treatment Compliance, Concomitant Medications, and Rescue Medication Use
Treatment Compliance
Compliance with use of background moisturizer was generally similar between treatment
groups, but lowest in the placebo group.
Table 13. Compliance with Background Moisturizer (Emollient)*
Trial 1334
Dupilumab 300 Dupilumab 300
Placebo
mg QW mg Q2W
Compliance 75% 76% 70%
*Source: Table 12 of the statistical review
Concomitant Medications
The Applicant reported that ≥ 96% of subjects in each treatment group used at least 1
concomitant medication during the 16-week treatment period. Generally, the proportion of

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Brenda Carr, MD
BLA 761055
subjects who used concomitant medications was similar between the placebo group and the
dupilumab groups. The most commonly used concomitant medications were in the therapeutic
class Emollients and Protectives, which may be reflective of the requirement for background
use of moisturizers. More than 20% of subjects in any treatment group reported use of
concomitant medications in the following therapeutic classes: Antihistamines for Systemic Use;
Corticosteroids, Dermatological Preparations; and Drugs for Obstructive Airway Diseases. This
pattern of background medication usage is consistent with the study population.
Rescue Medications and Procedures
“Corticosteroids, Dermatological Preparations,” were the most commonly used dermatological

rescue medications by therapeutic class. These topical products were used by 48.7% of subjects
in the placebo group compared to 18.8% in the dupilumab 300 mg Q2W and 21.1% dupilumab
300 mg QW arms. Corticosteroids of Group III potency were the most commonly used in all
treatment groups. Systemic corticosteroids were used by 7.6% of subjects in the placebo group
compared to 0.9% in the dupilumab 300 mg Q2W and 2.2% dupilumab 300 mg QW arms.
“Calcineurin inhibitors” were used in approximately 2% of placebo-treated subjects and ≤ 1% of
dupilumab-treated subjects. However, in the text of Section 6.5.4.3 of the study report, the
Applicant specifically referenced tacrolimus or pimecrolimus as the products categorized in the
therapeutic class “Other Dermatological Preparations” (sub-categorized as “Agents for
dermatitis, excluding corticosteroids”). Based on this information, an additional 7.6%, 4.0%, and
5.4% of subjects used calcineurin inhibitors in the placebo, 300 Q2W and 300 mg QW,
respectively. See Table 14.


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Brenda Carr, MD
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Table 14. Number (%) of Patients Taking Rescue Treatment During the 16-Week Treatment Period – FAS*


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BLA 761055
Efficacy Results – Primary Endpoint
The primary endpoint was the proportion of subjects with both IGA 0 to 1 (on a 5-point scale)
and a reduction from baseline of ≥2 points at Week 16. The statistical reviewer found that both
dupilumab dosing regimens were superior to placebo treatment at Week 16 (p<0.0001). The
results for the primary endpoint are presented in Table 15.
Table 15.Table Proportion of Subjects Achieving Treatment Success at Week 16 for Trial 1334*

FAS+ 223 224 224
IGA 0 or 1 83 (37%) 84 (38%) 23 (10%)
*Source: Table 1 statistical review
+Full Analysis Set (FAS) defined as all randomized subjects
IGA assessments were performed Weeks 1, 2, 4, 6, 8, 12, and 16. Figure 3 presents the IGA
successes over time.


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BLA 761055
Figure 3. Success on the IGA(1) for the initial treatment period for Trial 1334*
*Source: Figure 1 from statistical review
Data Quality and Integrity – Reviewers’ Assessment
The data quality and integrity appeared adequate.
Efficacy Results – Secondary and other relevant endpoints
Both dupilumab dosing regimens were superior to placebo treatment at Week 16 for the
secondary endpoint, proportion of subjects with EASI75 (≥75% improvement from baseline)
(p<0.0001). The results for the EASI 75 endpoint are presented in Table 16.


Clinical Review
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BLA 761055
Trial 1334
FAS 223 224 224
EASI 75 117 (53%) 114 (51%) 33 (15%)
*Source: Table 1 from statistical review
secondary endpoint, proportion of subjects with improvement (reduction) of weekly average of
peak daily pruritus ≥4 from baseline to Week 16 (p<0.0001).
Table 17. Proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from
baseline to Week 16
Trial 1334
FAS 223 224 224
Pruritus FAS
201 213 212
(Baseline NRS≥4)
Reduction of at least 4-
point change from 81 (40%) 86 (40%) 24(12%)
baseline+
*Source: Statistical review Table 1
+Statistical reviewer’s analysis based on the Full Analysis Set (FAS) defined as all randomized subjects. (1) Proportion of subjects
with a reduction of weekly average of peak daily pruritus NRS ≥4. Missing data as well as those that received rescue medication
at any time within the 16 weeks was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel
(CMH) test stratified by baseline disease severity and region as the primary analysis method.
Secondary endpoints also included the proportion of subjects achieving improvement

(reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 4 and from
baseline to Week 2. Results for pruritus for all time points (Weeks 2, 4, and 16) are presented in
Table 18 below.
Table 18. Proportion of Subjects with at least 4-point change from baseline Weeks 2, 4, 16 for Trials 1334*
Trial 1334
Pruritus ≥4 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo
FAS 223 224 224
Week 2 19 (10%) 20 (9%) 7 (3%)
Week 4 47 (23%) 34 (16%) 12 (6%)
Week 16 81 (40%) 86 (40%) 24 (12%)
The statistical reviewer found that all comparisons were statistically significant, with p<0.0001
for Week 16, and p<0.01 for Weeks 4 and 2.

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BLA 761055
Dose/Dose Response
See Section 7.1.4
Durability of Response
The study was not designed to assess the durability of response.
Persistence of Effect
The study was not designed to assess the persistence of effect. Subjects with IGA scores of 0 or
1 or EASI-75 at Week 16 and who had not received rescue treatment, were eligible for
immediate transition into the maintenance study at Week 16 and received no additional follow-
up in study 1334.
Follow-up visits were every 4 weeks from Week 20 through Week 28, for subjects who declined
to participate in the OLE or maintenance study. The duration of this 12-week follow-up period
was based on the time expected for drug levels to reach zero (below the lower limit of
quantification) in most subjects after the last dose of dupilumab. There were no endpoints
designated after Week 16.
Additional Analyses Conducted on the Individual Trial
Dr. Kim found that subjects with severe disease at baseline (IGA of 4) generally had lower
treatment responses relative to subjects with moderate disease at baseline. The proportion of
subjects with moderate disease at baseline who were responders was higher for the Q2W
treatment group (52%) compared to the QW group (46%). The proportion of subjects with
severe disease at baseline who were responders was higher for the QW treatment group (27%)
compared to the Q2W group (21%).
Table 19. IGA Responders by Baseline IGA Severity for Trial 1334*
Trial 1334


IGA
54/117 (46%) 61/116 (52%) 16/113 (14%)
Moderate=3
29/106 (27%) 23/108 (21%) 7/111 (6%)
Severe=4
*Source: Table 26 from the statistical review


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BLA 761055
6.2. R668-AD-1416 (1416); SOLO 2

Monotherapy Administered to Adult Patients with Moderate to Severe Atopic Dermatitis”
6.2.1. Study Design
This study was identical in design to 1334; see 6.1 for a description of the study design.
The Applicant assured that the study was conducted with the ethical principles that have their
origin in the Declaration of Helsinki and that are consistent with the International Conference
on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory
requirements.
Two sites were closed due to GCP-related issues, involving a total of 19 subjects. Subjects from
these sites were included in the full analysis set but excluded from the per protocol analysis set.
The Applicant disclosed financial interests for two clinical investigators for study 1416:
• (b) (6)
, a sub-investigator at sites (b) (6)
and (b) (6)
(location of both sites:
(b) (6)
) was reported to have shares of
Regeneron stock valued at $59,134.
• (b) (6)
, who was a principal investigator at Site (b) (6)
( (b) (6)
, received a total of $41,848 for consulting services and

(b) (6) (b) (6)
“steering committee member” from Regeneron from until
(b) (6) (b) (6)
. Dr. was also a principal investigator in the covered
The same bias-minimization measures that were applied in study 1334 were applied to study
1461.
Patient Disposition
Disposition of subjects for the 16-week treatment period is presented in Table 20.


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BLA 761055
Table 20. Initial Treatment Period Subject Disposition for Trials 1416*
Study 1416
Placebo Dupilumab Dupilumab
300 mg Q2W 300 mg QW
Discontinued 15 (6%) 10 (4%) 17 (7%)
Adverse events 3 1 1
Physician decision 1 2 1
Death 1 0 0
Other 0 1 0
Subjects who used at least one topical corticosteroids (TCS; dermatological preparations)(1)
TCS 67 (28%) 24 (11%) 24 (10%)
1 Subjects who used topical corticosteroids within the initial treatment period were considered as nonresponders for the
efficacy analyses.
Major protocol deviations were identified in all treatment arms: 6.4% (15/236) of subjects in
the placebo group, 9.4% (22/233) in the dupilumab 300 mg Q2W group, and 7.5% (18/239) in
the dupilumab 300 mg QW group. “Personnel not qualified and/or designated to perform
study-related activities” was the most commonly reported major protocol deviation in all
treatment groups: 4.2% in the placebo group, 3.4% in the dupilumab 300 mg Q2W group, and
4.6% in the dupilumab 300 mg QW group. The incidence of each of the other major protocol
deviation categories was low (<2% in any treatment group). The types of major protocol
deviations identified were unlikely to impact the results of the study.


Clinical Review
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BLA 761055
Table 21. Summary of Protocol Deviations – All Randomized Patients*
*Source: Table 5 of the study report
Demographic characteristics were generally similar between treatment arms. Most subjects
were white and male, and the mean age was approximately 37 years.
Table 22. Summary of Baseline Demographic Characteristics*
Trial 1416
Gender
Male 139 (58%) 137 (59%) 132 (56%)
Female 100 (42%) 96 (42%) 104 (44%)
Age
Mean 37.1 36.9 37.4
SD 14.5 14.0 14.1
Range 18-87 18-88 18-83
Median 35 34 35
<65 226 (95%) 223 (96%) 227 (96%)
≥65 13 (5%) 10 (4%) 9 (4%)
Race
White 168 (70%) 165 (71%) 156 (66%)


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BLA 761055
Black 15 (6%) 13 (6%) 20 (9%)

Asian 45 (19%) 44 (19%) 50 (21%)
Other* 11 (5%) 11 (5%) 10 (4%)
Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs)
Severity and extent of AD were similar between the placebo and dupilumab treatment groups
at baseline. The proportion of subjects with moderate (3) and severe (4) disease was similar
across treatment groups, with a slightly higher proportion of subjects having moderate disease
in all treatment groups. The mean BSA affected by AD was 54.3 ± 23.1 for the placebo group,
52.7 ± 21.2 for the dupilumab 300 mg Q2W group, and 52.2 ± 21.5 for the dupilumab 300 mg
QW group. The mean EASI score was 33.6 ±14.3 for the placebo group, 31.8 ± 13.1 for the
dupilumab 300 mg Q2W group, and 31.9 ± 12.7 for the dupilumab 300 mg QW group. The
mean peak weekly averaged pruritus NRS was 7.5 ± 1.85 for the placebo group, 7.6 ± 1.60 for
the dupilumab 300 mg Q2W group, and 7.5 ± 1.81 for the dupilumab 300 mg QW group. The
summary of baseline disease characteristics is presented in Table 23.
Table 23. Baseline Disease Characteristics for Study 1416*
Trial 1416
IGA
Moderate=3 127 (53%) 118 (51%) 121 (51%)
Severe=4 112 (47%) 115 (49%) 115 (49%)
EASI score
Mean 31.9 31.8 33.6
SD 12.7 13.1 14.3
Median 29.0 28.6 30.5
Range 9-72 12-72 16-72
Mean 7.5 7.6 7.5
SD 1.8 1.6 1.9
Median 7.8 7.8 7.7
Range 1-10 2-10 1-10
≥3 234 (98%) 231 (99%) 226 (96%)
≥4 228 (95%) 225 (97%) 221 (94%)
BSA
Mean 52.2 52.7 54.3
SD 21.5 21.2 23.1
Median 50 50 53
Range 13-100 13-100 11-100


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BLA 761055
The general medical history for study participants is presented in Table 24. Asthma was the
most commonly reported comorbid disease and was reported in approximately 43% of the
study subjects. Allergic rhinitis was the second most commonly reported condition in each
treatment group: placebo- 20.5%, dupilumab 300mg Q2W- 24.6%, and dupilumab 300 mg QW-
21.9%.
Table 24. Medical History Findings (≥10% of Patients in Any Treatment Group) by Primary System Organ Class
and Preferred Term – SAF*
*Source: Table 9 study report-1416
The Applicant collected the medical history by using a general questionnaire. However, the
Applicant collected history pertaining to atopy by using a targeted questionnaire. Therefore,
there may be disparities in the reports of some events because of the differing methods of
collection the information.
From the collection of history using the targeted questionnaire for atopic disease, the most
common comorbidity reported in this category was “other allergies,” with approximately 67%
of subjects reporting this category of events. Approximately 42 % of subjects had a current

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BLA 761055
history of asthma, with the highest proportion of subjects being in the dupilumab 300 mg Q2W
group (45%). Approximately 27% of subjects had a history of allergic conjunctivitis.
Additionally, subjects in each treatment group reported a history of atopic keratoconjunctivitis:
2.6% in the placebo group, 4.2% in the dupilumab 300 mg Q2W group, and 5.5% in the
dupilumab 300 mg QW group. Approximately 15% of study subjects reported a history of hives.
Table 25. Table 10: Atopic/Allergic Disease History – SAF*
Source: Table 10 study report- 1416


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BLA 761055
Subjects were required to apply stable doses of a moisturizer (emollient) twice daily for at least
7 days before the baseline visit and at least 7 days after the baseline visit. Compliance with use
of background moisturizer was generally similar between treatment groups, but lowest in the
placebo group.
Trial 1416
Placebo
mg QW mg Q2W
The Applicant reported that approximately 97% of subjects received at least one concomitant
medication during the study. The proportion of subjects who used concomitant medications
was generally similar between treatment groups: placebo-98.3%, dupilumab 300mg Q2W-
96.2%, and dupilumab 300 mg QW- 97%. The most commonly used concomitant medications
were in the therapeutic classes Emollients and Protectives and Antihistamines for Systemic Use,
and ≥50% in any treatment group used products in these classes. Emollients and Protectives
were the most commonly used therapeutic class of concomitant medications.
Rescue Medication Use
Corticosteroids, Dermatological Preparations were the most commonly used dermatological

rescue medications by therapeutic class. These topical products were used by 45.3% of subjects
in the placebo arm compared to 13.7% in the dupilumab 300 mg Q2W and 15.9% in the
dupilumab 300 mg QW arms. Group III corticosteroids were most commonly used in all
treatment groups. Systemic corticosteroids were used by 12.7% of subjects in the placebo
group compared to 1.3% in the dupilumab 300 mg Q2W and 2.5% dupilumab 300 mg QW arms.
Calcineurin inhibitors were used in 5.5 % of placebo-treated subjects and ≤ 1% of dupilumab-
treated subjects. Other Dermatological Preparations (tacrolimus or pimecrolimus) were used by
10.2% of subjects in the placebo group compared to 1.3% in the dupilumab 300 mg Q2W and
6.7% dupilumab 300 mg QW arms.
Efficacy Results - Primary Endpoint


Clinical Review
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BLA 761055
As with study 1334, both dupilumab dosing regimens were superior to placebo treatment at
Week 16 (p<0.0001). The results for primary endpoint for study 1416 are presented in Table 27.
Table 27. Proportion of Subjects Achieving Treatment Success at Week 16 for Trial 1416*

FAS+ 239 233 236
IGA 0 or 1 86 (36%) 83 (36%) 20 (9%)
+Full Analysis Set (FAS) defined as all randomized subjects
*Source: Figure 1 Statistical Review
Data Quality and Integrity - Reviewers' Assessment
The data quality was adequate.
Efficacy Results - Secondary and other relevant endpoints


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BLA 761055
Trial 1416
FAS 239 233 236
EASI 75 113(47%) 102 (44%) 28 (12%)
peak daily pruritus ≥4 from baseline to Week 16 (p<0.0001). See Table 29.
baseline to Week 16*
Trial 1416
FAS 239 233 236
Pruritus FAS
228 225 221
(Baseline NRS≥4)
point change from 87 (38%) 79 (35%) 21 (10%)
baseline+
+Reviewer’s analysis based on the Full Analysis Set (FAS) defined as all randomized subjects. (1) Proportion of subjects with a
reduction of weekly average of peak daily pruritus NRS ≥4. Missing data as well as those that received rescue medication at any
time within the 16 weeks was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel (CMH)
test stratified by baseline disease severity and region as the primary analysis method.

baseline to Week 2. Comparisons were statistically significant at all 3 time points: p< 0.01 at
Weeks 2 and 4 and p<0.0001 at Week 16. Results for pruritus for the various time points are
presented in Table 30 below.
Table 30. Proportion of Subjects with at least 4-point change from baseline Weeks 2, 4, 16 for Trials 1334*


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BLA 761055
Trial 1334
Pruritus ≥4 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo
FAS 239 233 236
Week 2 29 (13%) 24 (11%) 2 (1%)
Week 4 58 (25%) 50 (22%) 14 (6%)
Week 16 87 (38%) 79 (35%) 21 (10%)
Dose/Dose Response
See Section 7.1.4
The study was not designed to assess durability of response.
The study was not designed to assess the persistence of treatment effect. See discussion in
Section 6.1.2.
As was seen in study 1416, subjects with severe disease at baseline (IGA of 4) generally had
lower treatment responses relative to subjects with moderate disease at baseline and slightly
(3%) higher responses with QW dosing relative to Q2W.
Table 31. IGA Responder by Baseline IGA Severity for Trial 1416*
Trial 1416

53/127 (42%) 53/118 (45%) 17/121 (14%)

Moderate=3
33/112 (29%) 30/115 (26%) 3/115 (3%)
Severe=4


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6.3. R668-AD-1224 (1224); CHRONOS
“A Randomized, Double-Blind, Placebo-Controlled Study to Demonstrate the Efficacy and Long-

Term Safety of Dupilumab in Adult Patients with Moderate-to-Severe Atopic Dermatitis”
6.3.1. Study Design
Overview and Objective
The primary objective was to demonstrate the efficacy of dupilumab administered

concomitantly with topical corticosteroids (TCS) through Week 16 in adult subjects with
moderate-to-severe atopic dermatitis (AD).
The secondary objectives were to evaluate the long-term efficacy and the long-term safety of
dupilumab when administered concomitantly with TCS for up to 52 weeks.
Trial Design
This was a 64-week (52-week treatment period and 12 week follow-up), randomized, double-
blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of dupilumab
administered concomitantly with TCS in adults with moderate-to-severe AD. During the 35-day
screening period, treatments for AD were to have been washed out for at least 7 days prior to
baseline (except moisturizers).
Background Treatment
Subjects were required to apply moisturizers twice daily for at least the 7 consecutive days
immediately before randomization and continue throughout the study (except for at least 8
hours before each clinic visit). Subjects were randomized in a 3:1:3 ratio to receive QW or Q2W
SC injections of 300 mg dupilumab, following a loading dose of 600 mg on Day 1, or matching
placebo, respectively. Randomization was stratified by baseline disease severity (moderate [IGA
= 3 vs. severe [IGA = 4] AD) and by region. Subjects or caregivers had the option to administer
study drug off site.
Starting on Day 1/baseline, all subjects were to initiate treatment with TCS using a standardized
regimen and continue the regimen through the end of the study:
• Apply medium potency TCS once daily to areas with active lesions.
- Low potency TCS should be used once daily on areas of thin skin (face, neck,
intertriginous, and genital areas, areas of skin atrophy, etc.) or for areas where
continued treatment with medium potency TCS is considered unsafe.
• After lesions were under control (clear or almost clear), switch from medium potency to
low potency TCS and treat once daily for 7 days, then stop.

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• If lesions returned, resume treatment with medium potency TCS, with the step-down
approach described above upon lesion resolution.
• For lesions persisting or worsening under once daily treatment with medium potency
TCS, patients may be treated (rescued) with high or super-high potency TCS, unless
higher potency TCS are considered unsafe.
• The subject was to be monitored for signs of local or systemic TCS toxicity and step
down or stop treatment as necessary.
Triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment were

recommended for medium potency, and hydrocortisone 1% cream for low potency.
Rescue Medications
After Week 2, if needed to control intolerable symptoms, subjects could receive rescue
treatment with any approved AD treatments. If rescue were needed after Week 2, investigators
were to try to approach therapy in a staged fashion, using a greater intensity of treatment
compared to that being used. Subjects could receive rescue after Week 2 with TCS and continue
treatment with study drug. If a subject received rescue with a systemic immunosuppressant,
systemic corticosteroids, or phototherapy, the subject had to stop study drug, but could be
eligible to restart treatment with study drug after discontinuing the rescue treatment. Subjects
who discontinued study drug were considered treatment failures, but were to remain in the
study and continue with the study visits and assessments.
If rescue with TCS were needed, mometasone 0.1% ointment was recommended for high
potency and either betamethasone dipropionate 0.05% optimized ointment or clobetasol
propionate 0.05% cream for super high potency TCS.
Subjects who received systemic corticosteroids or systemic nonsteroid immunosuppressive

drugs (e.g., cyclosporine) or phototherapy were to be discontinued from study drug. These
subjects could re-initiate study drug approximately 5 half-lives after the systemic treatment was
stopped. Subjects treated with phototherapy could re-initiate study drug 1 month after
completing phototherapy. Subjects who discontinued study drug were to remain in the study
and complete all study visits and assessments.
The end-of-treatment visit was at Week 52, 1 week after the last dose of study drug, followed
by a 12-week post-treatment follow-up period (time expected for drug levels to reach zero,
below the lower limit of quantification). The end of study visit was at Week 64. Subjects who
completed this study could be eligible to enroll in an open-label extension study (1225) in which
they might receive treatment with dupilumab.


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BLA 761055
Permitted Medications and Procedures
Basic skin care (cleansing and bathing), emollients, bleach baths, topical anesthetics, and
antihistamines were permitted for any duration.
The use of TCI was to be reserved for “problem areas” (e.g., face, intertriginous, and genital
areas). TCS and TCI were not be used concomitantly to treat the same affected areas.
Medications used to treat chronic disease such as diabetes, hypertension, and asthma were
also permitted.
Figure 5. Study Flow Diagram*
*Source: Figure 1 protocol
Inclusion Criteria
Disease criteria were the same as for studies 1334 and 1416.
Key Exclusion Criteria Included:

• Important side effects of topical medication (e.g., intolerance to treatment,
hypersensitivity reactions, significant skin atrophy, systemic effects), as assessed by the
investigator or patient’s treating physician
• At baseline visit ≥30% of the total lesional surface located on areas of thin skin that
cannot be safely treated with medium or higher potency TCS (e.g., face, neck,
intertriginous areas, genital areas, areas of skin atrophy)
• Treatment with TCS or TCI within 1 week before the baseline visit
• Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit
• Active chronic or acute infection requiring systemic treatment with antibiotics,
antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the

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BLA 761055
baseline visit, or superficial skin infections within 1 week before the baseline visit. NOTE:
subjects could be rescreened after the infection resolved.
• Known or suspected history of immunosuppression, including history of opportunistic
infections (e.g., tuberculosis, histoplasmosis) despite infection resolution; or unusually
frequent, recurrent, or prolonged infections, per investigator judgment
• Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks
before the baseline visit
• History of human immunodeficiency virus (HIV) infection or positive HIV serology at
screening
• Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or
hepatitis C antibody at the screening visit
• History of malignancy within 5 years before the screening visit, except completely
treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic
squamous or basal cell carcinoma of the skin
• Severe concomitant illness(es) that, in the investigator’s judgment, would adversely
affect the patient’s participation in the study.
• Diagnosed active parasitic infections; suspected or high risk of parasitic infection, unless
clinical and (if necessary) laboratory assessment have ruled out active infection before
randomization
• Pregnant or breastfeeding women, or planning to become pregnant or breastfeed
during study participation
• Women unwilling to use adequate birth control, if of reproductive potential and sexually
active.


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Table 32. Schedule of Events - Screening, Baseline, and Treatment Period – Visits 1 through 14*


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BLA 761055
*Source: protocol
1 The site will contact the patient by telephone to conduct these visits. The patient/caregiver may administer study drug on
these days. Patients who receive study drug outside the study center will complete a dosing diary to document compliance with
study drug administration and to document any related issues.
2 For patients who decide to participate and provide specific written informed consent for the optional genomics sub-study
(DNA and RNA sample collection). DNA sample should be collected at the day 1 visit, but can be collected at any visit during the
study. RNA sample must be collected before the administration of the first dose of study drug
3 Patients will be trained at the screening visit on using the appropriate diary system to report pruritus, well-controlled weeks,
and provide other information, as required.
4 Patients will be monitored at the study site at visits 2, 3, and 4 for a minimum of 30 minutes after study drug administration.
Vital signs (blood pressure and heart rate) and AE assessments will be done at 30 minutes (+/- 10 minutes) post-injection.
completion/reporting of each dose of study drug that is administered outside of the clinic.
Patients will return the study drug vial or the original kit box (for patient dosed using prefilled syringes) at each clinic visit.
7 Patients will complete a paper diary to record every time they take medication for their eczema during the study (see
reference study manual).
9 Assessments/procedures should be conducted in the following order: patient reported outcomes, investigator assessments,
safety and laboratory assessments, administration of study drug.
10 The questionnaires will be administered only to the subset of patients who speak fluently the language in which the
questionnaire is presented (based on availability of validated translations in participating countries). ACQ-5 will be administered
only to patients with a medical history of asthma. SNOT-22 will be administered only to patients with chronic inflammatory
conditions of the nasal mucosa and/or paranasal sinuses (eg, chronic rhinitis/rhinosinusitis, nasal polyps, allergic rhinitis). All
questionnaires will be administered before any invasive procedures (blood draws, study drug injection, etc).
11 Select US sites only. If the photograph is not taken at the recommended visit, it should be taken at the next visit.
12 TB testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities
or ethics boards


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BLA 761055
Table 33. Schedule of Events - Treatment Period Cont. – Visits 15 through 27*
*Source: protocol
1 The site will contact the patient by telephone to conduct these visits. The patient/caregiver may administer study drug on
these days. Patients who receive study drug outside the study center will complete a dosing diary to document compliance with
study drug administration and to document any related issues.
2 The patient (or caregiver) will administer study drug during the weeks in which no clinic visit is scheduled.


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BLA 761055
completion/reporting of each dose of study
drug that is administered outside of the clinic
Patients will return the study drug vial or the original kit box (for patient dosed using prefilled syringes) at each clinic visit.
5 Patients will complete a paper diary to record every time they take medication for their eczema during the study .6 To be
collected before the injection of study drug.
7 Assessments/procedures should be conducted in the following order: patient reported outcomes, investigator assessments,
safety and laboratory assessments, administration of study drug.
8 Patients will be trained at the screening visit on using the appropriate diary system to report pruritus, well-controlled weeks,
and provide other information, as required,
9 Pruritus NRS and Pruritus Categorical Scale will be collected daily for the first 16 weeks and weekly thereafter until the end of
the study. Clinical sites will receive alerts when patients do not complete IVRS items; sites will be expected to contact patients
who have missed 2 consecutive IVRS entries to encourage patient compliance.
questionnaire is presented (based on availability of validated translations in participating countries). ACQ-5 will be administered
only to patients with a medical history of asthma. SNOT-22 will be administered only to patients with chronic inflammatory
conditions of the nasal mucosa and/or paranasal sinuses (eg, chronic rhinitis, rhinosinusitis, nasal polyps, allergic rhinitis). All
questionnaires will be administered before any invasive procedures (blood draws, study drug injection, etc).
13 Patients who have an ADA titer of ≥240 at their last study visit may be asked to return to the clinic to provide additional ADA
samples for analysis.


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BLA 761055
Table 34. Schedule of Events – Follow-up, Unscheduled Visit, and Early Termination*
*Source: protocol
1 During an unscheduled visit, any of the study procedures noted may be performed, but not all are required.
2 Patients will complete a paper diary to record every time they take medication for their eczema during the study.
questionnaire is presented (based on availability of validated translations in participating countries). ACQ-5
will be administered only to patients with a medical history of asthma. SNOT-22 will be administered only to patients with
chronic inflammatory conditions of the nasal mucosa and/or paranasal sinuses (eg, chronic rhinitis/rhinosinusitis, nasal polyps,
allergic rhinitis). All questionnaires will be administered before any invasive procedures (blood draws, study drug injection, etc).

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BLA 761055
6 Patients with an ADA titer of ≥240 at their last study visit may be asked to return to the clinic to have additional ADA samples
collected for analysis.
Study Endpoints
The primary endpoint was the proportion of subjects with both an IGA 0 to 1 (on a 5-point
scale) and a reduction from baseline of ≥2 points at Week 16
Key secondary endpoints were:

• Proportion of subjects with EASI-75 response (reduction of EASI score by ≥75% from
baseline) at Week 16
• Percent change from baseline to Week 16 in weekly average of peak daily Pruritus NRS
• Proportion of patients with improvement (reduction) in weekly average of peak daily
Pruritus NRS ≥4 from baseline to Week 16
• Proportion of patients with IGA 0 or 1 and a reduction from baseline of ≥2 points at
Week 52
• Proportion of patients with EASI-75 response at Week 52
• Percent change from baseline to Week 52 in weekly average of peak daily Pruritus NRS
Other secondary endpoints were:

• Percent change in EASI score from baseline to Week 16
• Change from baseline to Week 16 in percent BSA
• Percent change in SCORAD from baseline to Week 16
• Percent change from baseline to Week 16 in GISS (erythema, infiltration/papulation,
excoriations, lichenification)
• Change from baseline to Week 16 in DLQI
• Change from baseline to Week 16 in POEM
• Change from baseline to Week 16 in HADS
• Reduction in topical AD medication use through Week 16 (determined by the amount of
TCS and/or TCI used since previous visit in weight)
• Percent change in EASI score from baseline to Week 52
• Change from baseline to Week 52 in percent BSA
• Percent change in SCORAD from baseline to Week 52
• Percent change from baseline to Week 52 in GISS (erythema, infiltration/papulation,
excoriations, lichenification)

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BLA 761055
• Change from baseline to Week 2 in weekly average of peak daily Pruritus NRS
• Change from baseline to Week 52 in DLQI
• Change from baseline to Week 52 in POEM
• Change from baseline to Week 52 in HADS
• Number of flares through Week 52
• Incidence of skin-infection treatment-emergent adverse events (TEAEs) requiring
systemic treatment from baseline through Week 56
• Incidence of serious TEAEs through Week 56
• Incidence of TEAEs leading to study drug discontinuation from baseline through Week
56
Statistical Analysis Plan
The following information is from the discussion of statistical methods in the statistical review:
The primary efficacy endpoint was the proportion of subjects with IGA 0 or 1 and with a
reduction from baseline ≥2 points at Week 16.
For each dose regimen, the protocol specified that if both co-primary endpoints were
statistically significant at the 2-sided 0.025 level, the following secondary endpoints
were analyzed using a serial gatekeeping procedure to control the overall Type I error
rate:
o The proportion of subjects with EASI 75 (≥75% improvement from baseline) at Week
o Proportion of subjects with improvement (reduction) of pruritus NRS ≥4 from baseline
to Week 16
o Proportion of subjects with improvement (reduction) of pruritus NRS ≥3 from
baselineto Week 16
o Proportion of subjects with IGA 0 or 1 and a reduction from baseline ≥2 points at
Week 52
o Proportion of patients with EASI 75 response at Week 52
o Percent change from baseline to Week 16 in weekly average of peak daily pruritus NRS
o Proportion of subjects with improvement (reduction) in weekly average of peak daily
pruritus NRS ≥4 from baseline to Week 52
o Proportion of subjects with improvement (reduction) in weekly average of
peak daily pruritus NRS ≥4 from baseline to Week 4
o Proportion of subjects with improvement (reduction) in weekly average of

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BLA 761055
peak daily pruritus NRS ≥4 from baseline to Week 2
For analysis of the binary endpoints, the (Cochran-Mantel-Haenszel) test adjusted by

randomization strata (baseline disease severity and region) was used. For handling
missing data, the protocol specified that if a patient withdraws from the study, then this
patient was counted as nonresponder for endpoints after withdrawal. In addition, if a
patient received rescue medication, then the patient will be specified as a non-
responder from the time the rescue was used. As sensitivity analyses for handling
missing data for the binary endpoints, the sponsor used the last observation carried
forward (LOCF), and also conducted sensitivity analyses by using all observed data.
Protocol Amendments
See this discussion in Section 6.1.1.
Data Quality and Integrity: Sponsor's Assurance
The protocol described the same measures as were described for study 1334 in Section 6.1.1.
The Applicant attested that this trial was conducted in accordance with the ethical principles
that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
Two sites were closed due to GCP-related issues, involving 7 subjects. Two of the 7 were
considered screen failures for this study. Therefore, a total of 5 subjects from these sites were
included in the full analysis set (FAS) but were excluded from the per protocol analysis set
(PPS).
The applicant reported no investigators with disclosable financial interests for this trial.
Patient Disposition
The study was ongoing at the time of submission of the BLA. A total of 740 subjects were
enrolled and randomized: 315 subjects in the placebo + TCS group, 106 in the dupilumab 300
mg Q2W + TCS group, and 319 in the 300 mg QW + TCS group. Of the 740, 682 subjects (92.2%)
had completed Week 16 treatment, and 496 subjects (77.6%) had completed Week 52.


Clinical Review
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BLA 761055
More subjects withdrew prior to Week 64 in the placebo + TCS group (16.5%) than in the
combined dupilumab + TCS groups (9.9%). “Withdrawal by subject” (7% of placebo + TCS
subjects and 3.5% of subjects in the combined dupilumab + TCS group) and adverse events
(3.2% of placebo + TCS subjects and 2.1% in the combined dupilumab group + TCS) were the 2
most frequently reported reasons for withdrawal from the study. See Table 36.
Disposition through Week 16, the time point of primary efficacy assessment, is presented in
Table 35.
Table 35. Initial (16-week) Treatment Period Subject Disposition for Trial 1224*
Trial 1224
Dupilumab Dupilumab 300 mg
Placebo
300 mg QW Q2W
+
+ +
TCS
TCS TCS
Discontinued 17 (5%) 6 (6%) 25 (8%)
Adverse Events 4 0 5
Physician Decision 4 2 3
Death 0 0 0
Other 0 0 0
Subjects with at least one rescue(1) medication
Rescue 35 (11%) 10 (9%) 116 (37%)


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BLA 761055
Table 36. Summary of Subject Accountability and Study Disposition – All Randomized Subjects*


Clinical Review
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BLA 761055
Major protocol deviations were reported as follows: 14.0% (44/315) of subjects in the placebo
+ TCS group, 13.2% (14/106) in the dupilumab 300 mg Q2W + TCS group, and 12.5% (40/319) in
the dupilumab 300 mg QW + TCS group. The most commonly reported major protocol
deviations were “Other” (4.8% in the placebo + TCS group, 3.8% in the dupilumab 300 mg Q2W
+ TCS group, and 3.4% in the dupilumab 300 mg QW + TCS group) and “procedure not
performed” (3.8% in the placebo + TCS group, 4.7% in the dupilumab 300 mg Q2W + TCS group,
and 4.1% in the dupilumab 300 mg QW + TCS group). Twenty-eight of the 30 protocol violations
in the “other” category related to use of high potency TCS as rescue treatment during the first 2
weeks of the trial (rescue treatment was prohibited during this period).
The incidence of each of the other major protocol deviation categories was low (<3% in any
treatment group).


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Brenda Carr, MD
BLA 761055
Table 37. Summary of Major Protocol Deviations – All Randomized Patients*
*Source: Table 7 study report
Most subjects were white and male, and the mean age was approximately 38 years.
Demographic and baseline characteristics were similar among the treatment groups.


Clinical Review
Brenda Carr, MD
BLA 761055
Table 38. Baseline Demographics for Trial 1224*
Trial 1224
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
Gender
Male 191 (60%) 62 (59%) 193 (61%)
Female 128 (40%) 44 (41%) 122 (39%)
Age
Mean 36.9 39.6 36.6
SD 13.7 14.0 13.0
Range 18-81 18-73 18-76
Median 34 41 34
<65 306 (96%) 101 (95%) 306 (97%)
≥65 13 (4%) 5 (5%) 9 (3%)
Race
White 208 (65%) 74 (70%) 208 (66%)
Black 13 (4%) 2 (2%) 19 (6%)
Asian 89 (28%) 29 (27%) 83 (26%)
Other* 9 (3%) 1 (1%) 5 (2%)
Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs)
The severity and extent of AD were similar between the placebo and dupilumab treatment
groups at baseline. The proportion of subjects with moderate (3) and severe (4) disease was
generally similar across treatment groups, with a slightly lower proportion of subjects having
moderate disease in the 300 mg Q2W group (making for a slightly higher proportion of subjects
with severe disease in the Q2W group) compared to the other 2 treatment groups. The mean
BSA with AD was 56.9 (21.7) for the placebo + TCS group, 59.5 (20.8) for the dupilumab + TCS
300 mg Q2W group, and 54.1 (21.8) for the dupilumab + TCS 300 mg QW group. The mean EASI
score was 32.6 (12.9) for the placebo + TCS group, 33.6 (13.3) for the dupilumab + TCS 300 mg
Q2W group, and 32.1 (12.8) for the dupilumab + TCS 300 mg QW group. The mean peak weekly
averaged pruritus NRS was 7.3 (1.8) for the placebo + TCS group, 7.4 (1.7) for the dupilumab +


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Brenda Carr, MD
BLA 761055
TCS 300 mg Q2W group, and 7.1 (1.9) for the dupilumab + TCS 300 mg QW group. The summary
of baseline disease characteristics is presented in Table 39.
Table 39. Baseline Disease Severity for Trial 1224*
Trial 1224
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
IGA
2 1 (1%) N/A N/A
3 171 (54%) 53 (50%) 168 (53%)
4 147 (46%) 53 (50%) 147 (47%)
EASI score
Mean 32.1 33.6 32.6
SD 12.8 13.3 12.9
Median 29.0 31.0 29.6
Range 1-72 14-67 16-71
Mean 7.1 7.4 7.3
SD 1.9 1.7 1.8
Median 7.4 7.7 7.6
Range 1-10 1-10 1-10
≥3 309 (97%) 105 (99%) 306 (97%)
≥4 295 (93%) 102 (96%) 299 (95%)
BSA
Mean 54.1 59.5 56.9
SD 21.8 20.8 21.7
Median 52.0 58.8 55.0
Range 7-100 11-100 10-100
From the collection of history using the targeted questionnaire for atopic disease (Table 40),
the most common comorbidity reported in this category was “other allergies,” with
approximately 65% of subjects reporting this category of events. Approximately 10% of subjects
had a current history of asthma, with the lowest proportion of subjects being in the dupilumab
+ TCS 300 mg Q2W group (7.3%). Approximately 2% of subjects in the placebo + TCS group had
a history of allergic conjunctivitis (keratoconjunctivitis) which was similar to the approximately
3% of subjects in the combined dupilumab + TCS groups.


Clinical Review
Brenda Carr, MD
BLA 761055
Table 40. Medical History Findings (≥5% of Patients in Any Treatment Group) by Primary System Organ Class and
Preferred Term– SAF*
*Source: study report


Clinical Review
Brenda Carr, MD
BLA 761055
Table 41. Atopic/Allergic Disease History – SAF*


Clinical Review
Brenda Carr, MD
BLA 761055
Subjects were required to apply moisturizers (emollients) at least twice daily for at least the 7
days immediately prior to randomization and to continue through the study (52-week
treatment period and 12-week post-treatment follow-up period). Compliance with background
moisturizer use was similar across treatment groups.
Trial 1224
mg QW mg Q2W Placebo
+ TCS + TCS + TCS


Clinical Review
Brenda Carr, MD
BLA 761055
Consistent with the objective of this study to compare treatment with dupilumab + TCS to
placebo + TCS, 99.9% (739/740) of subjects reported concomitant use of Dermatological
Preparations of corticosteroids during the entire study. Concomitant use of TCI was reported by
27.7% (205/490) of subjects over the course of the 64-weeks study. Concomitant use of TCI was
reported by 3.0% (22/740) of subjects during the 52-week treatment period: placebo + TCS
group- 5.1% (16/315), dupilumab 300 mg Q2W + TCS- 0.9% (1/110) and dupilumab 300 mg QW
+ TCS- 1.6% (5/315).
Rescue Medication Use
Corticosteroids, Dermatological Preparations were the most commonly used dermatological

rescue medications by therapeutic class through Week 16. These topical products were used by
34.6% of subjects in the placebo + TCS arm compared to 9.1% in the dupilumab 300 mg Q2W +
TCS and 10.5% in the dupilumab 300 mg QW + TCS arms. Similarly, Corticosteroids for Systemic
Use and Immunosuppressants were used by a higher proportion of subjects in the placebo +
TCS group compared with the dupilumab + TCS groups (with no use of systemic corticosteroids
reported for the 300 mg QW + TCS group). Calcineurin inhibitors were used in 1.9% of placebo-
treated subjects and ≤ 1% of subjects in the dupilumab + TCS groups.


Clinical Review
Brenda Carr, MD
BLA 761055
Table 43. Rescue Medication Taken during the 16-Week Period – SAF*
A generally similar pattern to use of rescue medications was noted during the 52-Week period.


Clinical Review
Brenda Carr, MD
BLA 761055
Table 44. Rescue Medication Taken during the 52-Week Period*
*Source: Table 14of study report
Efficacy Results - Primary Endpoint
Both dupilumab dosing regimens were superior to placebo treatment at Week 16 (p<0.0001).
The results for the primary endpoint for trial 1224 are presented in Table 45.
Table 45. Proportion of Subjects Achieving Treatment Success at Week 16 for Combination Trial 1224*
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
FAS+ 319 106 315
IGA 0 or 1 125 (39%) 41 (39%) 39 (12%)
*Source: Table 2 of the statistical review; results based on the Full Analysis Set (FAS) defined as all randomized subjects.


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Brenda Carr, MD
BLA 761055
*Source: Figure 2 from the statistical review
Data Quality and Integrity - Reviewers' Assessment
The data quality was adequate.
Efficacy Results - Secondary and other relevant endpoints


Clinical Review
Brenda Carr, MD
BLA 761055
Trial 1224
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
FAS 319 106 315
EASI 75 204 (64%) 73 (69%) 73 (23%)
*Source: Table 2 from the statistical review
peak daily pruritus ≥4 from baseline to Week 16 (p<0.0001). See Table 47.
baseline to Week 16*
Trial 1224
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
FAS 319 106 315
Pruritus FAS
295 102 299
(Baseline NRS≥4)
baseline+
+Reviewer’s analysis based on the Full Analysis Set (FAS) defined as all randomized subjects. (1) Proportion of subjects with a reduction of
weekly average of peak daily pruritus NRS ≥4. Missing data as well as those that received rescue medication at any time within the 16 weeks
was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel (CMH) test stratified by baseline disease severity
and region as the primary analysis method.

baseline to Week 2. Both dupilumab dosing regimens were superior to placebo at Weeks 2, 4,
and 16. Results for pruritus for all time points (Weeks 2, 4, and 16) are presented in Table 48
below.


Clinical Review
Brenda Carr, MD
BLA 761055
Table 48. Proportion of Subjects with at least 4-point change from baseline Weeks 2, 4, 16 for Trial 1224*
Trial 1224
Dupilumab Dupilumab
Placebo
Pruritus ≥4 +
+ +
TCS
TCS TCS
FAS 319 106 315
Week 2 40 (14%) 18 (18%) 24 (8%)
Week 4 80 (27%) 38 (37%) 49 (16%)
Week 16 150 (51%) 60 (59%) 59 (20%)
Week 52 97 (39%) 44 (51%) 32 (13%)
+Reviewer’s analysis based on the Full Analysis Set (FAS) defined as all randomized subjects. (1) Proportion of subjects with a reduction of
weekly average of peak daily pruritus NRS ≥4. Missing data as well as those that received rescue medication at any time within the 16 weeks
was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel (CMH) test stratified by baseline disease severity
and region as the primary analysis method.
Dose/Dose Response
See Section 7.1.4
The proportion of IGA responders (0/1) at Week 16, who were also IGA responders at Week 52
are presented in Table 49. At Week 52, the results are similar for the Dupilumab 300 mg Q2W +
TCS and placebo + TCS groups. The numbers of subjects in those 2 groups (41 and 39,
respectively) is also relatively small.
Table 49. Proportion of Subjects with IGA success(1) at Week 52 among those that were IGA responders(1) at
Week 16 for Trial 1224*
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
Responders at
125 41 39
Week 16
Week 52 72 (58%) 20 (49%) 18 (46%)
*Source: Table 15 of the statistical review; results based on the Full Analysis Set (FAS) defined as all randomized subjects.
analysis based on the Full Analysis Set (FAS) defined as all randomized subjects. (1) IGA score of 0 or 1. Missing data as well as those that
received rescue medication was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel (CMH) test stratified by
baseline disease severity and region as the primary analysis method.


Clinical Review
Brenda Carr, MD
BLA 761055
The study was not designed to evaluate persistence of effect.
As was observed in the monotherapy trials, subjects with severe disease at baseline (IGA of 4)
generally had lower treatment responses relative to subjects with moderate disease at
baseline, but the proportion of responders was slightly higher for subjects who received weekly
dosing. Consistent with the monotherapy pivotal studies, a higher proportion of subjects with
moderate disease were responders with Q2W dosing compared to QW dosing. See Table 50.
Table 50. Success on the IGA at Week 16 by Baseline IGA Severity for Trial 1224*
Trial 1224
Dupilumab Dupilumab
Placebo
+ TCS+ + TCS
+ TCS
79/171 (46%) 26/53 (49%) 31/168 (18%)

Moderate=3
46/147 (31%) 15/53 (28%) 8/147 (5%)
Severe=4
*Source: Table 27 from statistical review (sourced as Table 10 of study report)
+ Not in the table: One subject in this treatment group who had mild disease at baseline was also an IGA success.
7 Integrated Review of Effectiveness
7.1. Assessment of Efficacy Across Trials
7.1.1. Primary Endpoints
The Applicant provided substantial evidence of efficacy from 3 adequate and well-controlled
studies the evaluated dupilumab for treatment of adult subjects with moderate-to-severe
atopic dermatitis whose disease was not adequately controlled with topical prescription
therapies or when those therapies were not advisable. Subjects were required to have disease
involving ≥ 10% body surface area (BSA) at baseline. Replicate studies 1334 and 1416 enrolled a

Clinical Review
Brenda Carr, MD
BLA 761055
combined total of 1,379 subjects and evaluated dupilumab as monotherapy. Study 1224
enrolled 740 subjects and evaluated dupilumab with protocol-specified, concomitant use of TCS
and with allowance for use of TCI. Baseline demographic and disease characteristics were
generally similar between treatment groups and across studies.
All 3 placebo-controlled studies evaluated 2 dupilumab dosing regimens:

• 300 mg QW (+ TCS in study 1224), following a 600 mg
loading dose on Day 1
• 300 mg Q2W (+ TCS in study 1224), following a 600 mg
loading dose on Day 1
The primary endpoint for all 3 studies was the proportion of subjects with both IGA 0 to 1 (on a
5-point scale) and a reduction from baseline of ≥2 points at Week 16.
Dupilumab was significantly superior to placebo in all 3 studies in the target AD population for
the primary endpoint. The treatment response was generally similar across the 3 studies.
Table 51. Proportion of Subjects Achieving Treatment Success at Week 16 for Monotherapy Studies 1334, 1416*
Study 1334 Study 1416

Dupilumab Dupilumab Dupilumab Dupilumab
Placebo Placebo
300 mg QW 300 mg Q2W 300 mg QW 300 mg Q2W
FAS+ 223 224 224 239 233 236
IGA 0 or 1 83 (37%) 84 (38%) 23 (10%) 86 (36%) 83 (36%) 20 (9%)
EASI 75 117 (53%) 114 (51%) 33 (15%) 113(47%) 102 (44%) 28 (12%)
+Full analysis set
Table 52. Proportion of Subjects Achieving Treatment Success at Week 16 for Combination Study 1224*
Study 1224
Dupilumab Dupilumab
Placebo
+ TCS
+ TCS + TCS
FAS+ 319 106 315
IGA 0 or 1 125 (39%) 41 (39%) 39 (12%)
EASI 75 204 (64%) 73 (69%) 73 (23%)
+Full analysis set
7.1.2. Secondary and Other Endpoints
The proportion of subjects with EASI-75 (≥75% improvement from baseline) at Week 16 was a
key secondary endpoint. In all 3 pivotal studies, both dupilumab dosing regimens were
significantly superior to placebo treatment at Week 16 for the key secondary endpoint, EASI-75.

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BLA 761055
Treatment responses for EASI-75 were generally similar between dupilumab dosing regimens
within each pivotal monotherapy study. See Tables 51 and 52 above for outcomes for the EASI-
75 endpoint.
The proportion of subjects with improvement (reduction) of weekly average of peak daily
pruritus NRS ≥4 from baseline to Week 16, was another key secondary endpoint. Dupilumab
was significantly superior to placebo in all 3 studies in the target AD population for this key
secondary endpoint. Treatment responses were the same or similar between the 2 dupilumab
dosing regimens in the monotherapy studies, 1334 and 1416. The treatment responses in all
arms i.e., including placebo, were noticeably higher in study 1224, which specified use of TCS.
This suggests that the TCS may have had impact on the pruritus.
Table 53. Proportion of Subjects Achieving Treatment Success at Week 16 for Monotherapy Studies 1334, 1416*
Trial 1334 Trial 1416

Placebo Placebo
Pruritus FAS
(Baseline 201 213 212 228 225 221
NRS≥4)
Reduction of
at least 4- 81 (40%) 86 (40%) 24(12%) 87 (38%) 79 (35%) 21 (10%)
point change
from
(1)
baseline
(1) Proportion of subjects with a reduction of weekly average of peak daily pruritus NRS ≥4. Missing data as well as those that received rescue
medication at any time within the 16 weeks was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel (CMH)
Table 54. Proportion of Subjects Achieving Treatment Success at Week 16 for Study 1224*
Study 1224
Dupilumab Dupilumab
Placebo
+ TCS
+ TCS + TCS
Pruritus FAS (Baseline
NRS≥4) 295 102 299
baseline (1)
(1) Proportion of subjects with a reduction of weekly average of peak daily pruritus NRS ≥4. Missing data as well as those that received rescue
medication at any time within the 16 weeks was imputed as non-responders. The protocol specified using the Cochran Mantel Haenszel (CMH)


Clinical Review
Brenda Carr, MD
BLA 761055
7.1.3. Subpopulations
IGA treatment success outcomes among subpopulations were generally similar or lower
compared to what was observed in the parent studies. However, the results may be difficult to
interpret because there are relatively small sample sizes in some subpopulations.
Table 55. Efficacy (IGA 0 or 1) by Baseline Demographics for Studies 1334 and 1416*

Placebo Placebo
Randomized 223 224 224 239 233 236
Gender
37/81 42/94 14/106 39/100 39/96 13/104
Female
(46%) (45%) (13%) (41%) (41%) (13%)
46/142 42/130 9/118 47/139 44/137 7/132
Male
(32%) (32%) (8%) (34%) (32%) (5%)
Age
80/215 78/208 22/216 81/226 77/223 20/227
<65
(37%) (38%) (10%) (36%) (35%) (9%)
3/8 6/16 1/8 5/13 6/10 0/9
≥65
(38%) (38%) (13%) (38%) (60%) (0%)
Race
59/149 63/155 18/146 63/168 63/165 16/156
White
(40%) (41%) (12%) (38%) (38%) (19%)
8/20 3/10 3/16 7/15 2/13 1/20
Black
(40%) (30%) (19%) (47%) (15%) (5%)
16/51 14/54 2/56 11/45 15/44 1/50
Asian
(31%) (26%) (4%) (24%) (34%) (2%)
0/3 4/5 0/6 5/11 3/11 2/10
Other
(0%) (80%) (0%) (45%) (27%) (20%)
Table 56. Efficacy (IGA 0 or 1) by Baseline Demographics for Trial 1224*
Study 1224
Gender
Female 55/128 (43%) 17/44 (39%) 15/122 (12%)
Male 70/191 (37%) 24/62 (39%) 24/193 (12%)
Age
<65 120/306 (39%) 37/101 (37%) 38/306 (12%)
≥65 5/13 (38%) 3/5 (60%) 1/9 (11%)
Race
White 87/208 (42%) 32/74 (43%) 33/208 (16%)
Black 6/13 (46%) 2/2 (100%) 4/19 (21%)
Asian 30/89 (34%) 7/29 (24%) 2/83 (2%)
Other 2/9 (22%) 0/1 (0%) 0/5 (0%)


Clinical Review
Brenda Carr, MD
BLA 761055
7.1.4. Dose and Dose-Response
The data do not adequately establish the benefit of the QW dosing regimen. Treatment
responses were identical (or essentially so) for the QW and Q2W dosing regimens within each
pivotal study and were generally similar across the 3 pivotal studies. Additional analyses by the
statistical reviewer revealed that treatment responses with the QW dosing were higher
compared to Q2W dosing in some subjects with severe disease at baseline (see discussion of
the individual studies in Section 6.1). However, in subjects with moderate disease, the reverse
was observed: treatment responses with the Q2W dosing were higher compared to QW. See
Tables 57 and 58 below. Additionally, the time to onset of effect was similar between the 2
dupilumab dosing groups. None of the studies were designed to evaluate whether subjects who
did not respond to Q2W dosing, would benefit from having their dose increased to QW
(b) (4)
frequency.
Table 57. IGA Responder by Baseline IGA Severity for Studie 1334 and 1416*

Placebo Placebo
Randomized 223 224 224 239 233 236
IGA
54/117 61/116 16/113 53/127 53/118 17/121
3
(46%) (52%) (14%) (42%) (45%) (14%)
29/106 23/108 7/111 33/112 30/115 3/115
4
(27%) (21%) (6%) (29%) (26%) (3%)
Table 58. Success on the IGA at Week 16 by Baseline IGA Severity for Study 1224*
Study 1224
Dupilumab Dupilumab
Placebo
+
+ +
TCS
TCS TCS
IGA
0/1
2 N/A N/A
(0%)


Clinical Review
Brenda Carr, MD
BLA 761055
79/171 26/53
3 31/168 (18%)
(46%) (49%)
46/147 15/53 8/147
4
(31%) (28%) (5%)
*Source: Statistical Review Table 27
7.1.5. Onset, Duration, and Durability of Efficacy Effects
The time to onset of effect was similar between the QW and Q2W dupilumab dosing groups.
See Figures 3, 4, and 6 in Sections 6.1.2, 6.2.2, and 6.3.2, respectively.
The monotherapy studies (1334 and 1416) did not specify any endpoints beyond Week 16, the
time point of primary efficacy assessment.
Significant impact of treatment on pruritus (≥ 4-point reduction) was noted as early as two
weeks into the treatment course in the monotherapy studies for approximately 10% of
dupilumab-treated subjects. The results were slightly higher for study 1224, which specified TCS
use, with approximately 16% of dupilumab-treated subjects experiencing ≥ 4-point reduction in
pruritus by Week 2. While this is may be meaningful for those subjects who showed this early
response, the data suggest that most individuals are not likely to experience that degree of
relieve in pruritus in the initial weeks of treatment.
Study 1224 had a 52-week treatment period, with no endpoints specified after Week 52. The
proportion of IGA responders (0/1) at Week 16, who were also IGA responders at Week 52 are
presented in Table 49 in Section 6.3.2. At Week 52, the results are similar for the dupilumab
300 mg Q2W + TCS and placebo + TCS groups, 49% and 46%, respectively (58% in the 300 mg
QW + TCS arm). These results reflect outcomes for a relatively small sample size.
The Applicant has an ongoing study that is evaluating maintenance treatment (1415); however,
they did submit data from this study in the BLA.
7.2. Additional Efficacy Considerations
7.2.1. Considerations on Benefit in the Postmarket Setting
There were no significant differences in efficacy in important subpopulations that would be

expected to impact the generalizability of benefit to the broader population who may use this
product. However, the sample sizes of some subpopulations were relatively small. The
enrollment criteria for the pivotal studies would not be expected to impact the generalizability
of benefit to the broader population.
7.2.2. Other Relevant Benefits


Clinical Review
Brenda Carr, MD
BLA 761055
Relevant benefits are discussed in the body of this review.
7.3. Integrated Assessment of Effectiveness
The Applicant provided substantial evidence of the effectiveness of dupilumab, 300mg

administered weekly or every other week (following an initial dose of 600mg) for treatment of
adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately
controlled with topical prescription therapies or when those therapies are not advisable. The
evidence is sufficient to rely on to conclude that dupilumab will have the purported effect in
the marketplace.
The evidence consisted of data from 3 adequate and well-controlled clinical studies: 1334,
1416, and 1224. These studies are discussed in detail in Section 6 of this review. Study subjects
were 18 years or older with disease involving ≥ 10% BSA and with an IGA score of 3 or 4,
corresponding to moderate and severe disease, respectively. In all 3 studies, the primary
endpoint was the proportion of subjects achieving IGA 0 or 1 (on a 5-point scale) and a
reduction from baseline of ≥2 points at week 16
According to the definitions on the IGA scale, an IGA score of 0 to 1 translates to subjects
having achieved the clinical status of being “clear” (no inflammatory signs of atopic dermatitis)
or “almost clear” [barely perceptible erythema and/or minimal lesion elevation
(papulation/infiltration)]. Further, this extent of improvement (IGA of 0 to 1) should be
considered in the context of subjects having to have had ≥ 10% BSA involvement at baseline.
Thus, attaining an IGA score of 0 to 1 is highly clinically meaningful. Additionally, it is an
outcome that permits both the subject and the investigator to readily appreciate treatment
benefit.
The EASI is a mathematically-derived assessment, and the extent of its routine use in clinical
practice in the United States is unclear. An EASI score may not translate into labeling that is
easily, clinically-interpretable because it may not permit visualization of a subject. However, an
EASI-75 score may communicate important outcome information, as it represents a 75%
improvement from the baseline EASI score. Higher EASI outcome scores (such as, EASI-90) may
be even more clinically interpretable (and meaningful) because they may more closely
approach the “clear” or “almost clear” states. However, almost certainly, subjects (and
patients) are not likely to self-report improvement in terms of an EASI score.
TCS are first line pharmacological treatment for AD. The specified use of TCS (with allowance
for TCI use) in study 1224, was an important element of study design, as it was reflective of
likely real-world scenarios of use of dupilumab with these topical therapies. That the IGA
treatment responses were similar across the 3 studies, supports that dupilumab as
monotherapy can yield this clinically- meaningful benefit.


Clinical Review
Brenda Carr, MD
BLA 761055
A key secondary endpoint was the proportion of subjects with improvement (reduction) of
weekly average of peak daily pruritus NRS ≥4. Reduction of at least 4-points from baseline
pruritus is also a highly clinically-meaningful endpoint and provides another measure of
treatment benefit. Pruritus is not only an essential disease characteristic, but it may, perhaps,
represent the most bothersome disease symptom. Sleep disturbance is a common association
of AD and is thought to be largely attributable to the considerable pruritus.1 Breaks in the skin
barrier from vigorous scratching may predispose affected individuals to secondary infections.
Additionally, scratching may result in skin injury that may lead to the release of
proinflammatory cytokines and chemokines, which may perpetuate the itch-scratch cycle and
worsen the AD.13 Thus, control of pruritus is an important aspect of disease management.
Significant impact of treatment on pruritus (≥ 4-point reduction) was noted as early as two
weeks into the treatment course in the monotherapy studies for approximately 10% of
dupilumab-treated subjects. The results were slightly higher for study 1224, which specified TCS
use, with approximately 16% of subjects experiencing ≥ 4-point reduction in pruritus by Week
2. While this may be meaningful for those subjects who showed this early response, the data
suggest that most individuals are not likely to experience that degree of relieve in pruritus in
the initial weeks of treatment. The results suggest that the benefit of the concomitant TCS may
be most notable on pruritus.
While weekly dosing of dupilumab was demonstrated to be effective in the target population, it
was not demonstrated to show clinically-meaningful benefit beyond the every other week
(b) (4)
dosing.
The studies were not designed to adequately evaluate maintenance of effect over time. While
the monotherapy studies included a 12-week post-treatment follow-up period, the Applicant
did not designate any endpoints for that time period. The 52-week concomitant TCS study did
not include endpoints that measured the durability of effect for subjects who were responders
at efficacy assessment, Week 16. While the 52-week trial also included a 12-week post-
treatment follow-up period, there were no endpoints designated for the post-treatment period.
The Applicant is evaluating maintenance treatment; however, they did not submit any of those
data in the BLA.
13 Leung DM, Eichenfield LF, Boguniewicz M. Chapter 14. Atopic Dermatitis (Atopic Eczema). In: Goldsmith LA, Katz
SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds. Fitzpatrick's Dermatology in General Medicine, 8e New York, NY:
McGraw-Hill; 2012.

Clinical Review
Brenda Carr, MD
BLA 761055
For patients and practitioners, dupilumab would represent an important addition to the
treatment armamentarium for moderate to severe AD. Currently, the only available FDA-
approved systemic treatment for AD of this severity is corticosteroids, and the AAD
recommends that they generally be avoided because of the potential for short and long-term
adverse reactions. Phototherapy is an option for this population, but its drawbacks include a
potentially time-intensive, in-office treatment schedule. Risks from phototherapy may vary
according to the type of phototherapy and may include actinic damage, sunburn like reactions,
skin cancer (nonmelanoma and melanoma), and cataracts.
The medical need of the patient population with moderate to severe AD is not currently being
adequately met by currently available therapies. Approval of dupilumab would represent an
important addition to the treatment options for moderate to severe AD that is not manageable
by topical therapies, a population for whom approved treatment options are extremely limited.
In my opinion, dupilumab would considerably advance the state of the treatment
armamentarium for this population. It would be the first systemic product approved for AD
since corticosteroids. It would represent a safe and effective alternative to corticosteroids, the
only approved systemic treatment for this indication and a treatment that is generally not
recommended for treatment of AD.
The Applicant has established that dupilumab is effective in the treatment of the target AD
population. I conclude that the Applicant has met the standard for providing substantial
evidence of effectiveness.
Labeling negotiations were ongoing when this review closed. When the clinical review was
closing, the FDA recommends that effectiveness evidence be presented in labeling as follows:
14 Clinical Studies
Three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a

total of 2119 subjects 18 years of age and older with moderate-to-severe atopic
dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was
defined by an Investigator’s Global Assessment (IGA) score ≥3 in the overall assessment
of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI)
score ≥16 on a scale of 0 to 72, and a minimum body surface area involvement of ≥10%.
At baseline, 59% of subjects were male, 67% were white, 52% of subjects had a baseline
IGA score of 3 (moderate AD), and 48% of subjects had a baseline IGA of 4 (severe AD).
The baseline mean EASI score was 33 and the baseline weekly averaged peak pruritus
Numeric Rating Scale (NRS) was 7 on a scale of 0-10.
In all three trials, subjects in the DUPIXENT group received subcutaneous injections of

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DUPIXENT 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the
monotherapy trials (Trials 1 and 2), subjects received DUPIXENT or placebo for 16
weeks.
In the concomitant therapy trial (Trial 3), subjects received DUPIXENT or placebo with
concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for
problem areas only, such as the face, neck, intertriginous and genital areas for 52
weeks.
All three trials assessed the primary endpoint, the change from baseline to Week 16 in
the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point
improvement. Other endpoints included the proportion of subjects with EASI-75
(improvement of at least 75% in EASI score from baseline), and in itch as defined by at
least a 4-point improvement in the peak pruritus NRS from baseline to Week 16.
Clinical Response at Week 16 (Trials 1, 2 and 3)

The results of the DUPIXENT monotherapy trials (Trials 1 and 2) and the DUPIXENT with
concomitant TCS trial (Trial 3) are presented in Table 2.
Table 59. Efficacy Results of DUPIXENT Monotherapy at Week 16 (FAS)
Trial 1 Trial 2
Placebo DUPIXENT Placebo DUPIXENT
n (%) 300 mg Q2W n (%) 300 mg Q2W
n (%) n (%)
Subjects
randomized 224 224 236 233
(FAS) a
IGA 0 or 1b, c 23 (10) 85 (38) 20 (9) 84 (36)
EASI-75 c 33 (15) 115 (51)d 28 (12) 103(44)
Number of
subjects with
baseline Peak 212 213 221 225
Pruritus NRS
score ≥4
Peak Pruritus
26 (12) 87 (41) 81 (36)
NRS (≥4-point 21 (10)
improvement)c
a Full Analysis Set (FAS) includes all subjects randomized.
b Responder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥2 points on a 0-4 IGA scale.
c Subjects who received rescue treatment or with missing data were considered as non-responders.
The results of the DUPIXENT with concomitant TCS (Trial 3) through Week 16 are
presented in Table 3.

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Table 60. Efficacy Results of DUPIXENT with Concomitant TCSa at Week 16
Week 16 (FAS)b
Placebo + DUPIXENT
TCS 300 mg Q2W
n (%) + TCS
n (%)
Subjects
randomized 315 106
(FAS)a
IGA 0 or 1b,c 39 (12) 41 (39)
EASI-75c 73 (23) 73 (69)
EASI-90c 35 (11) 42 (40)d
Number of
subjects with 299 102
baseline Peak
Pruritis NRS
score ≥4
Peak Pruritus 59 (20) 60 (59)
NRS (≥4-point
improvement)c
a Full Analysis Set (FAS) includes all subjects randomized.
b Responder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥2 points on a 0-4 IGA scale.
c Subjects who received rescue treatment or with missing data were considered as non-responders.
Treatment effects in subgroups (weight, age, gender, race, and prior treatment,
including immunosuppressants) in Trials 1,2 and 3 were generally consistent with the
results in the overall study population.
In Trials 1, 2, and 3, a third randomized treatment arm of DUPIXENT 300 mg QW did not
(b) (4)
demonstrate additional treatment benefit than DUPIXENT 300 mg Q2W.
8 Review of Safety
8.1. Safety Review Approach
The Applicant’s safety database is intended to provide information regarding the use of
dupilumab in adults with AD, when used as monotherapy, with concomitant TCS (and
allowances for use of TCI), and long-term treatment. The Applicant integrated safety data to
form 3 safety pools, which are described below.

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1. Primary Safety Pool (“Pool 2”)

This pool consisted of data from the 16-week treatment periods for 3 monotherapy studies:
the Phase 3 studies, 1334 and 1416, and the relevant arms from the Phase 2 dose-ranging
study, 1021 (i.e., the 300mg Q2W and QW arms). Data from this pool were presented by 4
categories: placebo, dupilumab 300mg Q2W, dupilumab 300 mg QW, and combined (reflects
the combined dupilumab groups).
2. The Supportive Safety Pool

This pool included all subjects from the placebo-controlled Phase 2 and 3 studies, who received
a total dupilumab dose of ≥300 mg monthly over treatment durations of 12 to 16 weeks. In
addition to the 3 studies in the Primary Safety Pool, this pool includes data from the Phase 2
studies 1117, 1307, and 1314. Unlike the Phase 3 studies, enrollment in the Phase 2 studies did
not require a baseline Pruritus NRS score ≥3. This pool includes dose regimens of 200 mg Q2W,
200 mg QW, 300 mg Q4W, 300 mg Q2W, and 300 mg QW. Data from this pool were presented
by 2 categories: dupilumab ≥300 mg monthly and placebo.
The Primary Safety Pool and the Supportive Safety Pool were used for the analyses of adverse
events, laboratory results, vital signs, electrocardiogram results, and immunogenicity, and for
subgroup analyses.
3. Exposure Pool
This pool included all subjects who received dupilumab in all of the Phase 1 to 3 studies that
were submitted in the BLA (a total of 11 studies). This pool included the long-term treatment
study, 1224 and the OLE study, 1225. The Applicant used this pool to calculate the number of
study drug treatments administered and the treatment duration.
The “safety analysis set” (SAF) is comprised of all subjects who received at least 1 dose of study
drug.
The safety review will focus on the Primary Safety Pool and the data from the placebo-
controlled Phase 3 study 1224, which evaluated use of dupilumab with TCS and also provided
for safety data from long-term treatment (LTT; 52weeks). The Applicant presented the data
from study 1224 by 2 study populations: through 16-weeks and through 52-weeks. Data from
the 52-week study are presented by the following categories: placebo + TCS, dupilumab 300mg
Q2W+ TCS, and dupilumab 300 mg QW+ TCS, and combined + TCS.
The review will also discuss data from the Supportive Pool and from the OLE study, 1225.
Study 1225 is an ongoing, 164-week (148-week treatment, 16-week follow-up) Phase 3 study
(b) (4)
intended to assess the long-term safety and efficacy of SC dupilumab,

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administered for up to 3 years. Study 1225 includes subjects who participated in a prior Phase 2
or Phase 3 dupilumab study and were not eligible to participate in the Phase 3 maintenance
study (1415) or were screened for a Phase 3 monotherapy study (either 1334 or 1416) but
could not be randomized because of randomization closure.
Data from study 1225 may be presented by the following categories: dupilumab-naïve (did not
receive any dupilumab doses in the parent study), re-treatment (gap of >13 weeks between the
last dupilumab injection in parent study and the first injection in current study), interrupted-
treatment (gap of ≥6 weeks to ≤13 weeks between the last dupilumab injection in parent study
and the first injection in current study), and continuous treatment (gap of <6 weeks between
the last dupilumab injection in parent study and the first injection in current study).
Potential safety issues that required particular attention in the safety evaluation included eye
disorders and herpes virus infections.
I conclude that the safety database is adequate in size and extent of exposure of study subjects
to permit a reasonable assessment of the safety of dupilumab.
8.2. Review of the Safety Database
8.2.1. Overall Exposure
By the cut-off date for BLA (04/26/2016), the AD safety database included 2,526 subjects
exposed to dupilumab in 11 studies that had treatment periods of at least 4 weeks. The
database included subjects with the following total durations of exposure to dupilumab :
• 739 subjects exposed ≥ 1 year [645 subjects dosed 300 mg weekly (QW) and 58 subjects
dosed 300 mg every 2 weeks (Q2W)]
• 309 subjects exposed ≥ 1.5 years (91 subjects dosed 300 mg QW)
• 160 subjects exposed ≥ 2 years (duration of any dupilumab dose).
The Primary Safety Pool included 1,567 randomized subjects. However, 3 subjects did not
receive any study drug. Therefore the SAF consists of 1564 subjects. See Table 61.


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Table 61. Sample Size by Study Number – Primary Safety Pool - (All Enrolled Subjects)*
*Source: Table 20 Summary of Clinical Safety
Of subjects who completed the studies in the Primary Safety Pool, the most commonly
reported reason for discontinuation was “withdrawal by subject,” and the highest proportion of
subjects reporting this reason was in the placebo groups.
Table 62. Primary Reason for Withdrawal from Study - Primary Safety Pool – SAF*
* Source: Table 21 Summary of Clinical Safety

The percentage is based on the number of treated patients in each treatment group as denominator.
a. Transition into the R668-AD-1415 maintenance study was based on the patients efficacy response in the parent study.


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b. Other reasons were transition into open label study, consent withdrawal, patient completed all visits except 18 and 19 (out
of visit window), patient moved, patient had a work conflict, and pregnancy
Similarly, the most commonly reported reason for discontinuation from the LTT, 1224, was
“withdrawal by subject,” and the highest proportion of subjects reporting this reason was in the
placebo groups.
Table 63. Summary of Patient Accountability and Study Disposition – R668-AD-1224 - All Randomized Subjects*
* Source: Table 23 Summary of Clinical Safety
Just on the basis of the LTT study, 1224, the numbers of subjects exposed to relevant doses of
dupilumab meets the minimum numbers recommended in the ICH E1A guideline. See Table 64.


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A total of 1,491 subjects were enrolled in the OLE, study 1225. The numbers of subjects in the
OLE study, 1225, would be inclusive of subjects exposed in the LTT study, 1224; see Table 65.
Table 64. Treatment Exposure and Duration of Observation Period – R668-AD-1224 -SAF*

b At the time of the CTD Data cut-off date (04/27/2016), not all subjects in the study had reached week 52 of the study.
Table 65. Summary of Treatment Exposure Study 1225– SAF*


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4-Month Safety Update Report
The Applicant submitted the 4-month safety update report (SUR) on 11/21/2016. The SUR
provided for additional data from the 2 ongoing, long-term studies: the LTT evaluating
dupilumab + TCS, study 1224 and the OLE study, 1225. The cut-off date for the SUR was
08/31/2016.
LTT Study 1224 (Dupilumab + Concomitant TCS)
At the cut-off date for the SUR, 100 more subjects had completed the 52-week treatment
period, for a total of 596/740 or 80.5%. Only one subject discontinued the study (“other”
reason: withdrew consent). See Table 66.
Table 66. Study R668-AD-1224: Summary of Patient Accountability and Study Disposition during the Study
Period, Cumulative until 31 August 2016 - All Randomized Patients*


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*Source: Table 2 of 4-month safety update report

Abbreviations: OLE = open-label extension, study R668-AD-1225
Note: The percentage is based on the number of randomized patients in each treatment group as the denominator.
a. Other category includes: car accident, consent withdrawal, incorrect randomization, lack of IP supply at site, lost to follow-up,
pregnancy, and protocol violation.
OLE Study 1225

At the cut-off date for the SUR, 805 more subjects were included in the SAF, for a total of 2296
subjects in the following breakdown: 764 dupilumab-naïve subjects, 1094 subjects who had
been previously exposed to dupilumab in another study, and 438 subjects whose treatment
in the parent study was still blinded. Of the 2296 subjects, 2133 had ongoing treatment. Status
of subjects relative to study competion was (see Table 67):
• No subjects had completed the study.
• 557/2296 subjects (24.3%) had completed treatment up to week 52.
• 239/2296 patients (10.4%) completed treatment up to week 100.
• 1 subject had completed treatment at week 148 (dupilumab naïve subject).
Table 67. Study R668-AD-1225: Summary of Patient Accountability and Study Disposition – Cumulative until 23
August 2016 (SAF)*


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*Source: Table 3 of 4-month safety update report

Abbreviations: SAF = safety analysis set; Trt = treatment
Note: Analysis groups were not randomized and not readily comparable.
a. Other category includes: consent withdrawal (administrative reasons, no reason given, personal reasons) lost to follow-up, PI
decision, and pregnancy.
8.2.2. Relevant characteristics of the safety population:
The enrollment criteria sufficiently defined a study population of adults with moderate-to-
severe atopic dermatitis whose disease was not adequately controlled with topical prescription
therapies or when those therapies were not advisable the target population.
The overall demographic and baseline characteristics were generally consistent between
treatment arms and across studies. Overall demographic and baseline characteristics for the
Primary Safety Population are primarily reflective of subjects from the pivotal monotherapy
studies 1334 and 1416 (188 subjects are from the Phase 2b study 1021). Therefore, a reader is
referred to Tables 9 and 10 in Section 6.1.2 and Tables 22 and 23 in Section 6.2.2 for
information on the demographic and baseline characteristics of subjects in this safety pool. The
population characteristics of subjects enrolled in the 3rd pivotal study 1224 (concomitant TCS)
have also been previously discussed; see Tables 38 and 39 in Section 6.3.2. Subjects from these
3 studies (and subjects who were eligible to participate in the Phase 3 monotherapy studies)
constitute the bulk of subjects in the OLE study, 1225.
8.2.3. Adequacy of the safety database:
The safety database was adequate in size and extent of drug exposures (concentrations and

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duration) to assess the safety of dupilumab in the target population of adults with moderate to
severe AD.
8.3. Adequacy of Applicant’s Clinical Safety Assessments
8.3.1. Issues Regarding Data Integrity and Submission Quality
The overall data quality was adequate, and the submission was sufficiently well-organized to
allow location of information with relative ease.
8.3.2. Categorization of Adverse Events
Adverse events (AEs) were collected from the time of informed consent signature and at each
visit. Adverse events were coded and classified by the primary System Organ Class (SOC), High
Level Term (HLT) and Preferred Term (PT) according to the Medical Dictionary for Regulatory
Activities (MedDRA), version 18.0. Treatment-emergent AEs (TEAEs) were defined as AEs that
developed or worsened in severity compared to the baseline during the treatment period or
the follow-up period.
The Applicant also classified certain AEs as Adverse Events of Special Interest (AESI). AESIs are
discussed in Section 8.4.4.
8.3.3. Routine Clinical Tests
The Applicant performed routine clinical laboratory testing (hematology, chemistry, urinalysis)
and electrocardiograms (ECGs) throughout the development program (Phase 1 through Phase
3). The frequency and schedule of testing varied according to the study.
The safety assessments methods appear reasonable and adequate for the population, disease,
and indication.
8.4. Safety Results
8.4.1. Deaths
Three deaths occurred in the development program for AD. The Applicant also reported that
three deaths occurred in the development program for asthma.
Subject 840050003 : Asthma; Hypoxic-ischaemic encephalopathy; Respiratory failure

This 49-year-old asthmatic white female (United States) was in the 1416 study and received
dupilumab 300 mg Q2W. Her multiple concomitant medications included: salbutamol (since
1990), valproic acid (1995), and citalopram (1995). She completed study treatment on Day 105
and had received a total of 16 doses of study treatment. Apparently since approximately Day


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165, she had been experiencing cough (the reported history was of cough for 5 days), and had
not improved with use of nebulizer at home. On Day 169, she presented to her primary care
physician with an exacerbation of asthma (cough and wheezing) for which she received in-office
treatment with beclomethasone dipropionate HFA inhalation aerosol. (She also received
diphenhydramine injection for pruritus; no additional details were described regarding this
event). She experienced extreme dyspnea and loss of consciousness on Day 170. She was
apneic when emergency personnel arrived and, eventually, intermittently pulseless for
unspecified periods. Care in the Emergency Department included epinephrine and intubation.
Events listed as occurring on Day 170 include: severe hypoxic ischemic encephalopathy,
asthma, and respiratory failure. She expired on Day 189.
The Applicant proposed the following be included in the Warnings and Precautions section of
the label:
(b) (4)
The Applicant notes this subject’s death, 84 days post treatment, in discussing their rationale
for the above proposed Warnings and Precaution. The Applicant is developing dupilumab for
treatment of asthma. I found no information regarding the status of this subject’s asthma while
receiving dupilumab for her AD (e.g. information indicating improvement in her asthma).
Additionally, I found no information indicating that she had modified use of her asthma
medications while receiving dupilumab. Further, in the Summary of Clinical Safety, the
Applicant describes that analyses of safety data identified no new TEAEs suggestive of rebound
or of worsening of allergic conditions with withdrawal of dupilumab, and I agree with this
(b) (4)
conclusion. The proposed labeling language should reflect the
narrow focus concerning asthma. From what I could determine, there was insufficient
information to conclude that this subject’s death was related to the discontinuation of
dupilumab. I agree with the investigator that this death does not appear to be related to
dupilumab.
Subject 840038007: Completed suicide

This 31-year-old white male (US) with a history of depression (including hospitalization) and
suicide ideation, received dupilumab 300 mg QW in study 1416. “Completed suicide” by
“intentional overdose” was reported on Day 93. He had received 13 doses of study treatment.
He reported his depression as largely being attributable to his severe AD. A grandmother had
also committed suicide. This death does not appear to be related to dupilumab.


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Subject 616007006: Road traffic accident

This 27-year-old female received 300 mg Q2W + TCS in study 1224. She died due to injuries
suffered in a road traffic accident on Day 288. This death does not appear to be related to
dupilumab.
The Applicant reported 3 deaths from the asthma program:
• Subject 643-007-008 (300 mg Q4W group): A 43-year-old male, with a history of

hypertension and treated with verapamil 80 mg, died in his sleep on Day 62, 8 days after
the last study drug injection. He had received total of 6 doses including the 2 loading
doses). The autopsy reported his death as being due to acute cardiovascular failure. The
report documented atherosclerotic cardiac disease and ethanol concentrations
indicative of severe alcohol intoxication. The investigator and Applicant considered the
event not related to the study drug administration.
• Subject 804-004-001 (300 mg Q4W group): A 45-year-old male completed his 24-week
treatment. Twelve days later (Day 275), he was hospitalized due to asthma
exacerbation. Workup revealed pleural fluid findings suggestive of malignancy. He died
on Day 289 due to severe metastatic gastric cancer, severe bilateral subtotal organizing
pneumonia, and severe acute cor pulmonale.
• Subject 012544-643-002-011(dosing included 200 mg Q4W with rollover to 300 mg
(b) (6)
Q2W): A 64-year-old male received dupilumab 600 mg loading dose on
(b) (6)
, followed by dupilumab 300 mg Q2W. On (Day 188), 18 days after
the last dose of the study drug, he experienced severe peripheral cancer of the upper
(b) (6)
lobe of the right lung with multiple brain metastases. On (Day 271), 101
days after the last dose of the study drug, he experienced cardiac and respiratory arrest,
and he died due to metastatic lung cancer, including metastases to the central nervous
system.
Based on the available information, I do not consider any of the deaths reported from the
asthma program to likely be related to dupilumab.
No additional deaths were reported in the 4-month SUR.
8.4.2. Serious Adverse Events
Primary Safety Pool (16-Week-Monotherapy)
In the Primary Safety Pool, more serious adverse events (SAEs) were reported in the placebo
group than in either dupilumab group during the 16-week treatment period: placebo- 5%
(26/517), dupilumab 300 mg Q2W- 2.5% (13/529), and dupilumab 300 mg QW 2.1% (11/518).


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There were single reports of most SAE preferred terms (PTs). For placebo and dupilumab
300mg Q2W subjects, SAEs were most frequently reported in the Skin and subcutaneous tissue
disorders system organ class (SOC): 9 (1.7%) and 4 (0.8%) subjects, respectively. All 9 of the
SAEs in the Skin and subcutaneous tissue disorders SOC in the placebo group were Dermatitis
atopic. The most frequently reported SAE in the Skin and subcutaneous tissue disorders SOC for
dupilumab 300mg Q2W subjects was Dermatitis atopic, and this SAE was reported in 3 (0.6%)
subjects. Dermatitis atopic was the only SAE for which there were multiple reports for
dupilumab 300mg Q2W subjects. No SAE was reported in more than one subject in the
dupilumab 300mg QW group. For dupilumab 300mg QW subjects, SAEs were most frequently
reported in the Infections and infestations SOC [4 (0.8%) subjects], and the SAEs were Cellulitis,
Erysipelas, Kidney infection, and Viral infection. See Table 68 for the specifics of the
occurrences of SAEs.
Table 68. Number of Patients with Serious Treatment-Emergent Adverse Events by Primary System Organ Class
and Preferred Term – 16-Week Period - Primary Safety Pool – SAF*

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Note: The treatment period is defined as period starting from the first dose date to the date of the week 16 visit (study day 113
relative to the first dose date if the week 16 visit is unavailable) or date of early termination visit,¬ whichever comes first. At
each level of patient summarization, a patient is counted once if the patient reported 1 or more events. Pool 2 (AD-1334, AD-
1416, AD-1021) MedDRA Version 18.0
Narratives for all SAEs from the Primary Safety Pool are found in Attachment A.
Supportive Safety Pool - Phase 2 and 3 Studies (12- to 16-Week Monotherapy)
The pattern of occurrence of SAEs was generally similar to the Primary Safety Pool, with the
following 3 exceptions:
Subject 840011001: Serum Sickness-Like Reaction

This 38 y/o black female received dupilumab received 300 mg QW dosing in study 1314. She
had received 3 doses of dupilumab (baseline and Days 8 and 15). On Day 12 she experienced
“mild urticaria.” She was premedicated with acetaminophen and loratadine prior to receiving
the Day 15 dose of study product. On Day 15, she experienced an unspecified injection site
reaction, chest congestion, and wheezing, which was treated with albuterol. Later that day, her
urticaria worsened, and she experienced severe joint pain (hips and knees). She was diagnosed
with a serum sickness-like reaction, and she was treated with oral prednisolone and
diphenhydramine. By Day 16, she reported “feeling better,” and her urticaria was resolving.
However, on Day 20, she complained of intense muscle pain, chest discomfort, and new
urticarial lesions (face). Oral corticosteroid dosage was increased and subsequently tapered.
She continued to improve, and the event was considered to be resolved on Day 36. Her C3 and

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C4 complement levels were within normal limits (time points not specified). She was positive
for anti-drug antibody (ADA) at Day 15 and at the early termination visit on Day 22, with a peak
titer of 122880 on Day 22. Study drug was permanently discontinued. Also, the event resulted
in emergency unblinding of treatment assignment.
Dupilumab will be labeled as being contraindicated in patients who have known

hypersensitivity to dupilumab or any of its excipients. Additionally, I recommend that serum
sickness, serum sickness-like, and urticaria be labeled as hypersensitivity reactions observed in
the clinical trials (based on AEs reported for other subjects discussed in this review).
Subject 840034007: Mycosis Fungoides

This 57 y/o black male in study 1314 received dupilumab 300 mg QW. He had received 7 doses
at the time of diagnosis of the SAE, and he received one additional dose post-diagnosis. On Day
35, he experienced a worsening of his AD. He presented with generalized changes in skin color
and texture (“thick, rough and dry” skin). Additionally, his facial features were reported to have
changed “dramatically” over the preceding 2 years. Apparently on Day 43, his disease was
considered “completely refractory to treatment,” and skin biopsies were obtained the same
day. On Day 48, he was diagnosed with stage IV mycosis fungoides. Study treatment was
permanently discontinued on Day 44.
The history (change in facial features) suggests that this subject’s mycosis fungoides may have
been present at baseline. Also, the timing of the diagnosis relative to treatment duration would
not appear to implicate dupilumab.
Subject 000003004: Anaphylactic Shock

This 19 y/o white female received dupilumab 200 mg Q2W in study 1021. She had a history of
anaphylactic reactions to cashews and pistachios. On Day 21, she experienced anaphylactic
shock to cashew nuts after eating a candy bar. The reaction was accompanied by throat,
tongue, and lip swelling and diffuse urticarial. She received multiple doses of epinephrine in the
Emergency Department, but was ultimately intubated and managed in the intensive care unit.
She was discharged on Day 26. She completed the treatment period, without experiencing any
similar AEs.
Food allergies are common associations of AD.
Study 1224 (Dupilumab + Concomitant TCS): 16-Week Data
A total of 13 SAEs were reported in the initial 16-week period of study 1224, as below:
• placebo+ TCS (n= 315): 6 (1.9%)
• dupilumab 300 mg Q2W + TCS (n= 110): 3 (2.7%)
• dupilumab 300 mg QW + TCS (n= 315): 4 (1.3%)

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No one PT was reported in more than one subject (i.e., single reports of each PT). Only the
Neoplasms benign, malignant and unspecified (incl cysts and polyps) SOC had multiple SAEs
reported, and SAEs were reported for two subjects in this SOC: Squamous cell carcinoma of
skin and Squamous cell carcinoma of the tongue. Both of these SAEs occurred in subjects in the
dupilumab 300 mg QW + TCS group.
Study 1224 (Dupilumab + Concomitant TCS): 52-Week Data

Fewer subjects reported SAEs in each dupilumab group compared to placebo:
• placebo + TCS: 5.1% (16/315); EAIR 5.856 nP/100 PY,
• dupilumab 300 mg Q2W + TCS 3.6% (4/110); EAIR 4.048 nP/100 PY, and
• dupilumab 300 mg QW + TCS 2.9% (9/315); EAIR 3.119 nP/100 PY.
No individual SAE was reported in more than one subject.

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Table 69. Number of Subjects with Serious Treatment-Emergent Adverse Events by Primary System Organ Class
and Preferred Term - 52-Week Period – R668-AD-1224 – SAF*
*Source: Table Summary of Clinical Safety

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Table 70. Number of Subjects with Serious Treatment-Emergent Adverse Events (TEAE) per 100 Subject-years
during 52-Week Period by Primary System Organ Class and Preferred Term-Study 1224 (Safety Analysis Set)*

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*Source: Post-text tables of study report

nP=number of patients with an event. PY= patient-years. nP/100 PY= number of patients with at least one event per 100
patient-year.
Three additional subjects in study 1224 experienced SAEs during the 4-month SUR period:
• Osteoarthritis and Spondylolisthesis (both subjects in the dupilumab 300 mg QW + TCS
group)
• Cataract (subject in the placebo + TCS group).
Study 1225 (OLE Study)

A total of 74/1491 subjects (5%; EAIR 7.346 nP/100 PY) had at least 1 SAE. The pattern of
occurrence of SAEs was generally similar to the Primary Safety Pool and in study 1224. Most PTs
were not reported more than once. SAEs for which there were 2 reports were: Ligament
rupture, Inguinal hernia, Syncope, Osteoarthritis, Depression, Dermatitis atopic, Non-cardiac
chest pain. Osteoarthritis and Dermatitis atopic were the only PTs with more than 2 reports
(there were 3 reports of each of these SAEs). Serum sickness was reported in one subject, and
this subject is discussed directly below.
Subject 8400007002: Serum sickness

This 30 y/o black female (United States) received dupilumab 300 mg QW. The most recent dose
of study product before the event was on Day 7, and she had received 2 doses at that time. On
Day 15, she experienced chills, sweats, severe headache, and severe joint discomfort. Her
symptoms progressed to the point of being unable to perform any activities of daily living. On
Day 18, she presented to the Emergency Department with joint pain, fever (38.3°C),
tachycardia, headache, and “rash.” She was hospitalized that same day for the SAE of serum
sickness. X-rays of hands were normal with no evidence for inflammatory arthritis. Laboratory
findings included: elevated white blood cell count, erythrocyte sedimentation rate and C-
reactive protein. Urinalysis findings included proteinuria. A lupus anticoagulant test was
negative, and the rheumatoid factor was < 10. Her treatment included vancomycin, cefepime,
tramadol hydrochloride (HCl), naproxen, omeprazole, prednisone taper, and trazodone. She
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was discharged on Day 21, with the event resolved. Study drug was permanently discontinued.
Subject 010013: Viral Corneal Ulcer

This 56 y/o male (Germany) received dupilumab 100 mg Q4W in the parent study, then 200mg
QW and 300 mg QW in the OLE. On Day 549, approximately 1.5 years after the first dose of
dupilumab, the SAE of Viral Corneal Ulcer was reported. He had received 79 doses of dupilumab
in the OLE. His history included blepharoconjunctivitis, corneal ulcer, herpes keratitis, and
herpes simplex infections. Study drug was temporarily discontinued on Day 561, and he was
hospitalized on Day 563. On study day 568, he underwent corneal transplantation in the left
eye and also received medical treatment. He experienced delayed wound healing, with no virus
detected. The event was resolved with unspecified sequelae on Day 575 and he was discharged
that same day on cyclosporine eye drops. Study drug was restarted on Day 609. The event of
Viral Corneal Ulcer was considered not related to study drug by the investigator. I agree with
the investigator.
Subject 007005: Anaphylactic Reaction

This 22 y/o female (Czech Republic) who had received dupilumab 200 mg Q2W in the parent
study. She had a history of multiple, unspecified allergies. Her most recent dose of dupilumab
was on Day 122. On Day 123, she experienced the SAE of anaphylactic reaction after receiving
17 doses of study drug. That same day, the patient drank banana soy milk and developed
localized urticarial 30 minutes later, with progression to facial edema, and difficulty breathing.
She was apparently treated in a hospital, but not admitted. The event was resolved the same
day (Day 123). Dupilumab was continued as planned. That dupilumab dosing was continued
supports that this reaction was not related to study product.
An additional 40 subjects (40/2296 or 1.7%) in study 1225 experienced SAEs during the 4-
month SUR period. “Squamous cell carcinoma of skin” was the only SAE that was reported for
more than one subject, and this PT was reported for 4 subjects (0.2%). All other SAEs were
reported in one subject each.
8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects
The incidence rates for subjects permanently discontinuing treatment due to an AE were similar
between the 3 treatment groups: placebo- 10 (1.9%) subjects, dupilumab 300 mg Q2W- 10
(1.9%), and dupilumab 300 mg QW- 8 (1.5%). Discontinuations were most frequently reported
in the Skin and subcutaneous tissue disorders SOC, and dermatitis atopic was the most
commonly reported PT within this SOC for the 3 treatment groups.

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Table 71. Summary of Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of Study Drug
by SOC and PT – Primary Safety Pool - Entire Study Period – SAF*

At each level of subject summarization, a subject is counted once if the patient reported 1 or more events.
Study 1224 (Dupilumab + TCS): 52-Week Data
The overall incidence rate for TEAE leading to discontinuation of treatment was higher in the
placebo + TCS group 24 (7.6%) than in either dupilumab group: 300 mg Q2W + TCS: 2 (1.8%)
and 300 mg QW + TCS: 9 (2.9%). Most were single reports of PTs. The SOC with the most
discontinuations for a TEAE was Skin and subcutaneous tissue disorders, and most of the
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discontinuations were in the placebo + TCS group. The PT that was most commonly reported as
the basis for discontinuation was dermatitis atopic: placebo + TCS group 14 (4.4%), 300 mg
Q2W + TCS: 1 (0.9%), and 300 mg QW + TCS: 0.
Three subjects discontinued treatment in the Eye disorders SOC [3 (1.0%)], and all 3 subjects
were reported in the dupilumab 300 mg QW + TCS group. The events were Allergic keratitis,
Cystoid macular oedema, and Eye pruritus.
Table 72. Number of Subjects with Treatment-Emergent Adverse Events Leading to Permanent Study Drug
Discontinuation During the 52-Week Period by Primary System Organ Class and Preferred Term-Study 1224 –
SAF*

At each level of summarization, a patient is counted once if the patient reported one or more events.

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The incidence of TEAEs leading to treatment discontinuation was low in the OLE study, 1225.
No particular pattern to occurrence of TEAEs was noted when the subgroups are compared. See
Table 73.
Table 73. Summary of Treatment-Emergent Adverse Events Leading to Permanent Study Drug Discontinuation in
Dupilumab-naïve and Re-treated Patients by System Organ Class and Preferred Term- 1225 – SAF*

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Abbreviations: nP, number of patients with an event; nP/100 PY, number of patients with at least 1 event per 100 patient year;
PY, patient-year; TEAE, treatment-emergent adverse event Note: Adverse events were coded according to MedDRA version
18.0. Note: Patients who experienced more than 1 TEAE were counted only once in each category. Note: For patients with
event, number of patient years was calculated up to date of the first event; for patients without event, it corresponded to the
length of study observation period. Note: Analysis groups were not randomized and not readily comparable.
8.4.4. Significant Adverse Events
The Applicant applied the following reasonable definitions in the evaluation severity of AEs:
• Mild: Does not interfere in a significant manner with the patient’s normal functioning
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief of
symptoms, but may be given because of personality of the patient.
• Moderate: Produces some impairment of functioning but is not hazardous to health. It
is uncomfortable or an embarrassment. Treatment for symptom may be needed.
• Severe: Produces significant impairment of functioning or incapacitation and is a
definite hazard to the patient’s health. Treatment for symptom may be given and/or
patient hospitalized.
The majority of TEAEs in all study arms were graded mild to moderate in severity. The highest
overall proportion of severe events (8.3%) was reported in the placebo group. Overall, severe
events were reported in < 5% in each of the dupilumab arms. In all treatment arms, severe

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TEAEs were most commonly reported in the Skin and subcutaneous tissue disorders SOC:
placebo- 29 (5.6%) subjects, dupilumab 300 mg Q2W- 9 (1.7%), and dupilumab 300 mg QW- 7
(1.4%). Dermatitis atopic was the most commonly reported severe AE in this SOC for all
treatment arms and was reported most commonly in the placebo group. There were single
reports for most PTs that were reported as severe. All severe conjunctivitis events (PTs:
Conjunctivitis, Conjunctivitis bacterial, Conjunctivitis allergic) were reported only in dupilumab
groups: dupilumab 300 mg Q2W- 3 (0.6%) and dupilumab 300 mg QW- 2 (0.4%). Conjunctivitis
allergic was the most commonly reported severe PT that was reported only in subjects treated
with dupilumab (three subjects): dupilumab 300 mg Q2W- 1 (0.2%) and dupilumab 300 mg
QW- 2 (0.4%).

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Table 74. Severe Treatment-Emergent Adverse Events by SOC and PT – 16-Week Treatment Period – Primary
Safety Pool – SAF (next page)*

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Overall incidence rates of severe events were similar across treatment arms: Placebo + TCS
group: 11 (3.5%), Dupilumab 300 mg Q2W + TCS: 4 (3.6%), and Dupilumab 300 mg QW + TCS:
9 (2.9%). Severe TEAEs were most commonly reported in the Skin and subcutaneous tissue
disorders SOC: Placebo + TCS group: 5 (1.6%), Dupilumab 300 mg Q2W + TCS: 2 (1.8%), and
Dupilumab 300 mg QW + TCS: 3 (1.0%). Dermatitis atopic was the most commonly reported
severe AE in this SOC for all arms and was reported most commonly in the placebo group.
Dermatitis atopic was the only PT for which there were multiple reports in all treatment arms.
All severe TEAEs that were reported for Dupilumab in the Eye Disorders SOC [4(1.3%)] were
reported in the Dupilumab 300 mg QW + TCS arm, and the events were: Allergic keratitis,
Conjunctivitis allergic, Cystoid macular oedema, and Ectropion.

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Table 75. Number of Patients with Severe Treatment-Emergent Adverse Events During the 16-Week Period by
Primary System Organ Class and Preferred Term-Study 1224 – SAF*

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Severe TEAEs were most commonly reported in the Skin and subcutaneous tissue disorders
SOC: Placebo + TCS group: 13 (4.1%); EAIR: 4.742 nP/100 PY, Dupilumab 300 mg Q2W + TCS: 4
(3.6%); EAIR: 4.073 nP/100 PY, and Dupilumab 300 mg QW + TCS: 5 (1.6%); EAIR: 1.730
nP/100 PY. Dermatitis atopic was the most commonly reported severe AE in this SOC for all
arms and was reported in a similar proportion of subjects in the placebo and Dupilumab 300 mg
Q2W + TCS groups: 11 (3.5%); EAIR: 4.004 nP/100 PY and 4 (3.6%); EAIR: 4.073 nP/100 PY,
respectively. Dermatitis atopic was least frequently reported as severe in the Dupilumab 300
mg QW + TCS: 3 (1.0%); EAIR: 1.034 nP/100 PY. All severe TEAEs that were reported for
Dupilumab in the Eye Disorders SOC [5 (1.6%); EAIR: 1.730 nP/100 PY] continued to be
reported in the Dupilumab 300 mg QW + TCS arm, and the additional events reported over the
52-week period were Keratitis and Meibomianitis.
Table 76. Number of Subjects with Severe Treatment-Emergent Adverse Events (TEAE) per 100 Subject-Years
during 52-Week Period by Primary System Organ Class and Preferred Term (Safety Analysis Set)*

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*Source: Post-text table 7.3.2.2/3 study report
Adverse Events of Special Interest
Except for conjunctivitis (as further discussed below), the Applicant had defined the following
events as “adverse events of special interest” (AESIs) by the time of the Phase 3 program:
• Anaphylactic reactions
• Acute allergic reactions requiring treatment
• Mycosis fungoides or cutaneous T-cell dyscrasias
• Any severe infection
• Any infection requiring treatment with parenteral antibiotics
• Any infection requiring treatment with oral antibiotics/anti-viral/anti-fungal for
longer than 2 weeks
• Any clinical endoparasitosis
• Any opportunistic infection
• Severe ISRs lasting longer than 24 hours
• Suicidal behavior (suicidal ideation, suicidal behavior, depression suicidal, suicide
attempt and completed suicide)
• Conjunctivitis
The Applicant considered several factors in developing the list:

• Dupilumab is a protein biologic that is administered by subcutaneous (SC) injection.
• The pharmacologic properties of dupilumab, e.g. blockade of IL-4 and IL-13 signaling.
• Conditions that are associated with or diagnosed in patients with AD.
From Section 2.1.5.2 of the Summary of Clinical Safety:
As an immunomodulatory of the Type 2 inflammatory pathway, parasitic (eg,

helminthic) infections were carefully monitored. Other types of infections, including
opportunistic infections were included based on a more empiric approach from
experience with other biologic drugs, and prior to dupilumab’s safety profile being more
fully understood.
Therefore, the dupilumab clinical program excluded patients with known or suspected
history of immunosuppression, history of invasive opportunistic infections, active

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endoparasitic infections, or suspected or high risk of endoparasitic infection, active

chronic or acute infection requiring treatment with systemic antibiotics, anti-virals,
antiparasitics, antiprotozoals, or anti-fungals within 2 weeks of the baseline visit.
The FDA requested that Suicidal Behavior (Suicidal Ideation, Suicide Attempt and Completed
Suicide) be included as an AESI. The Agency made this request in the pre-BLA communication;
however, the rationale was not stated in the communication.
The Applicant used search criteria (e.g., SMQ, SOC) based on the MedDRA PTs listed in Table 77.
The Applicant applied these criteria in the analyses of Phase 3 data and the Primary and
Supportive Safety Pools. Because the search criteria could identify relevant PTs and PTs that
were not pertinent to the analyses of AESIs, an event incidence determined from the search
criteria might not reflect the incidence of the actual event of interest. Therefore, a study
medical monitor conducted a blinded, manual adjudication of relevant PTs under each HLT
prior to database lock for studies 1334 and 1416 (the pivotal monotherapy studies). In the
Summary of Clinical Safety, the Applicant presented the analyses for the Primary and
Supportive Safety Pools and for the LTT study, 1224 and the OLE study, 1225.

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AESIs in the Primary Safety Pool (16-Week-Monotherapy)
During the 16-week treatment period, subjects in the placebo group experienced the highest
proportion of AESIs, and there was no evidence of a dose-response in the dupilumab groups.
“Any severe infection” was the most commonly-reported AESI in both the placebo and
dupilumab groups. Infections are discussed in more detail below.
During the 12-week post treatment follow up period, the highest proportion of subjects
reporting AESIs was in the dupilumab 300mg QW. During this period, the only AESI that was
reported in more than one subject was “any opportunistic infection,” and those multiple
reports were in subjects who received dupilumab 300mg QW.
Table 78. Overall Summary of Number of Patients with Treatment-Emergent Adverse Events of Special Interest –
Treatment Period and Follow-Up Period -Primary Safety Pool*
Most of AESIs were not reported as SAEs. However, the majority of those that were reported as
SAEs, were in the placebo group, and the events were “Any severe infection” and “Suicidal
behavior.” Most AESIs were reported during the 16-week treatment period. The two AESIs that
were reported during the follow-up period were both reported in the placebo group: one
report each of “Any severe infection” and “Suicidal behavior.”

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Table 79. Overall Summary of Number of Subjects with Serious Treatment-Emergent Adverse Events of Special
Interest – Treatment Period and Follow-Up Period - Primary Safety Pool*
Supportive Safety Pool - Phase 2 and 3 Studies (12- to 16-Week Monotherapy)
The AESI results for this pool were generally similar in pattern to those reported in the Primary
Safety Pool, which may not be too surprising, since the supportive pool incorporates the studies
that constitute the Primary Safety Pool. The proportion of subjects who had at least one AESI
during the study period was 2.7% in the dupilumab ≥300 mg group and 4.5% in the placebo
group. Anaphylactic reaction and mycosis fungoides were AESIs that were also SAEs, and these
events were discussed in Section 8.4.2 of this review.
AESIs in Study 1224 (Dupilumab + TCS): 16-Week Data
AESIs reported for more than one subject were reported in the following proportions: 1.8% in
the dupilumab 300 mg Q2W + TCS group, 1.0% in the dupilumab 300 mg QW + TCS group, and
3.2% in the placebo + TCS group. The only event that was reported in more than one subject
was eczema herpeticum, and most of the events were reported in the placebo + TCS group: 4
(1.3%) placebo and 1 (0.9%) in the 300 mg Q2W combination group. The one report of herpes
zoster occurred in the placebo group: 1(0.3%).

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Table 80. Number of Subjects with Treatment-Emergent Adverse Events of Special Interest during the 16-Week
Period by AESI Category, High Level Term, and Preferred Term-Study 1224– SAF*

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AESIs in Study 1224 (Dupilumab + TCS): 52-Week Data
During this period, the proportion of subjects reported to have at least one AESI was lower in
both dupilumab groups compared to the placebo group: dupilumab 300 mg Q2W + TCS group
(3.6% [4/110]; EAIR 4.045 nP/100 PY), dupilumab 300 mg QW + TCS group (2.5% [8/315]; EAIR
2.789 nP/100 PY), and placebo + TCS group (7.3% [23/315]; EAIR 8.554 nP/100 PY). Herpes
zoster and eczema herpeticum were the only events reported in more than one subject, and
these events were reported at a higher incidence in the placebo group compared to the
dupilumab groups:
• The reported EAIRs for herpes zoster were: 0.9% (1/110; EAIR 0.997 nP/100 PY) in the
dupilumab 300 mg Q2W + TCS group, 0.3% (1/315; EAIR 0.343 nP/100 PY) in the
dupilumab 300 mg QW + TCS group, and 1.6% (5/315; EAIR 1.801 nP/100 PY) in the
placebo + TCS group.
• The reported EAIRs for eczema herpeticum were: 0.9% (1/110; EAIR 1.005 nP/100 PY) in
the dupilumab 300 mg Q2W + TCS group, 0 in the dupilumab 300 mg QW + TCS group,
and 1.9% (6/315; EAIR 2.168 nP/100 PY) in the placebo + TCS group.
No new concerns were raised from assessment of data from longer-term exposures (52 weeks)
to dupilumab.
An AESI was reported for 2 additional subjects in the 4-moth SUR. The PTs were Urticaria and
Sinusitis, and both subjects were in dupilumab arms (one subject in each arm).

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Table 81. Number of Subjects with Treatment-Emergent Adverse Events of Special Interest during the 52-Week
Treatment Period by AESI Category, High Level Term, and Preferred Term-Study 1224 – SAF*

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AESIs in Study 1225 (OLE)

In this study, 67 of 1491 subjects (4.5%) experienced at least 1 AESI, EAIR of
6.638 nP/100 PY. A total of 9 subjects (0.6%) had an AESI that was also an SAE (EAIR of 0.868
nP/100 PY).
Table 82. Table 32: Summary of Treatment-Emergent Adverse Events of Special Interest – SAF

Abbreviations: nP, number of patients with an event; nP/100 PY, number of patients with at least 1 event per 100 patient year;
PY, patient-year; TEAE, treatment-emergent adverse event
Note: For patients with event, number of patient years was calculated up to date of the first event; for patients without event,
it corresponded to the length of study observation period.
An AESI was reported for 43 additional subjects in study 1225 during the 4-month SUR period.
The Applicant reported that “Acute allergic reactions” were the most common type of AESI, and
the following 4 PTs were reported: Food allergy, Angioedema (unspecified etiology), Eye
Swelling (verbatim term: “swelling of eye due to mild allergic due to unknown cause reaction”),
and Rash Pruritic (verbatim term: “pruritic papular rash post-dose”).
Discussion by AESI by Category
Any Opportunistic Infection
All opportunistic infections reported in the Primary Safety Pool were herpes virus infections,
specifically eczema herpeticum and herpes zoster. These events were reported in a higher
proportion of placebo subjects or in similar proportions between placebo and dupilumab
groups. See Table 83.

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Table 83.p. 149Table 53: Summary of Treatment-Emergent Adverse Events of Special Interest Opportunistic
Infection by HLT and PT – Treatment Period and Follow-Up Period - Primary Safety Pool*

a The treatment period is defined as period starting from the first dose date to the date of the week 16 visit (study day 113
relative to the first dose date if the week 16 visit is unavailable) or date of early termination visit,¬ whichever comes first.
All opportunistic infections reported in Study 1224 (dupilumab + TCS) through Week 52 were
also herpes virus infections and were eczema herpeticum and herpes zoster, except for a single
report of cytomegalovirus infection in the placebo + TCS group. There were only single reports
of eczema herpeticum and herpes zoster in the dupilumab treatment arms.
Table 84. Number of Patients with Treatment-Emergent Adverse Events of Special Interest during the 52-Week Treatment
Period by AESI Category, High Level Term, and Preferred Term-Study 1224 – SAF*
All opportunistic infections in the OLE study (1225) were Herpes Viral Infections (HLT): herpes
zoster (17/1491 [1.1%]) and eczema herpeticum (9/1491 [0.6%]).
Infection Requiring Treatment with Parenteral Antibiotics

Investigators reported no events in this category as AESIs in the Primary Safety Pool. The

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Applicant confirmed this.
Through 52 weeks in study 1224, infections requiring treatment with parenteral antibiotics
were reported at similar incidences across treatment arms: 3 (1%) placebo + TCS, 1 (0.9%)
dupilumab 300 mg Q2W + TCS, and 4 (1.3%) dupilumab 300 mg QW + TCS. No one event was
reported more than once. Two of the events were reported as SAEs: pneumonia in a subject in
the placebo + TCS group and “superinfection bacterial” in a subject in the dupilumab 300 mg
Q2W + TCS group.
Period by AESI Category, High Level Term, and Preferred Term – SAF*
In the OLE study (1225), AESI of infection requiring treatment with parenteral antibiotics was
reported in 6/1491 (0.4%) of subjects. All events were single reports and included diverticulitis,
parotitis, bronchitis, gonorrhea, infected dermal cyst, and erysipelas.

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Any Severe Infection
The incidence of severe infections during the 16-week period in the Primary Safety Pool was
higher in the placebo group compared to the dupilumab groups. Sepsis and folliculitis were the
only events reported in more than one subject, and all events were reported in the placebo
group. Two subjects had a severe infection during the follow-up period: one subject in the
placebo group experienced three events: device related infection, sepsis, and Staphylococcal
Infection, and one subject in the dupilumab 300 QW group experienced Impetigo. See Table 86.
Table 86. Summary of Treatment-Emergent Adverse Events of Special Interest Any Severe Infection by HLT and
PT – 16-Week Treatment Period - Primary Safety Pool*
In the 52-week treatment period of Study 1224, severe infections were reported at the
following incidences: 5 (1.6%) in the placebo + TCS group, 0 in the Q2W + TCS group, and 1
(0.3%) in the dupilumab 300 mg QW + TCS group. The event in the dupilumab group was
conjunctivitis bacterial.

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Period by AESI Category, High Level Term, and Preferred Term – SAF*
Severe infections in the OLE study (13/1491 [0.9%]) included the following: conjunctivitis
(unspecified etiology) (4/1491 [0.3%]), herpes ophthalmic- (1/1491 [<0.1%]) and herpes simplex
(1/1491 [<0.1%]). No other AESIs of severe infection were reported in more than one subject.
Infections treated with Oral Antibiotics, Anti-Virals, or Anti-Fungals for Longer than 2 Weeks
No events were reported for this AESI category during the 16-week treatment period for the
Primary Safety Pool.
For the 52-week treatment period in Study 1224, events were reported at the following
incidences: 1.9% in the placebo + TCS group, 0.9% in the Q2W + TCS group, and 0.6% in the
dupilumab 300 mg QW + TCS group. No one PT was reported in more than one subject in a

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treatment group. The one SAE in this category was eczema herpeticum, and it occurred in the
Period by AESI Category, High Level Term, and Preferred Term-Study 1224 – SAF*
Clinical Endoparasitosis
The Summary of Clinical safety describes that there was only one report of an event in this
category, and it was from the 52-week treatment period of Study 1224: the verbatim term
“Strongyloides Serology Positive” was reported for an 18 y/o male subject (03008012) in the
dupilumab 300 mg QW + TCS group. The subject was asymptomatic, and it is unclear what
prompted this serology testing in this subject. Study treatment was not discontinued. However,
R668-AD-1224 Listing 2.7.5 includes a second subject in the same treatment arm (subject
036008013, a 19 y/o female) with this same PT reported. No action was taken with the study
product for her either. The reason for the testing was also unclear for this subject.
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No AESIs of clinical endoparasitosis were reported in the OLE study, 1225.
Malignancy - Mycosis Fungoides or Cutaneous T-Cell Dyscrasias
The Applicant designated these events as AESIs because they may be misdiagnosed as chronic
AD. Mycosis fungoides and “cutaneous T-Cell dyscrasias” were not reported in the Primary
Safety Pool.
One subject (036004008) who was in the placebo + TCS group of study 1224 (LTT), was
diagnosed with cutaneous T-Cell lymphoma 124 days after discontinuing study treatment.
Two subjects in the safety database were diagnosed with mycosis fungoides:
• Subject 840034007 (57 y/o male) in the dupilumab 300 mg QW group in
study 1314 was reported with mycosis fungoides on Day 49; treatment was
permanently discontinued (from the Supportive Safety Pool and previously discussed).
• Subject 1416-840036006 (59 y/o F) in the OLE study (1225) was diagnosed with
cutaneous T-cell lymphoma on Day 89, leading to treatment discontinuation.
Severe Injection Site Reactions
Severe injection site reactions (ISRs) were those lasting longer than 24 hours. There were no
such reports in the Primary or Supportive Safety Pools or in study 1224 (LTT).
Severe ISRs were reported for one subject (344002) on Days 7 and 14 from the OLE study, 1225.
The events (redness, swelling, and heat around the injection sites) were nonserious and
persisted for more than two weeks and resolved without treatment. Study drug was
permanently discontinued.
Acute Allergic Reactions Requiring Treatment
The proportions of subjects reporting an acute allergic reaction requiring treatment in the
Primary Safety Pool were: 0.6% for the placebo and 300 mg Q2W groups and 0.2% for the 300
mg QW group. Drug hypersensitivity was the only PT with more than one report, (2 reports),
and both of those reports were in the placebo arm (subjects reacted to Lurasidone or to
Bactrim).

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Table 89. Summary of Treatment-Emergent Adverse Events of Special Interest Acute Allergic Reactions Requiring
Treatment by HLT and PT – Treatment Period - Primary Safety Pool*
Three events were reported in the Supportive Safety Pool: angioedema (placebo group),
anaphylactic Shock (due to cashew nuts; this subject was discussed in Section 8.4.2) and Serum
Sickness-Like Reaction occurred in the dupilumab 300 mg QW group. Details of the subject
(840011001) who experienced the Serum Sickness-Like Reaction are found in the discussion of
SAEs in Section 8.4.2.
One subject in the LTT study (1224) experienced an acute allergic reaction, and she was in the
A total of 14 subjects were reported to have experienced acute allergic reactions requiring
treatment in the OLE study, 1225: 6 events of urticaria, 3 events of anaphylaxis (discussed in
the next section), 2 events of hypersensitivity, 2 events of injection site urticaria, 1 event of
drug hypersenstivity, and 1 event of urticaria papular (one subject experienced two events:
urticaria and anaphylaxis). The following events were considered by investigators to be related
to dupilumab: the 2 events of injection site urticaria (study drug was not discontinued) and one
event of urticaria (study drug was permanently discontinued). Study drug was continued
unchanged for all subjects except the previously-referenced subject who experienced urticaria
and for one subject who experienced hypersensitivity and had study drug temporarily
discontinued, then restarted.

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For 5 of the 6 subjects who experienced urticaria, investigational treatment was continued
without change. However, dupilumab was discontinued for the 6th subject, who experienced
“systemic” urticaria with breathing difficulties one day following administration of study drug.
This subject is further discussed below:
Subject 1334-233004029 (OLE: 1225-225014): Urticaria

This was a 21 y/o white female (Estonia) who received dupilumab 300 QW and whose most
recent dose before the event was on Day 86. At that time, she had received a total of 12 doses.
On Day 53 to Day 54, she experienced a mild nonserious adverse event of urticarial reaction
that was considered related to study drug. Dupilumab was continued as planned, and the event
recovered/resolved. Concomitant medications at the time of this event included dienogest,
which was not considered suspect. No other medications were taken prior to the event of
urticaria. On Day 87, she experienced “acute systemic urticarial reaction of moderate intensity
with mild difficulty breathing.” She was treated with prednisolone on Day 88, and the event
was considered to be resolved that same day. Study drug was permanently discontinued due to
the event of urticaria; she received no more doses after Day 86. The investigator and Applicant
considered the event to be related to study drug, and I agree that this appears likely.
Anaphylactic Reactions
No anaphylactic reactions were reported in the Primary Safety Pool or in the LTT study, 1224.
The subject from the Supportive Safety Pool has been previously discussed (cashew nuts). The 3
reports of anaphylaxis that were reported in the OLE study, 1225, were all attributed to
reactions to food products (walnuts, “nuts,” and banana soy milk). No action was taken for
dupilumab for any of the 3 subjects; treatment was continued as planned.
Suicidal Behavior (Suicidal Ideation, Suicidal Behavior, Depression Suicidal, Suicide Attempt
and Completed Suicide)
Suicidal behavior was reported as follows in the Primary Safety Pool during the 16-week
treatment period: no subjects in the dupilumab 300 mg Q2W group, 0.2% (1/518) in the
dupilumab 300 mg QW group, and 0.6% (3/517) in the placebo group. No events in this
category were reported in the Supportive Safety Pool, the LTT study, or the OLE study.

Clinical Review
Brenda Carr, MD
BLA 761055
Table 90. Summary of Treatment-Emergent Adverse Events of Special Interest Suicidal Behavior by HLT and PT –
16-Week Treatment Period - Primary Safety Pool*
No AESIs of suicidal behavior were reported in the OLE study, 1225.
8.4.5. Treatment Emergent Adverse Events and Adverse Reactions
The Applicant defined an AE as “any untoward medical occurrence in a patient administered a

study drug which may or may not have a causal relationship with the study drug...(A)n AE is any
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease
which was temporally associated with the use of a study drug, whether or not considered
related to the study drug.” The definition also included any “worsening (i.e., any clinically
significant change in frequency and/or intensity) of a pre-existing condition that was temporally
associated with the use of the study drug.”
Overall, TEAEs were reported in approximately 69% of subjects in each of the three treatment
arms. TEAEs were most commonly reported in the Infections and infestations SOC, and the
most commonly reported PT in all treatment arms was Nasopharyngitis, which was reported at
similar incidences in all arms (~10%). There was a suggestion of a dose-response for the general
PT Upper respiratory tract infection: placebo- 15 (2.9%) subjects, dupilumab 300 mg Q2W- 18
(3.4%), and dupilumab 300 mg QW- 24 (4.6%) that was not observed for the following, more
specific PTs: Nasopharyngitis, Bronchitis, and Sinusitis. Bronchitis was reported at similar
incidences in all arms (~1%). The incidence of Sinusitis was highest for the placebo group.
TEAEs were next most commonly reported in the Skin and subcutaneous tissue disorders SOC.
Dermatitis atopic was the most commonly reported PT and was reported at a higher incidence
in the placebo group.
A dose-response pattern is noted with the PT Injection site reaction.

Clinical Review
Brenda Carr, MD
BLA 761055
The following TEAEs were reported at ≥ 1% and at a higher incidence in a Dupilumab arm
compared to placebo: Nasopharyngitis, Upper respiratory tract infection, Conjunctivitis, Oral
herpes, Herpes simplex, Conjunctivitis bacterial, Alopecia, Rash, Injection site reaction, Fatigue,
Injection site erythema, Headache, Arthralgia, Myalgia, Diarrhea, Nausea, Conjunctivitis allergic,
Blepharitis, Dry eye, Cough, Oropharyngeal pain, Eosinophilia, and Hypertension.

Clinical Review
Brenda Carr, MD
BLA 761055
Table 91. Number of Subjects with Treatment-Emergent Adverse Events ≥1% in any Treatment Group by Primary System
Organ Class and Preferred Term – 16-Week Treatment Period - Primary Safety Pool – SAF*

Clinical Review
Brenda Carr, MD
BLA 761055
Overall, TEAEs occurred in similar proportions of subjects in all 3 treatment groups: 67.9% in
the placebo QW + TCS group, 73.6% in the dupilumab 300 mg Q2W + TCS group, and 72.1% in
the dupilumab 300 mg QW + TCS group. The pattern of TEAEs was generally similar to what was
seen in the Primary Safety Pool.
The TEAEs were reported at ≥ 1% and at a higher incidence in dupilumab + TCS arms compared
to placebo + TCS were: Nasopharyngitis, Oral herpes, Viral upper respiratory tract infection
Conjunctivitis bacterial, Rhinitis, Herpes simplex, Injection site reaction, Erythema Conjunctivitis
allergic, Blepharitis, Eye pruritus, Dry eye, and Ligament sprain.

Clinical Review
Brenda Carr, MD
BLA 761055
Table 92. Number of Subjects with Treatment-Emergent Adverse Events ≥1% in any Treatment Group by Primary
System Organ Class and Preferred Term – 16-Week Data - R668-AD-1224 – SAF*

Clinical Review
Brenda Carr, MD
BLA 761055
For the longer exposure period for study 1224, TEAEs continued to be in similar proportions of
subjects across treatment groups: 84.4% in the placebo QW + TCS group, 88.2% in the
dupilumab 300 mg Q2W + TCS group, and 82.9% in the dupilumab 300 mg QW + TCS group. The
general pattern of occurrence of TEAEs did not appear to change with longer term exposure to
dupilumab.
TEAEs that were reported at ≥ 2% and at a higher incidence in dupilumab + TCS arms compared
to placebo + TCS were: Oral herpes, Conjunctivitis bacterial, Herpes simplex, Conjunctivitis
allergic, Eye pruritus, Blepharitis, Dry eye, and Injection site reaction.

Clinical Review
Brenda Carr, MD
BLA 761055
Table 93. Number of Patients with Treatment-Emergent Adverse Events ≥2% in any Treatment Group by Primary
System Organ Class and Preferred Term – 52-Week Treatment Period - R668-AD-1224 – SAF*

Clinical Review
Brenda Carr, MD
BLA 761055
TEAEs that have been identified as adverse reactions include conjunctivitis, injection site
reactions, oral herpes, and eosinophilia. Also, see the discussions in Sections 8.4.6 and 8.5.
8.4.6. Laboratory Findings
Analyses of laboratory data from the Primary Safety Pool and the LTT study (1224) are
presented in this section.

Red Blood Cells and Platelets

Clinical Review
Brenda Carr, MD
BLA 761055
Subjects in dupilumab groups showed a greater mean decrease in platelets compared to

subjects in the placebo groups from baseline to Week 16. See Table 94 and Figure 7. However,
mean counts were reported to remain within the normal range. By 12 weeks post-treatment, all
treatment groups showed a trend towards return to baseline. This trend in decrease was not
noted for hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular hemoglobin,
erythrocyte mean corpuscular hemoglobin concentration, or erythrocyte mean corpuscular
volume.
The PT “platelet count decreased” was reported for 2 subjects (0.4%) in the the dupilumab 300
mg QW group and no subjects in the placebo or dupilumab 300 mg Q2W groups. However, the
PT “thrombocytopenia” was only reported in the placebo group (2 subjects [0.4%]).
Table 94. Summary statistics for Hematology (Red Blood Cells and Platelets) values and changes from baseline by visit
platelets*
Mean (SD) Mean (SD) Mean Change Mean (SD) Mean

Baseline Value Value at Week from Baseline Value at Change
16 at Week 16 Week 28/32 from
(EOT)** (EOS)+ Baseline at
Week 28/32
Placebo 273.9 (64.71) 268.4 (61.89) -2.2 260.7 (65.53) -18.3
Dupilumab 271.6 (67.80) 265.6 (63.04) -6.9 269.3 (64.06) -12.0
300 mg Q2W
Dupilumab 272.0 (66.93) 261.1 (63.25) -11.9 269.1 (62.89) -18.8
300 mg QW
*Source: Post-text Table 9.1.1.1/1 Pool 2
**EOT= end of treatment
+EOS= end of study

Clinical Review
Brenda Carr, MD
BLA 761055
Figure 7. Mean Change (+/-SE) of Hematology (Red Blood Cells and Platelets) From Baseline
(Safety Analysis Set)*
*Source: Post-Text Figure 9.1.1.1/1; Pool 2
White Blood Cells

Neutrophils and eosinophils showed changes over time that suggested a dupilumab effect.
Neutrophils
Dupilumab-treated subjects showed a greater mean decrease from baseline in neutrophils
compared to placebo-treated subjects. See Table 95 and Figure 8. Although increased relative
to the Week 16 value, by 12 weeks post-treatment, the mean counts remained decreased
compared to baseline, but trending towards baseline values.
“Neutrophil count decreased” was reported in one subject in each of the dupilumab arms (0.2%
incidence for each arm) and no subjects in the placebo group. “Neutropenia” was reported in a
similar proportion of subjects in all 3 treatment arms: 2 subjects in both the placebo group and
in the dupilumab 300 mg Q2W group (0.4% rate for each of those treatment arms) and in one
subject (0.2%) in the dupilumab 300 mg QW group.

Clinical Review
Brenda Carr, MD
BLA 761055
Table 95. Summary statistics for Hematology (White Blood Cells) values and changes from baseline by visit

Baseline Value at Week from Baseline at Value at Change from
Value 16 Week 16 Week 28/32 Baseline at
(EOT)** (EOS)+ Week 28/32
Placebo 4.728 (1.937) 4.578 (1.811) -0.135 4.433 (1.700) -0.015

Dupilumab 4.618 (1.729) 4.197 (1.531) -0.431 4.372 (1.788) -0.139
300 mg Q2W
Dupilumab 4.631 (1.801) 4.084 (1.673) -0.533 4.275 (1.716) -0.482
300 mg QW
*Source: Post-Text Table 9.1.1.1/2; Pool 2
+EOS= end of study
Figure 8. Mean Change (+/-SE) of Hematology (White Blood Cells) From Baseline (Safety Analysis Set)(Safety
Analysis Set)*
*Source: Post-text Table 9.1.1.1/2; Pool 2

Clinical Review
Brenda Carr, MD
BLA 761055
Eosinophils
Dupilumab-treated subjects showed a greater mean initial increase in eosinophils (from
baseline to Week 4) compared to placebo subjects. By Week 16, counts were essentially at
baseline levels for the dupilumab groups. However 12 weeks post-treatment, mean counts for
all 3 treatment groups were below baseline values. See Table 96 and Figure 9.
“Eosinophil increased” was reported in no subjects in the placebo group, 2 subjects (0.4%) in
the dupilumab 300 mg Q2W group, and 3 subjects (0.6%) in the dupilumab 300 mg QW group.
“Eosinophilia” was reported in 2 subjects (0.4%) in the placebo group, 9 subjects (1.7%) in the
dupilumab 300 mg Q2W group, and one subject (0.2%) in the dupilumab 300 mg QW group.
Eosinophils (Safety Analysis Set)*
Mean Mean Mean Mean (SD) Mean Mean (SD) Mean

(SD) (SD) Change Value at Change Value at Change
Baseline Week 4 from Week 16 from Week from at
Value Value Baseline at (EOT)** Baseline at 28/32 Baseline
Week 4 Week 16 (EOS)+ Week
28/32
Placebo 0.611 0.624 0.015 0.484 -0.128 0.491 -0.077
(0.612) (0.617) (0.486) (0.692)
Dupilumab 0.587 0.681 0.093 0.579 -0.014 0.357 -0.190
300 mg Q2W (0.563) (0.790) (0.666) (0.242)
Dupilumab 0.604 0.718 0.112 0.626 0.013 0.410 -0.128
300 mg QW (0.551) (0. 865) (0.686) (0.342)
*Source: Post-text Table 9.1.1.1/2; Pool 2
+EOS= end of study
Figure 9. Mean Change (+/-SE) of Hematology (White Blood Cells) From Baseline (Safety Analysis Set)*

Clinical Review
Brenda Carr, MD
BLA 761055
Red Blood Cells and Platelets

A similar pattern of decrease in platelets was observed through Week 52 in the Dupilumab +
TCS trial. See Table 97. The Applicant reported that the mean platelet values were within the
normal range at each visit for each treatment group.
“Platelet count decreased” was reported in one subject in the dupilumab 300 mg QW + TCS
group and no subjects in the other two treatment arms. The EAIRs [nP/PY (nP/100 PY)] for
“Platelet count decreased” were: placebo + TCS group- 0/280.4 (0.000), dupilumab 300 mg
Q2W + TCS- 0/100.4 (0.000), and dupilumab 300 mg QW + TCS- 1/291.4 (0.343).
“Thrombocytopenia” was reported in 2 subjects in the placebo + TCS group [2/279.3 (0.716)],
one subject in the dupilumab 300 mg Q2W + TCS group [1/100.4 (0.996)], and no subjects in the
dupilumab 300 mg QW group [0/291.9 (0.000)].

Clinical Review
Brenda Carr, MD
BLA 761055
Table 97. Summary statistics for Hematology (Red Blood Cells and Platelets) values and changes from baseline
by visit platelets*

Baseline Value Value at Week from Baseline at Value at Change
52 Week 52 Week 64 from
(EOT)* (EOS)+ Baseline at
Week 64
Placebo + TCS 275.4 (70.60) 271.2 (61.65) -2.3 266.6 (64.80) -6.9
Dupilumab 284.4 (74.55) 272.1 (65.60) -16.4 277.3 (75.20) -17.9
300 mg Q2W+ TCS
Dupilumab 277.4 (76.70) 266.1 (63.58) -14.5 257.7 (61.57) -23.1
300 mg QW+ TCS
*Source: Post-Text Table 9.1.1.1/1; 1224
+EOS= end of study
Similar trends were not seen with mean/median erythrocyte counts, hematocrit, hemoglobin,
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, or mean
corpuscular volume over the 52 weeks.
Neutrophils
A similar pattern of decrease in mean neutrophil values was observed through Week 52 in the
dupilumab + TCS trial. See Table 98. “Neutrophil decreased” was reported for one subject in the
dupilumab 300 mg QW + TCS group. “Neutrophil increased” was reported for one subject in the
dupilumab 300 mg QW + TCS group. “Neutropenia” was reported for one subject in the placebo
+ TCS group, one subject in the dupilumab 300 mg Q2W + TCS group, and 2 subjects in the
dupilumab 300 mg QW + TCS group. The EAIRs [nP/PY (nP/100 PY)] for “Neutropenia” were:
Placebo + TCS group: 1/280.4 (0.357), Dupilumab 300 mg Q2W + TCS: 1/99.5 (1.005), and
dupilumab 300 mg QW + TCS: 2/291.0 (0.687).
One subject in the placebo + TCS group permanently discontinued treatment due to the event
of neutropenia:
• Subject 826003006 was a 22-year-old male who experienced Neutropenia on Day 28. On
that day, his neutrophil count was 1.72 x 109/L (reference range 1.96 to 7.23 x 109/L).
He had received 5 doses of placebo. His neutrophil count was 1.53 x 109/L the following
week. The event resolved after 22 days.

Clinical Review
Brenda Carr, MD
BLA 761055

Baseline Value at Week from Baseline Value at Week Change from
Value 52 at Week 52 64 Baseline at
(EOT)* (EOS)+ Week 64
Placebo + TCS 4.659 (1.615) 4.578 (1.711) -0.153 4.211 (1.430) -0.627
Dupilumab 300 mg 4.622 (1.924) 4.085 (1.557) -0.665 4.473 (1.510) -0.371
Q2W + TCS
Dupilumab 4.691 (1.800) 4.083 (1.584) -0.583 4.243 (1.623) -0.546
300 mg QW + TCS
*Post-Text Table 9.1.1.1/2; 1224
+EOS= end of study
Eosinophilia
The initial increase in eosinophils was not observed in the 52-week dupilumab + TCS trial.
“Eosinophil count increased” was reported in one subject in the placebo + TCS group, one
subject in the 300 mg Q2W + TCS group and no subjects in the dupilumab 300 mg QW + TCS
group. The EAIRs for “Eosinophil count increased” were 1/280.3 (0.357) for the placebo + TCS
group, 1/100.4 (0.996) for the 300 mg Q2W + TCS group, and 1/100.4 (0.996) for the dupilumab
300 mg QW + TCS group. “Eosinophilia” was reported in no subjects in the placebo + TCS group
[0/280.4 (0.000)], one subject in the dupilumab 300 mg Q2W + TCS group [1/99.4 (1.006)], and
one subject in the dupilumab 300 mg QW + TCS group [1/290.9 (0.344)].
Chemistry
In the Primary Safety Pool, lactate dehydrogenase (LDH) was the only chemistry parameter to
show a trend in change over time. LDH progressively decreased over time, and the decrease
was greater in the Dupilumab groups compared to placebo.
LDH was the only chemistry parameter to show a notable difference in mean changes from
baseline over the 52 weeks in study 1224. Mean LDH values decreased for subjects in the
Dupilumab + TCS groups more than in the placebo + TCS group. However, mean values
remained within the normal range over the 52 weeks.
Urinalysis
There were no trends in mean values or notable differences between treatment groups in
urinalysis parameters shifts.
8.4.7. Vital Signs

Clinical Review
Brenda Carr, MD
BLA 761055
Primary Safety Pool (16-Week Monotherapy)
No trends in mean or median changes were noted in any dosing groups for any of the
parameters: weight, blood pressure (systolic and diastolic), respiratory rate, heart rate, and
body temperature. Table 99 below presents a summary of potentially clinically significant
values for each treatment group. No events were reported as SAEs or led to discontinuation of
treatment.
Table 99. Summary of Treatment Emergent potentially clinical significant value (PCSV) for vital sign and weight
Dupilumab
Parameter (unit) Treatment- Placebo QW 300 mg Q2W 300 mg QW
emergent PCSV (N=517) (N=529) (N=518)
Category n/N1 (%) n/N1 (% n/N1 (%)
Subjects with ≥ 1 39/517 (7.5) 39/517 (7.5) 47/518 (9.1)
treatment- ---
emergent PCSV for
vital sign
<=50 bpm and 6/517 (1.2) 6/529 (1.1) 8/518 (1.5)
decrease from
Heart Rate baseline >=20 bpm
(BEATS/MIN) >=120 bpm and 6/517 (1.2) 2/529 (0.4) 8/518 (1.5)
increase from
baseline >=20 bpm
<=95 mmHg and 10/517 (1.9) 14/517 (2.7) 20/529 (3.8)
decrease from
baseline >=20
Systolic Blood mmHg
Pressure (mmHg) >=160 mmHg and 14/517 (2.7) 20/529 (3.8) 20/529 (3.8)
increase from
baseline >=20
mmHg
<=45 mmHg and 4/517 (0.8) 1/529 (0.2) 3/518 (0.6)
decrease from
baseline >=10
Diastolic Blood mmHg
Pressure (mmHg) >=110 mmHg and 5/517 (1.0) 9/529 (1.7) 7/518 (1.4)
increase from
baseline >=10
mmHg
>=5% decrease from 52/516 (10.1) 36/529 (6.8) 42/518 (8.1)
baseline
Weight (kg) >=5% increase from 55/516 (10.7) 81/529 (15.3) 76/518 (14.7)
baseline
*Source: Pool 2 Post-text Table 10.1.1/7; p. 13348

Clinical Review
Brenda Carr, MD
BLA 761055
No trends in mean or median changes were noted in any dosing groups for any of the
parameters: weight, diastolic blood pressure, respiratory rate, heart rate, and body
temperature. Table 100 below presents a summary of potentially clinical significant values for
each treatment group. No events were reported as SAEs or led to discontinuation of treatment.
Table 100. Summary of Treatment Emergent potentially clinical significant value (PCSV)*
Dupilumab
Parameter (unit) Treatment- Placebo QW +TCS 300 mg Q2W+TCS 300 mg QW+TCS
emergent PCSV (N=315) (N=110) (N=315)
Category n/N1 (%) n/N1 (% n/N1 (%)
Subjects with ≥ 1
treatment- --- 34/315 (10.8) 15/110 (13.6) 40/315 (12.7)
emergent PCSV for
vital sign
<=50 bpm and
decrease from 3/315 (1.0) 2/110 (1.8) 3/315 (1.0)
Heart Rate baseline >=20 bpm
(BEATS/MIN) >=120 bpm and
increase from 2/315 (0.6) 0 0
baseline >=20 bpm
<=95 mmHg and
decrease from 14/315 (4.4) 8/110 (7.3) 22/315 (7.0)
baseline >=20
Systolic Blood mmHg
Pressure (mmHg) >=160 mmHg and
increase from 10/315 (3.2) 2/110 (1.8) 10/315 (3.2)
baseline >=20
mmHg
<=45 mmHg and
decrease from 7/315 (2.2) 2/110 (1.8) 3/315 (1.0)
baseline >=10
Diastolic Blood mmHg
Pressure (mmHg) >=110 mmHg and
increase from 3/315 (1.0) 1/110 (0.9) 4/315 (1.3)
baseline >=10
mmHg
Patients with at
least 1 treatment- 128/315 (40.6) 34/110 (30.9) 146/315 (46.3)
emergent PCSV for ----
Weight Parameter
>=5% decrease from 53/315 (16.8) 7/110 (6.4) 40/315 (12.7)
baseline
Weight (kg) >=5% increase from 81/315 (25.7) 27/110 (24.5) 108/315 (34.3)
baseline
Sources: Post-Text Tables 10.1.1/7 and 10.1.1/8; study report for 1224

Clinical Review
Brenda Carr, MD
BLA 761055
There were greater decreases from baseline in systolic blood pressure for the dupilumab +TCS
treatment groups compared to the placebo + TCS treatment group over the 52-week treatment
period. See Figure 10. Systolic blood pressure ≤95 mmHg and decrease from baseline ≥20
mmHg was reported for 4.4% (14/315) in the placebo + TCS group, 7.3% (8/110) in the
dupilumab 300 mg Q2W + TCS and 7.0% (22/315) in the dupilumab 300 mg QW + TCS group.
This trend was not observed in the Primary Safety Pool.
Figure 10. Mean Change (SE) in Sitting Systolic Blood Pressure (mmHg) from Baseline through Week 52
TreatmentPeriod – SAF*
Source: Figure 27; study report for 1224; p. 275

Clinical Review
Brenda Carr, MD
BLA 761055
Figure 11. Mean Change (+/-SE) of sitting systolic blood Pressure (mmHg) From Baseline(Safety Analysis Set)*
Source: Post-Text Figure 10.1.1/2; Pool 2
8.4.8. Electrocardiograms (ECGs)
The Applicant performed standard 12-Lead ECGs for all clinical trials and identified no clinically
meaningful trends in mean and median change from baseline or shifts from baseline.

Clinical Review
Brenda Carr, MD
BLA 761055
Table 101. Shift Table for Electrocardiogram (ECG) status by Visit(Safety Analysis Set)*
*Source: Post-text Table 10.1.2/2; Pool 2

Clinical Review
Brenda Carr, MD
BLA 761055
Table 102. Shift Table for Electrocardiogram (ECG) status by Visit (Safety Analysis Set)*
Sources: Post-Text Table 10.1.2/2; study report study 1224
8.4.9. QT
The Applicant did not conduct a thorough QT study. Per the EOP2 meeting minutes,
“Monoclonal antibodies do not need to be evaluated in a thorough QT study. Routine ECG
monitoring in Phase 3 trials should be performed to capture important cardiac effects.”
8.4.10. Immunogenicity
The Applicant collected serum samples in all dupilumab clinical studies for immunogenicity
assessments. In their review, the clinical pharmacology team summarized the incidences of
immunogenicity across the Phase 3 studies. Their results are presented below:
In the combined Phase 3 monotherapy Studies AD-1334 and AD-1416, approximately

13.6% (61/447) and 7.2% (31/429) of subjects had anti-drug antibodies to dupilumab
following 16 weeks of treatment with dupilumab Q2W and QW dosing regimens,
respectively. Of the subjects who developed anti-drug antibodies to dupilumab while
receiving Q2W and QW dosing regimen, approximately 18% (11/61) and 13% (4/31),
respectively, had neutralizing antibodies.

Clinical Review
Brenda Carr, MD
BLA 761055
In the Phase 3 concomitant treatment with TCS Study R668-AD-1224, approximately 9.5%
(10/105) and 10.7% (33/308) of subjects had anti-drug antibodies to dupilumab following
52 weeks of treatment with dupilumab Q2W and QW dosing regimens, respectively. Of the
subjects who developed anti-drug antibodies to dupilumab while receiving Q2W and QW
dosing regimen, approximately 10% (11/10) and 0% (0/33), respectively, had neutralizing
antibodies.
The following discussion pertains to Table 103 below:
Anti-drug antibodies positive (ADA+) subjects were defined as subjects with a positive
ADA response at any time. Treatment-emergent (TE) ADA + (TE-ADA+) subjects were
defined as subjects with no positive ADA response at baseline but with any positive
response after receiving the treatment. Incidene of neutralizing ADA (Nab) is calculated
to reflect the percentage among ADA+ subjects because NAb was only measured in
ADA+ samples. Monotherapy data represent pooled data for studies AD-1334 and AD-
1416.
Table 103. Summary of incidences of anti-drug antibodies (ADA), treatment-emergent ADA (TEADA) and
neutralizing ADA (NAb) in AD Phase 3 studies.*
ADA incidence, % (n/N)

Studies ADA status
Dupilumab
Placebo
300 mg Q2W 300 mg QW Combined
3.8% 14.4% 7.3% 11.0%
AD-1334 ADA+
(8/209) (32/222) (15/206) (47/428)
(16 weeks)
0.96% 6.8% 2.9% 4.9%
T-E ADA+
(2/209) (15/222) (6/206) (21/428)
0% 15.6% 13.3% 14.9%
NAb+
(0/8) (5/32) (2/15) (7/47)
7.3% 12.9% 7.2% 10.0%
AD-1416 ADA+
(16/218) (29/225) (16/223) (45/448)
(16 weeks)
1.8% 8.00% 2.7% 5.4%
T-E ADA+
(4/218) (18/225) (6/223) (24/448)
12.5% 20.7% 12.5% 1.8%
NAb+
(2/16) (6/29) (2/16) (8/45)
5.6% 13.6% 7.2% 10.5%
Combined AD- ADA+
(24/427) (61/447) (31/429) (92/876)
1334 and AD-
1.4% 7.4% 2.8% 5.1%
1416 T-E ADA+
(6/427) (33/447) (12/429) (45/876)
(Monotherapy)
8.3% 18.0% 12.9% 16.3%
(16 Weeks) NAb+
(2/24) (11/61) (4/31) (15/92)

Clinical Review
Brenda Carr, MD
BLA 761055
12.8% 9.5% 10.7% 10.4%

AD-1224 ADA+
(39/305) (10/105) (33/308) (43/413)
(52 weeks)
6.6% 5.7% 4.6% 4.8%
T-E ADA+
(20/305) (6/105) (14/308) (20/413)
5.1% 10% 0% 2.3%
NAb+
(2/39) (1/10) (0/33) (1/43)
*Source: Table 4.5.1.a Clinical Pharmacology review
Impact of ADA on PK profile

Overall, development of ADA was associated with reduced serum dupilumab
concentrations.
Impact of ADA on efficacy

Overall, it is not feasible to draw a definitive conclusion on the impact of ADA, or lack
thereof, on the clinical efficacy measures because of the small number of subjects with
ADA.
Impact of ADA on safety

Two adverse reactions, one patient with serum sickness reaction and one patient with
serum sickness-like reaction were reported in dupilumab clinical studies. These two
adverse reactions were associated with development of ADA with high ADA titers, as
described below.
• Subject 840011001 (38-year-old female) in the dupilumab 300 mg QW group in Study

R668- AD-1314 experienced a treatment-emergent SAE of serum sickness-like reaction.
The patient received a total of 3 doses of study drug prior to the onset of the treatment-
emergent SAE: Day 1/baseline, Day 8, and Day 15. This patient was ADA positive at Day
15 and at the early termination visit (Day 22), with a peak titer of 122,880 at the early
termination visit.
• Subject 137007 (30-year-old female) had a serious event of serum sickness in Study AD-
122(5) (Open-label Extension Study). This subject had previously received placebo
treatment in study R668-AD-1334 (1334-840007002). This subject experienced serum
sickness on Day 18 after receiving 2 doses of dupilumab 300 mg QW following a 600 mg
loading dose at Week 0. At Week 0, the patient exhibited a low titer ADA. No additional
titers were measured until the end of treatment (approximately 79 days) at which time
the patient had a ADA titer of 15,360.
In the primary safety pool including studies AD-1334, AD-1416 and AD-1021 (16-week
monotherapy, the overall incidence of treatment-emergent adverse events (TEAE) was
78.8% in subjects who had treatment-emergent or boosted ADA compared to 70.9% in
subjects who did not have treatment-emergent or boosted ADA.

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Brenda Carr, MD
BLA 761055
The 2 subjects, referenced in the above information from the clinical pharmacology review, are
further discussed in Section 8.4.2 of this review.
8.5. Analysis of Submission-Specific Safety Issues
8.5.1. Eye Disorders
Conjunctivitis and other eye disorders were noted at higher incidences on analyses of data from
the Phase 3 program. The signal has not been detected in the other clinical development
programs (asthma, nasal polyposis). Based on this signal, the Applicant added conjunctivitis to
the list of AESIs (conjunctivitis had not been prospectively identified as an AESI). The Applicant
indicated that there was limited narrative information on these events because the signal was
only identified while the Phase 3 trials were underway and because only one event was
considered serious.
Two ophthalmologists affiliated with the Applicant selected conjunctivitis PTs and select PTs
suggestive of conjunctivitis-like events for post-hoc analyses of eye disorders. The Applicant
included 5 PTs in the customized MedDRA query (CMQ) for the “narrow” analyses and 16 PTs in
the CMQ for the “broad” analyses; see Table 104 below.
Table 104. Table 3: Search Criteria for Conjunctivitis Events*

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Brenda Carr, MD
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Amendment 6 of the protocol for the ongoing OLE study, 1225, added ophthalmological
examination to the Schedule of Events at baseline, week 4, week 12, week 16, week 32, week
48, week 60, week 76, week 92, week 108, week 124, week 140, end of study visit, and
unscheduled visits:
Ophthalmological Examination
This exam will be performed for certain patients of interest, as decided by the sponsor
medical monitor in consultation with the investigator, at select study centers that have
access and can refer patients to an eye specialist, either a General ophthalmologist or a
Cornea and External Eye Disease (‘front-of-the-eye’) subspecialty expert. Any baseline
findings will be documented as part of the patient’s medical history and/or physical
exam, as appropriate. Any inflammatory ophthalmological condition that occurs post-
baseline will be captured as an AE. Additional tests and assessments may be performed
to help understand the AEs. The method and procedure for the exam are provided in
the study reference manual.
Narrow CMQ Analyses: Primary Safety Pool (16-Week Monotherapy)
Analyses of baseline demographic and disease characteristics of subjects who developed eye
disorders compared to those who did not, revealed the following comparative characteristics of
those affected:
• Older: median 41.5 years vs 35.0 years
• Longer duration of AD: median 32.5 years vs 25.5 years
• Higher baseline EASI score: 35.0 vs 28.7
• More likely to have a history of treatment with systemic immunosuppressants
• More likely to have co-morbid allergic conditions, such as asthma, allergic rhinitis, food
allergies.
Additionally, in the narrow CMQ analyses, the Applicant found that dupilumab-treated subjects
who developed Eye Disorders may have had lower efficacy responses compared to those who
did not develop such disorders, as noted in the difference in IGA response rates compared to
placebo:
• With Eye Disorders:
- 300 mg Q2W difference vs placebo [95% CI] was 5.2 [-30.25, 39.27].
- 300 mg QW the difference was 1.1 [-33.30, 35.41].
• Without Eye Disorders:
- 300 mg Q2W the difference was 29.0 [22.51, 35.24.]
- 300 mg QW the difference was 30.3 [23.90, 36.59].
A similar pattern of lower efficacy responses was also seen for the percent change in EASI and
percent change in NRS outcomes.

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Brenda Carr, MD
BLA 761055
“Conjunctivitis” was the most commonly reported PT, and “conjunctivitis allergic” was the most
commonly reported specific subtype. By default, conjunctivitis events were coded in the
Infections and Infestations SOC. Those events that were specifically reported as Viral or
Bacterial conjunctivitis lacked microbiological confirmation. See Table 105.
Table 105. Number of Subjects with Narrow Conjunctivitis CMQ by PT Primary Safety Pool – 16-Week
Treatment Period –SAF*
No SAEs were identified in the narrow CMQ, and most events in this query were graded as mild
or moderate severity. Severe events were reported as below:
• 3 subjects in the 300 mg Q2W group: Conjunctivitis, Conjunctivitis Allergic,
Conjunctivitis Bacterial (one event per subject)
• 2 subjects in the 300 mg QW group: Conjunctivitis Allergic (both subjects)
• 0 subjects in the placebo group.
One subject permanently discontinued treatment (300 mg QW group) due to the event of
Conjunctivitis allergic.
Corticosteroid, antibiotic, and anti-allergic ophthalmic drugs were the most common classes of
medications prescribed for treatment. The Applicant reported outcomes during the treatment
period for the 103 conjunctivitis events as:
• 65%-recovered/resolved,
• 1%-recovered/resolved with sequelae (sequelae not specified),
• 12.6%-recovering/resolving ,
• 19.4%-not recovered/not resolved, or
• 1.9% unknown.
Narrow CMQ Analyses: Study 1224 (Dupilumab + TCS): 16-Week and 52-Week Data
No events were reported as serious, and no subject permanently discontinued study treatment
due an event. “Conjunctivitis allergic” was the most commonly reported event in in both

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Brenda Carr, MD
BLA 761055
treatment periods. Three subjects experienced severe events: 2 subjects with Conjunctivitis
allergic (1 in the placebo + TCS group and 1 in the dupilumab 300 mg QW + TCS group) and 1
subject with Conjunctivitis bacterial (dupilumab 300 mg QW + TCS group).
For both the 16-week and 52-week treatment periods, the incidence rates for Conjunctivitis
were higher in the dupilumab + TCS groups compared to the placebo group: dupilumab 300
QW + TCS group- 8.6% and 19.4%, respectively, 300 mg Q2W + TCS group- 7.3% and 13.6%, and
placebo group- 4.1% and 7.9%. For the Week 16 period, the EAIRs were: 25.275 nP/100 PY in
the dupilumab 300 mg Q2W + TCS group, 29.569 nP/100 PY in the dupilumab 300 mg QW + TCS
group, and 14.038 nP/100 PY in the placebo + TCS group. For the 52-week period, the EAIRs
were 16.355 nP/100 PY in the 300 mg Q2W + TCS group, 23.808 nP/100 PY in the 300 QW +TCS
group, and 9.422 nP/100 PY in the placebo group.
Table 106. Number of Subjects with Narrow Conjunctivitis Events Per 100 Patient-Years by Preferred Term
during the 52-Week Treatment Period (Safety Analysis Set)
*Source: Post-Text Table 7.6.2.4/1 (study 1224)
Broad CMQ Analyses: Primary Safety Pool (16-Week-Monotherapy)
There were no reports of the PTs Ocular hyperemia or Conjunctival hyperemia. There were no
SAEs in the broad CMQ analyses for the Primary Safety Pool. In this analysis, there were 6
subjects with severe conjunctivitis events, all of whom were in dupilumab groups (3 in each
dupilumab group).

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Brenda Carr, MD
BLA 761055
Table 107. Number of Patients with Broad Conjunctivitis CMQ by PT Primary Safety Pool- Treatment Period - SAF
Dupilumab*
Broad CMQ Analyses: Study 1224 (Dupilumab + Concomitant TCS): 16-Week and 52-Week
Data
During the 16-week period, the EAIRs were higher in the Dupilumab 300 Q2W + TCS group
(63.307 nP/100 PY) and 300 mg QW + TCS group (55.002 nP/100 PY) compared to the placebo +
TCS group (18.487 nP/100 PY). During the 52-week treatment period, the EAIRs were: 37.302
nP /100 PY in the Dupilumab 300 QW + TCS group, 31.100 nP /100 PY in the 300 mg Q2W + TCS
group (31.100 nP /100 PY), and 12.650 nP /100 PY in the placebo + TCS group.
In the broad CMQ analyses for study 1224, the rates of Conjunctivitis were higher in the
Dupilumab + TCS groups than in the placebo + TCS group at Week 52. The EAIR for conjunctivitis
during the 52-week treatment period, was higher in the Dupilumab 300 QW + TCS group
(37.302 nP /100 PY) and 300 mg Q2W + TCS group (31.100 nP /100 PY) compared to the
placebo + TCS group (12.650 nP /100 PY).

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Brenda Carr, MD
BLA 761055
Table 108. Number of Patients with Broad Conjunctivitis Events per 100 Patient-Years by Preferred Term during
the 52-week Treatment Period (Safety Analysis Set)*
*Source: Post-Text 7.6.3.4/1; study report 1224
Keratitis
In the Applicant’s overall safety database, the PT “Atopic keratoconjunctivitis” was grouped
under the HLT “Corneal infections, oedemas and inflammations” under the Eye Disorders SOC.
Except for Atopic keratoconjunctivitis, keratitis events were not included in the CMQ for the
post-hoc analyses of Eye Disorders.
In the Primary Safety Pool, keratitis events, were reported only in subjects in the dupilumab
groups. PTs included allergic keratitis, ulcerative keratitis, and atopic keratoconjunctivitis. See
Table 109.
Table 109. Number of patients with treatment-emergent adverse events (TEAE) during the treatment period by
high level term and preferred term (Safety Analysis Set)*
Dupilumab
High Level Term Placebo QW 300 mg Q2W 300 mg QW Combined
Preferred Term (N=517) (N=529) (N=518) (N=1047)
Corneal infections, 0 1 (0.2) 5 (1.0) 6 (0.6)
oedemas and
inflammations
Keratitis 0 0 3 (0.6) 3 (0.3)
Atopic 0 1 (0.2) 1 (0.2) 2 (0.2)
keratoconjunc-
tivitis
Allergic keratitis 0 0 1 (0.2) 1 (<0.1)
Ulcerative keratitis 0 0 1 (0.2) 1 (<0.1)
*Source: Post Text Table 7.2.1.6/1; Pool 2

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BLA 761055
Similarly, for the 16-Week period in study 1224 (Dupilumab + TCS), keratitis PTs were reported
only in subjects in the dupilumab groups.
Table 110. Number of patients with treatment-emergent adverse events (TEAE) during the 16-week period by
primary system organ class, high level term and preferred term (Safety Analysis Set)*
Dupilumab
Preferred Term + TCS + TCS + TCS + TCS
(N=315) (N=110) (N=315) (N=425)
Corneal infections, 0 4 (3.6) 4 (1.3) 8 (1.9)
oedemas and
inflammations
Keratitis 0 1 (0.9) 3 (1.0) 4 (0.9)
Allergic keratitis 0 2 (1.8) 1 (0.3) 3 (0.7)
Ulcerative keratitis 0 1 (0.9) 0 1 (0.2)
*Source: Post-Text Post-text Table 7.2.1.6/1; study 1224
For the 52-Week period in study 1224 (dupilumab + TCS), keratitis PTs were reported in all
treatment arms. However, incidence rates were generally higher for the dupilumab groups.
Dupilumab
(N=315) (N=110) (N=315) (N=425)
Corneal infections, 5 (1.6) 4 (3.6) 9 (2.9) 13 (3.1)
oedemas and
inflammations
Keratitis 4 (1.3) 1 (0.9) 6 (1.9) 7 (1.6)
Allergic keratitis 0 2 (1.8) 2 (0.6) 4 (0.9)
Atopic 1 (0.3) 0 2 (0.6) 2 (0.5)
keratoconjunc-
tivitis
Ulcerative keratitis 0 1 (0.9) 0 1 (0.2)
*Source: Post-Text Post-text Table 7.2.1.7/1; study 1224

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BLA 761055
Table 112. Number of patients with Treatment Emergent Adverse Events per 100 Patient-years during 52-week
period by primary System Organ Class and Preferred Term (Safety Analysis Set)*
Dupilumab
(N=315) (N=110) (N=315) (N=425)
nP/PY nP/PY nP/PY nP/PY
(nP/100 PY) (nP/100 PY) (nP/100 PY) (nP/100 PY)
Corneal infections,
oedemas and ** ** ** **
inflammations
Keratitis 4/279.1 (1.433) 1/99.5 (1.005) 6/288.5 (2.080) 7/387.9 (1.805)
Allergic keratitis 0/280.4 (0.000) 2/99.2 (2.016) 2/290.4 (0.689) 4/389.6 (1.027)
Atopic 1/279.8 (0.357) 0/100.4 (0.000) 2/290.9 (0.688) 2/391.2 (0.511)
keratoconjunc-
tivitis
Ulcerative keratitis 0/280.4 (0.000) 1/99.7 (1.003) 0/291.9 (0.000) 1/391.5 (0.255)
*Source: Post-Text Post-Text Table 7.2.2.2/3; study 1224
**Rates per 100 Patient-years were not provided for HLT.
The 4-month SUR did not provide for any information that would impact conclusions drawn
from the analyses of Eye Disorders submitted in the initial BLA submission. There were no SAEs
in the Eye Disorders SOC in the 4-month SUR.
8.5.2. Herpes Virus Infections
Herpes virus infections generally occurred at higher incidences in the dupilumab groups
compared to placebo. The Applicant stated that a signal for herpes virus infections had not
been detected in the asthma and nasal polyposis programs. This was the only infection to show
a pattern of increased incidence in dupilumab-treated subjects. These infections were coded to
the Infections and infestations SOCs under numerous PTs, as shown in the Tables 113, 114, and
115 (below). Generally, these infections appeared to be non-serious and localized (i.e., not
disseminated). The most common specific type of infection was “Oral herpes.” The nonspecific
“Herpes simplex” was the next most commonly reported PT in this category. Eczema
herpeticum was considered to be an SAE for one subject in the LTT, study 1224, and that
subject was in the placebo group. No other herpes virus infections were reported as SAEs.
Subjects who developed eczema herpeticum or herpes zoster while receiving dupilumab either
had the study treatment temporarily held until resolution of the infection or continued study
treatment according to schedule; all ultimately completed dupilumab treatment. The incidence
rates of eczema herpeticum and herpes zoster were either similar between placebo and
dupilumab groups or higher in the placebo group relative to the dupilumab groups.

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Brenda Carr, MD
BLA 761055
Table 113. Number of subjects with treatment-emergent adverse events (TEAE) during the treatment period by
preferred term (Safety Analysis Set)*
Dupilumab
Placebo QW 300 mg Q2W 300 mg QW Combined
(N=517) (N=529) (N=518) (N=1047)
Herpes viral 17 (3.3) 30 (5.7) 23 (4.4) 53 (5.1)
infections (HLT)
Oral herpes 8 (1.5) 20 (3.8) 13 (2.5) 33 (3.2)
Herpes simplex 4 (0.8) 9 (1.7) 4 (0.8) 13 (1.2)
Eczema herpeticum 3 (0.6) 3 (0.6) 2 (0.4) 5 (0.5)
Genital herpes 1 (0.2) 0 1 (0.2) 1 (<0.1)
Herpes ophthalmic 1 (0.2) 0 1 (0.2) 1 (<0.1)
Herpes simplex 0 1 (0.2) 0 1 (<0.1)
otitis externa
Herpes virus 1 (0.2) 0 1 (0.2) 1 (<0.1)
infection
Herpes zoster 2 (0.4) 1 (0.2) 0 1 (<0.1)
Ophthalmic herpes 0 0 1 (0.2) 1 (<0.1)
simplex
Dupilumab
Placebo QW + TCS 300 mg Q2W + TCS 300 mg QW + TCS Combined
(N=315) (N=110) (N=315) (N=425)
Herpes viral 12 (3.8) 5 (4.5) 11 (3.5) 16 (3.8)
infections (HLT)
Oral herpes 5 (1.6) 3 (2.7) 8 (2.5) 11 (2.6)
Herpes simplex 1 (0.3) 1 (0.9) 4 (1.3) 5 (1.2)
Eczema herpeticum 4 (1.3) 1 (0.9) 0 1(0.2)
Herpes ophthalmic 1 (0.3) 0 0 0
Herpes zoster 1 (0.3) 0 0 0
*Source: Post-Text Table 7.2.1.6/1; study report 1224

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BLA 761055
R668-AD-1224 (Dupilumab plus Concomitant TCS): 52-Week Data
Table 115. Number of patients with Treatment Emergent Adverse Events per 100 Patient-years during 52-week
period by primary System Organ Class and Preferred Term (Safety Analysis Set)*
Dupilumab
Placebo QW + TCS 300 mg Q2W + TCS 300 mg QW + TCS Combined
(N=315) (N=110) (N=315) (N=425)
nP/PY nP/PY nP/PY nP/PY
(nP/100 PY) (nP/100 PY) (nP/100 PY) (nP/100 PY)
Oral herpes 9/276.1 (3.259) 4/97.6 (4.097) 15/283.2 (5.297) 19/380.8 (4.989)
Herpes simplex 2/279.6 (0.715) 3/98.9 (3.034) 5/289.0 (1.730) 8/387.9 (2.062)
Herpes virus 1/280.2 (0.357) 1/100.0 (1.000) 2/291.3 (0.687) 3/391.3 (0.767)
infection
Herpes zoster 5/277.7 (1.801) 1/100.3 (0.997) 1/291.4 (0.343) 2/391.7 (0.511)
Eczema herpeticum 6/276.8 (2.168) 1/99.5 (1.005) 0/291.9 (0.000) 1/391.4 (0.256)
Ophthalmic herpes 0/280.4 (0.000) 0/100.4 (0.000) 1/291.3 (0.343) 1/391.6 (0.255)
simplex
Herpes ophthalmic 2/279.4 (0.716) 0/100.4 (0.000) 1/291.4 (0.343) 1/391.8 (0.255)
Genital herpes 1/280.2 (0.357) 0/100.4 (0.000) 1/291.8 (0.343) 1/392.2 (0.255)
Ophthalmic herpes 1/280.3 (0.357) 0/100.4 (0.000) 0/291.9 (0.000) 0/392.3 (0.000)
zoster
*Source: Post-Text Table 7.2.2.2/3; study report 1224
8.6. Specific Safety Studies/Clinical Trials
The Applicant conducted study 1314 to evaluate the effect of dupilumab on antibody responses
to meningococcal (T-cell independent) and tetanus toxoid adsorbed vaccinations (T-cell
dependent). The review division consulted the Division of Vaccines and Related Product
Applications (DVRPA) in the Center for Biologics Evaluation and Research (CBER) on the
adequacy of this study to support the Applicant’s proposed labeling language, presented below:
7.1 Live Vaccines

(b) (4)
7.2 Non-Live Vaccines

Immune responses to vaccination were assessed in a study in which patients
with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of
dupilumab. After 12 weeks of dupilumab administration, patients were
(b) (4)
vaccinated with a Tdap vaccine ( Adacel®) and a meningococcal
(b) (4) (b) (4)
polysaccharide vaccine ( Menomune®)
responses were assessed 4 weeks later. Antibody responses to both tetanus
vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-

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Brenda Carr, MD
BLA 761055
(b) (4)
treated and placebo-treated patients.
.
(b) (4)
The DVRPA team stated that, “Even without definitive evidence of vaccine effectiveness, the
benefit/risk balance of using inactivated vaccines as indicated in patients with atopic dermatitis
likely remains positive. Practitioners would therefore likely benefit from knowing about the
above study, with appropriate clarifying language in regards to the study limitations.” The
DVRPA team recommended the following revised language for Section 7.2 of the label:
Immune responses to vaccination were assessed in a study in which subjects with atopic
dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab. After 12
weeks of dupilumab administration, subjects were vaccinated with a Tdap vaccine
(Adacel®) and a meningococcal polysaccharide vaccine (Menomune®), and antibody
responses to tetanus toxoid and serogroup C meningococcal polysaccharide were
assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal
polysaccharide vaccine were similar in dupilumabtreated and placebo-treated subjects.
Immune responses to the other active components of the Tdap and Menomune
(b) (4)
vaccines were not assessed.
8.7. Additional Safety Explorations
8.7.1. Human Carcinogenicity or Tumor Development
Malignancies reported in the 52-week controlled LTT study, 1224, were:

• Placebo: keratoacanthoma, squamous cell carcinoma (site unspecified), cervix
carcinoma (2 reports), mycosis fungoides, and penile squamous cell carcinoma
• Dupilumab 300 Q2W + TCS: squamous cell carcinoma of skin
• Dupilumab 300 QW + TCS: basal cell carcinoma, squamous cell carcinoma of the
tongue, squamous cell carcinoma (site unspecified)
The following information is from the discussion of carcinogenicity in the pharmacology/

toxicology review:
No carcinogenicity studies were conducted with dupilumab or homologous monoclonal

antibodies…in any species.

Clinical Review
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BLA 761055
The sponsor provided an updated/amended carcinogenicity risk assessment for

dupilumab… include(ed) a literature evaluation and weight of evidence analysis for the
potential role of the IL-4 and IL-13 pathways in tumor and anti-tumor immunity. This
evaluation together with an evaluation of data from tissue-cross reactivity studies and
repeat-dose toxicology studies in mice and cynomolgus monkeys, form the basis of this
assessment for dupilumab. A weight of evidence analysis of published literature
regarding the potential biological effects of IL-4Rα inhibition does not support a causal
mechanistic/target-related link between IL-4Rα inhibition and increased cancer risk.
…Overall, data from toxicology studies do not suggest carcinogenic potential for
dupilumab.
Labeling recommendations from the pharmacology/toxicology team for Section 13.1

(Carcinogenesis, Mutagenesis, Impairment of Fertility) are discussed in Section 4.4 of this
review.
8.7.2. Human Reproduction and Pregnancy
As of the cut-off date for the BLA (04/27/2016), the Applicant reported 32 pregnancies in the
pharmacovigilance database, which covers clinical studies of dupilumab across all indications.
The Applicant provided information (including outcomes) for 23 of these pregnancies:
• 7 resulted in the live births of 8 healthy children (one set of twins)
• 2 induced (elective) abortions
• 6 spontaneous abortions (possible confounding factors, per the Applicant, for 2
subjects: one subject had an elevated parathyroid hormone level, which, may increase
the risk of spontaneous abortion; the other subject had a history of congenital clotting
disorder and of infertility, both of which may increase the risk of spontaneous abortion)
• 5 pregnancies were ongoing with no known malformations
• 3 subjects were lost to follow-up.
There were reports of 17 female partner pregnancies of male patients in the pharmacovigilance
database:
• 5 healthy, live births of 5 children,
• 1 induced (elective) abortion
• 2 spontaneous abortions
• 8 ongoing pregnancies
• 1 has been lost to follow-up.
120-day Safety Update

An additional 9 new pregnancies in female subjects were reported in the safety update, with 3
of the pregnancies reported in subjects exposed to dupilumab. Outcomes were reported for 2
of those 3 pregnancies: 2 live births of 2 healthy children.

Clinical Review
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BLA 761055
A total of 14 new pregnancies were reported in female partners of male subjects. Outcomes
were reported as follows: 3 new healthy, live births (3 children) and 2 spontaneous abortions.
Labeling
Labeling recommendations from the Pregnancy and Lactation Labeling Rule (PLLR) Labeling
review by the Division of Pediatric and Maternal Health follow:
8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
(b) (4)
Risk Summary
There are no available data on DUPIXENT use in pregnant women to inform any drug
associated risk. Human IgG antibodies are known to cross the placental barrier;
therefore, DUPIXENT may be transmitted from the mother to the developing fetus. In
an enhanced pre- and post-natal developmental study, no adverse developmental
effects were observed in offspring born to pregnant monkeys after subcutaneous
administration of a homologous antibody against interleukin-4-receptor alpha (IL-
4Rα) during organogenesis through parturition at doses up to 10-times the maximum
recommended human dose (MRHD) [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss or
other adverse outcomes. In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and
15 to 20%, respectively.
Data
Animal Data
In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus
monkeys were administered weekly subcutaneous doses of homologous antibody
against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from
the beginning of organogenesis to parturition. No treatment-related adverse effects on
embryofetal toxicity or malformations, or on morphological, functional, or
immunological development were observed in the infants from birth through 6 months
of age.

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BLA 761055
8.2 Lactation
Risk Summary
There are no data on the presence of dupilumab in human milk, the effects on the
breastfed infant, or the effects on milk production. Human IgG is known to be
present in human milk. The effects of local gastrointestinal and limited systemic
exposure to dupilumab on the breastfed infant are unknown. The developmental
and health benefits of breastfeeding should be considered along with the mother’s
clinical need for DUPIXENT and any potential adverse effects on the breastfed
child from DUPIXENT or from the underlying maternal condition.
(b) (4)
8.7.3. Pediatrics and Assessment of Effects on Growth
At the pre-IND meeting, the FDA advised the Applicant that data from adults would be needed
to support pediatric study. The Applicant has an Agreed initial pediatric study plan (iPSP), with
the letter of agreement dated 11/10, 2015. The Agreed iPSP covers pediatric age cohorts down
to 6 months. Per the Agreed iPSP, the Applicant will conduct the following clinical studies in
children with AD:
1. A randomized, double-blind, placebo-controlled phase 3 study to investigate the efficacy
and safety of dupilumab in patients, 12 years to less than 18 years of age, with
moderate-to-severe Atopic Dermatitis
and safety of dupilumab in patients, 6 years to less than 12 years of age, with severe
Atopic Dermatitis
3. A two-part phase II/III study to evaluate the safety, pharmacokinetics (PK) and efficacy
of dupilumab in patients, 6 months to less than 6 years of age, with severe Atopic
Dermatitis
(b) (4)
4. An open-label extension study to assess the long-term safety and efficacy of dupilumab
in patients ≥6 months to <18 years of age with Atopic Dermatitis
The planned pediatric studies will be listed Pediatric Research Equity Act (PREA) postmarketing
requirements (PMRs).
Clinical Review
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Per the Agreed iPSP, study of subjects younger than 6 months has been waived because studies
in these patients would be impossible or highly impractical to conduct for the following reason:
Since dupilumab is being developed for the treatment of moderate to severe atopic
dermatitis (e.g., IGA ≥3) in pediatric patients who are not adequately controlled with, or
who are intolerant to topical (TCS) medications, it will be impractical to make this
determination in patients younger than 6 months of age.
The Applicant submitted Amendment 1 of the iPSP on 09/16/2016, which mainly revised the
timeline (some of the dates in the Agreed iPSP fell before submission of the BLA).
Based on agreement with the EMA Pediatric Committee (PDCO), the Applicant has conducted
(b) (4)
8.7.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound
Draft language for the Overdose section of the label is presented below:
There is no specific treatment for DUPIXENT overdose. In the event of overdosage,

monitor the patient for any signs or symptoms of adverse reactions and institute
appropriate symptomatic treatment immediately.
The Applicant reviewed the potential impact of withdrawal of dupilumab on TEAEs related to
allergic conditions by evaluating TEAEs that occurred during the follow-up period. The Applicant
found no indications that withdrawal of dupilumab was associated with more TEAEs suggesting
worsening allergic conditions.
The Applicant evaluated rebound in the Phase 2b study, 1021 by examining the effects of
discontinuation of dupilumab on the EASI scores and pruritus and reported a trend of EASI
scores and pruritus towards baseline status in the post-treatment period.
The Applicant identified no pattern of TEAEs that suggested withdrawal or rebound.
8.8. Safety in the Postmarket Setting
8.8.1. Safety Concerns Identified Through Postmarket Experience
Dupilumab is not marketed in any jurisdiction.

Clinical Review
Brenda Carr, MD
BLA 761055
8.8.2. Expectations on Safety in the Postmarket Setting
The review identified no apparent potentially important differences in how the dupilumab was
administered and used in the clinical trial versus its expected use in the postmarket setting that
could lead to increased risk.
8.9. Additional Safety Issues From Other Disciplines
There are no additional safety issues.
8.10. Integrated Assessment of Safety
The Applicant comprehensively assessed the safety of dupilumab in the target population.
The safety database consisted of 2,526 subjects exposed to dupilumab in 11 studies in the
clinical development program. The numbers of subjects at relevant exposures exceeded those
recommended for the time points outlined in the ICH E1A guideline. The types and frequency of
the safety evaluations identified local and systemic TEAEs that might generally be expected
from SC injections (e.g., erythema) and might specifically be expected from SC injection of a
protein product (e.g., injection site reactions and hypersensitivity). Additionally, analyses
identified categories of events that, at least to this point, appear to be specific to the AD
population, i.e. these signals have not been identified in the dupilumab development programs
for asthma or nasal polyposis.
Eye Disorders
The Applicant identified a signal for eye disorders on analyses of the Phase 3 data. Overall,
events in this category were reported at higher incidences in both dupilumab treatment groups
compared to placebo. The imbalance was principally driven by reports of conjunctivitis,
specifically allergic conjunctivitis. Not unexpectedly, these TEAEs were primarily captured under
the Eye Disorders SOC. However, some events were coded to the Infections and infestations
SOC, and events coded under this SOC (e.g., “conjunctivitis bacterial”) lacked microbiological
confirmation. Keratitis events were perhaps the most noteworthy types of events reported
here because of the potential risk of impaired vision as an outcome. All keratitis events (e.g.
keratitis, allergic keratitis, ulcerative keratitis, etc.) that were reported in the Primary Safety
Pool and in the LTT study (1224) were reported only in the dupilumab groups. In the Supportive
Safety Pool, one keratitis event was reported in the placebo arm (compared to 10 in the
dupilumab group). Other events that showed a clear imbalance in occurrence in the dupilumab
groups compared to placebo included blepharitis, and dry eye. Overall, there was a suggestion
of a dose response in the occurrence of eye disorders in the Primary Safety Pool. However, this
trend was not noted in the LTT study. Most events were mild to moderate in severity, did not
lead to discontinuation of treatment, and resolved or were resolving during dupilumab
treatment.

Clinical Review
Brenda Carr, MD
BLA 761055
Other than to (reasonably) suggest a drug-disease interaction, the Applicant did not theorize as
to the basis for occurrence of eye disorders only in the AD population and not in other atopic or
atopic-related conditions for which dupilumab is being investigated. The Applicant has
undertaken comprehensive assessment of this signal, with particular focus on conjunctivitis and
select, related events. Post hoc analyses suggest some differences in baseline demographic and
disease characteristics. Additionally, those who developed eye disorders appeared to have
lower treatment responses on multiple endpoints compared to those who did not develop
these events. The Applicant has amended the protocol for the ongoing OLE study (1225) to
formally incorporate ophthalmological examination at specified time points at select centers for
certain subjects. The amended protocol also specifies recording of any post baseline,
inflammatory ophthalmological condition as an AE. “Conjunctivitis” is now a designated AESI.
These efforts will be helpful in further evaluating the signal and, along with routine
pharmacovigilance, may be helpful in further defining and identifying the nature of this risk.
Herpes Viral Infections
In the Primary Safety Pool, overall herpes viral infections occurred at higher incidences in the
dupilumab arms compared to placebo. However, this pattern was not noted in the placebo-
controlled, 52-Week, LTT study, where the overall incidence of herpes viral infections was
highest in the placebo group compared to both dupilumab groups. However, the safety
analyses revealed an increased incidence of certain types of herpes virus infections in
dupilumab-treated subjects compared to subjects treated with placebo. Across the safety
database, the PT “Oral herpes” was reported at higher incidences in dupilumab treatment arms
compared to placebo. Similarly, “Herpes simplex” was more commonly reported in dupilumab
treatment groups versus placebo. Patients with AD may generally be at increased risk for HSV
infections because of the compromised skin barrier.9 The Applicant did not theorize regarding
the possible reasons for the increased incidence of these HSV infections in dupilimab-treated
subjects relative to those who received placebo. Of note, the Applicant has not detected a
signal for herpes virus infections in their other clinical development programs.
Although eczema herpeticum and herpes zoster occurred at low incidences in all treatment
groups, these events occurred at higher or similar incidences in the placebo group compared to
dupilumab groups. None of these events were considered serious. Subjects who developed
eczema herpeticum or herpes zoster while receiving dupilumab either had the study treatment
temporarily held until resolution of the infection or continued study treatment according to
schedule; all ultimately completed dupilumab treatment. The generalizability of this approach
(holding or continuing dupilumab) is unclear, as there were so few subjects who experienced
these events. However, this may be a management consideration for patients who develop
either of these events. Ophthalmic herpes viral infections (PTs included Herpes ophthalmic,
Ophthalmic herpes simplex, Ophthalmic herpes zoster), which can be associated with

Clinical Review
Brenda Carr, MD
BLA 761055
significant morbidity, occurred at low overall incidence (generally single reports) and at similar
incidences between the placebo and dupilumab groups.
Impact on Atopic Conditions
Dupilumab is being developed for treatment of asthma. Although efficacy has not been
established for asthma, it is possible that asthmatic AD patients who receive dupilumab for AD
might experience improvement in their asthma. Thus, the Applicant has raised the concern
that, under this scenario, asthmatic AD patients might scale back on their asthma medications,
because of improvement in the respiratory condition. This self-determined reduction in asthma
medications could potentially have life-threatening consequences on the withdrawal of
dupilumab. The Applicant’s concern appears to be specifically driven by the death of an
asthmatic subject in an AD trial, 84 days following her last dupilumab dose. In my opinion, the
available information for the particular subject was too limited to determine if the exacerbation
of asthma that followed the withdrawal of dupilumab and eventuated in her demise, was a
direct function of the withdrawal of dupilumab. No information was provided regarding
whether she had indeed scaled back her asthma medication while receiving dupilumab. The
overall safety database provided for no evidence suggesting worsening of co-morbid allergic
events on discontinuation of dupilumab. However, I agree that this is a reasonable theoretical
concern and may be acceptable for communication in the label as a theoretical risk.
Safety Profiles of Q2W versus QW Dosing
Although there was a suggestion of a dose-response in the occurrence of some TEAEs, such
patterns were not sufficiently consistent across databases for me to conclude that weekly
dosing was associated with more adverse events compared to every other week dosing.
Generally, I would consider the safety profiles between the Q2W and QW dosing regimens to
be similar. I would also consider the safety profile of dupilumab when administered as
monotherapy to be similar to when it was administered with concomitant TCS.
9 Advisory Committee Meeting and Other External Consultations
An Advisory Committee meeting was not held for dupilumab.
10 Labeling Recommendations
10.1. Prescribing Information

Clinical Review
Brenda Carr, MD
BLA 761055
Labeling is discussed in the body of this review. Labeling negotiations were ongoing.
10.2. Patient Labeling
The Applicant proposed a patient package insert (PPI). The Office of Prescription Drug
Promotion reviewed and provided comment on the applicant’s PPI, and final labeling will reflect
their input.
10.3. Non-Prescription Labeling
Not applicable.
11 Risk Evaluation and Mitigation Strategies (REMS)

No risk management strategies beyond product labeling and routine pharmacovigilance
strategies are recommended at this time.
12 Postmarketing Requirements and Commitments
Clinical postmarketing requirements and commitments will be discussed in this section.
The following studies are outlined in the Agreed iPSP. These studies will be required under the
Pediatric Research Equity Act (PREA) and will be deferred:

and safety of dupilumab in patients, 12 years to less than 18 years of age, with
moderate-to-severe Atopic Dermatitis
and safety of dupilumab in patients, 6 years to less than 12 years of age, with severe
Atopic Dermatitis
3. A two-part phase II/III study to evaluate the safety, pharmacokinetics (PK) and efficacy
of dupilumab in patients, 6 months to less than 6 years of age, with severe Atopic
Dermatitis
(b) (4)
4. An open-label extension study to assess the long-term safety and efficacy of dupilumab
in patients ≥6 months to <18 years of age with Atopic Dermatitis

Clinical Review
Brenda Carr, MD
BLA 761055
Pregnant and breastfeeding women, and women planning to become pregnant and breastfeed
during the study were excluded from participation in the studies. Therefore the following
evaluations will be postmarketing requirements:
1. A prospective, registry-based observational exposure cohort study that compares the

maternal, fetal, and infant outcomes of women exposed to dupilumab during pregnancy
to an unexposed control population. The registry will detect and record major and
minor congenital malformations, spontaneous abortions, stillbirths, elective
terminations, small for gestational age births, and any other adverse pregnancy
outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes,
including effects on postnatal growth and development, will be assessed through at
least the first year of life.
2. Conduct a retrospective cohort study using administrative databases to identify

pregnancy outcomes in a cohort of women exposed to dupilumab and a non-dupilumab
systemic medication exposure cohort. The outcomes will include major congenital
malformations, spontaneous abortions, stillbirths, and small for gestational age births.
This study may use multiple data sources in order to obtain a sufficient sample size as
women with atopic dermatitis are counseled to avoid systemic treatments.
13 Appendices
13.1. References
See footnotes.
13.2. Financial Disclosure

Clinical Review
Brenda Carr, MD
BLA 761055
from Applicant)
Attachment A: Narratives of Serious Adverse Events from Primary Safety Pool
1334/SOLO 1

Clinical Review
Brenda Carr, MD
BLA 761055
Dupilumab 300 mg Q2W

1. 276006010: Limb operation
A 49 y/ white male (Germany) experienced a “pre-planned hospitalization because of former
leg operation” on Day 79. He “was hospitalized for removal of metal pedals in his leg, which had
been placed 3 years prior due to fracture.” No complications were reported. He recovered.
Comment: I assess this event as being not related to dupilumab.
2. 276014007: Abscess sweat gland

A 33 y/o white male (Germany) was hospitalized on Day 10 for “excision” of the abscess. The
event was reported four days after last dose of dupilumab (two doses; cumulative dose
reported as: 600mg. The abscess was said to be due to the subject’s “perspiring strongly in the
warm weather.” Additionally, he had shaved his “axilla.” He recovered fully and continued to
receive study treatment.
Comment: The event was reported four days after the subject had received only his loading
doses of study treatment. Based on the extent of exposure to IP relative to the day of the event,
I assess this event as being unrelated to dupilumab.
3. 276019008: lipoma
A 37 y/o white male (Germany) was hospitalized on Day 100 and underwent “thoracoscopy
with enucleation” of a tumor identified on an x-ray, which had been obtained for suspected
pneumonia (no “confirmed” infiltrates, no congestion reported on the x-ray). Pathology
revealed a “hemorrhagic lipoma with granulocytic demarcation.” (He received prophylactic
antibiotic treatment for a suspected pneumonia.) He recovered.
Comment: I assess this event as being unrelated to dupilumab.
4. 392021002: atopic dermatitis

A 43 y/o Asian male (Japan) was hospitalized on Day 7 for treatment of severe “aggravation of
atopic dermatitis.” On Day 2, he was reported to have developed erythema which had “spread
over the entire body.” Treatment included a variety of topical corticosteroids. He was
discharged after four days, with the event reported as being “ongoing.” Dupilumab was
resumed on Day 22, and the subject received all remaining doses.
Comment: The onset of this event was reported as being one day after the subject received his
loading doses. The history suggests that he may have been experiencing an impending flare of
AD at the outset of study treatment. Further, he went on to receive all doses of dupilumab.
Therefore, I assess this event as being unrelated to dupilumab.

Clinical Review
Brenda Carr, MD
BLA 761055
5. 724002001: atopic dermatitis

A 20 y/o white male (Spain) was hospitalized on Day 22 (three doses of dupilumab; last dose on
Day 15) for treatment of severe exacerbation of atopic dermatitis, described as “very
symptomatic atopic erythroderma with incoercible (sic) pruritus.” Treatment included
intravenous corticosteroids (for one week) and antibiotics. A skin biopsy and Sezary cell count
were performed during the hospitalization; results were pending at “last report.” He was
discharged on Day 27, and treatment included continuation of prednisone. Study treatment
was permanently discontinued.
Comment: I assess this event as being unlikely related to dupilumab. The subject’s disease
exacerbation may have been underway
6. 840004004: Clavicle fracture; Laceration

A 79 y/o white male (US) sustained the above injuries after being struck by a car On Day 1. He
was walking on the sidewalk, and the vehicle backed out of a driveway, striking the subject.
Study treatment was permanently discontinued, as the subject withdrew consent.
7. 840033004: Acute myocardial infarction

A 46 y/o white male (US) with a history of coronary artery disease and hypertension and a BMI
of 30.0 kg/m2 experienced substernal chest pain on Day 56 and was admitted to the hospital for
the event of “acute myocardial infarction of severe intensity” on Day 57. At that time, he had
received a total of 8 doses of 300 mg dupilumab Q2W. The last dose prior to the event was on
Day 50.The MI “appeared to be (sic) a ruptured plaque without significant obstruction of the
right coronary artery.” He was discharged on Day 59. Study treatment was permanently
discontinued (Day 50 was last dose received). The subject’s father had a history of “heart attack
and coronary intervention.”
Comment: This subject had multiple risk factors for MI. It is unclear whether there is a
mechanistic basis for considering that dupilumab may have played some contributory role in the
timing of the event (i.e., dupilumab superimposed on the existing risk factors). Given the
temporal relationship to study treatment, I cannot exclude a role for dupilumab in the
occurrence of the event.
Dupilumab 300 mg QW
1. 276004003: Myocardial infarction
A 52 y/o hypertensive white female (Germany) experienced a myocardial infarction on Day 96
(BMI: 26.6 kg/m2). The most recent dose of IP before the event was Day 94. At that time, she
had received a total of 14 doses of 300 mg dupilumab. Her treatment was “conservative.” She

Clinical Review
Brenda Carr, MD
BLA 761055
was discharged in good condition on Day 101, and received the Week 14 dupilumab dose that
same day. She completed study treatment, receiving the Week 15 does on Day 108. The
myocardial infarction was considered resolved on Day 144.
Comment: I assess this event as being unlikely related to dupilumab. Although there is a
temporal relationship to study treatment, she did not experience a recurrence on rechallenge
and, in fact, received a dose on the day of hospital discharge. She ultimately completed planned
dosing of IP.
2. 840046006: Nephrolithiasis; Kidney infection

A 56 y/o white female (US) with a history of nephrolithiasis (since 2005) and had been
diagnosed with a kidney stone approximately six months prior to study entry. She was
hospitalized for the “nephrolithiasis” and “kidney infection” on Day 58. The most recent dose of
IP before the event was on Day 57. At that time, she had received a total of 9 doses. Findings
included multiple calculi in the left ureter with marked ipsilateral hydronephrosis. Treatment
included stent placement, and she was discharged on Day 61. She received antibiotics and
underwent laser fragmentation post-discharge (antiobiotcs were not mentioned as having been
given during the hospitalization). She continued receiving study treatment according to
schedule (through the end of treatment at Week 15).
1416/SOLO 2

1. 616021006: Radius fracture (distal)
This 36 y/o white male (Poland) fractured a radius in fall while skating. The event occurred on
Day 17. He completed study treatment.
2. 840016015: Subarachnoid haemorrhage; Fall

This 77 y/o white female (United States) tripped and fell, landing on her face. She sustained
several injuries from the fall, including the subarachnoid hemorrhage. Study treatment was not
changed due to the events.
3. 840026006: Dermatitis exfoliative

This 43 y/o white male (United States) experienced worsening of atopic dermatitis, with
erythroderma on Day 1. That day, he presented to the study site with “generalized

Clinical Review
Brenda Carr, MD
BLA 761055
erythroderma, severe pruritus, and difficulty with thermoregulation.” Dupilumab loading doses
were administered, then he was sent for hospitalization. The event occurred after a four-week
washout of methotrexate, prednisone, and topical corticosteroids. The subject received the first
dose of study treatment, then was sent for hospitalization. A skin biopsy was reported to show
“psoriasiform dermatitis most consistent with psoriasis.” Hospital treatment included wet
wraps, topical corticosteroids, and antihistamines. He was recovered and discharged on Day 4.
He continued in the study as planned.
Comment: I assess this event as being unrelated to dupilumab. He was erythrodermic at the
time of first exposure to IP dose. The disease exacerbation was underway prior to any exposure
to IP and may have been related to washout of previous mediation.
4. 840034005: Pyelonephritis
This 56 y/o white female (United States) was hospitalized for pyelonephritis on Day 183, 10
weeks after the final dose of study treatment. The most recent dose of IP before the event was
on Day 108. At that time, she had received all 16 doses of dupilumab. She apparently presented
to urgent care with fever (> 103◦ F) on Day 159, and findings on urinalysis were consistent with
a UTI. She was prescribed antibiotics. Her course until Day 179 was not described. However, the
adverse event of “Pyrexia” was reported on Day 179 to Day 182. Fever recurred and she was
admitted for treatment of pyelonephritis on Day 183. She was discharged on Day 185 and
considered to be recovered on Day 194.
Comment: The subject had been off of study drug for approximately 2 months. What is half
life? I assess this event as being unlikely related to dupilumab.
5. 840034008: Headache
This 54 y/o black female (US) with a history of migraines and hypertension was admitted for a
headache on Day 41. The most recent dose of IP before the event was on Day 37. At that time,
she had received 6 doses of dupilumab. She received oral treatment for the headache, and the
event resolved on Day 43, with discharge the same day. Study treatment was continued as
planned.
Comment: I assess this event as being unrelated to dupilumab. She did not experience
recurrence of headache with rechallenge and completed the treatment period.
6. 840050003: Death; Asthma Hypoxic-ischaemic; encephalopathy Respiratory failure
Comment: This subject was discussed in the body of the review; see Section xx.
Dupilumab 300 mg QW

Clinical Review
Brenda Carr, MD
BLA 761055
1. 250012019: Abdominal pain

This 24 y/o white male (France) was hospitalized on Day 71 for abdominal pain, reported as
being spasmodic and approximately 17 hours in duration. The most recent dose of IP before the
event was on Day 64. At that time, he had received 10 doses of dupilumab. He was monitored
in the Emergency Department overnight, had an eventful course and workup, with no
recurrence of the pain, and was discharged on Day 72. The pain was self-reported as being due
to “viral infection.” No action was taken with the investigational product (IP).
Comment: I assess this event as being unrelated to dupilumab. No recurrence of the pain was
reported on re-exposure to dupilumab.
2. 276003006: Atopic dermatitis

This 18 y/o white male (Germany) experienced on Day 87 a skin eruption on the right forehead.
He was also experiencing ipsilateral headache and pruritus and fatigue. The most recent dose of
IP before the event was on Day 85. At that time, he had received 13 doses of dupilumab. The
investigator suspected emerging herpes zoster infection. The rash became generalized on the
face and was ultimately considered to be to be eczema. Study treatment was temporarily
discontinued on Day 85 and resumed on Day 99. The facial eruption improved after IP was
discontinued, but did not recur with resumption of treatment.
Comment: I assess this event as being unrelated to dupilumab because the eruption was
localized to the face (i.e., not generalized) and did not recur with resumption of IP.
3. 410003001: cellulitis
This 24 y/o Asian male (Republic of Korea) was hospitalized on Day 85, apparently for suspected
meningitis and following multiple visits to the emergency room for fever, headache and
myalgia. The most recent dose of IP before the event was on Day 77. At that time, he had
received 12 doses of dupilumab. The history was somewhat vague and unclear. Apparently, an
incidental finding on admission was of erythema on a foot, which was clinically diagnosed as
cellulitis. The meningitis workup was apparently negative. The date of discharge was not
provided. The cellulitis was reported as resolved on Day 132. He continued IP as planned.
Comment: The vagueness of the history of illness challenges the assessment of causality. I
assess this event as being unlikely related to dupilumab. The subject experienced no recurrence
of this event with continuation of IP.
4. 616004002: Abortion spontaneous

This 35 y/o white female (Poland) experienced a spontaneous abortion on Day 56. Treatment
had been permanently discontinued on Day 50 (last of eight doses). The event occurred 35 days
after her last menstrual period. Pregnancy was detected by self-administered pregnancy test

Clinical Review
Brenda Carr, MD
BLA 761055
(study day not provided) and confirmed by a positive serum human chorionic gonadotropin (on
Day 64 after the event).
Comment: I cannot exclude a role for dupilumab in this event. However, loss of first trimester
pregnancy is common…unplanned as pregnancy/contraception issues in protocol…
5. 616012004: Hodgkin's disease

This 26 y/o white female (Poland) was diagnosed four days after the first and only doses of
study treatment (loading doses), which was then permanently discontinued.
6. 840009001: Acute myocardial infarction; Cardiac failure congestive; Colonic

pseudoobstruction
This 62 y/o white male (United States) former smoker with a history of MI, coronary artery
disease, dyslipidemia, and hypertension was reported to experience an MI and CHF on Day 105.
He had received 16 doses of 300 mg dupilumab once weekly, with the last dose prior to the
events being on Day 99. As “corrective treatment,” he underwent coronary artery bypass
grafting x 3. He experienced Ogilvie Syndrome on Day 113, which was treated by colonoscopy
decompression. All events were considered resolved on Day 117, the day of discharge. He
administered his Week 15 injection on Day 120.
Comment: This subject had multiple risk factors for MI, including a previous history of MI.
Although there is a temporal relationship of the event to IP, he received additional IP without
recurrence. I assess this event as being unlikely related to dupilumab.
7. 840038007: Completed suicide

This 31 y/o male with a history of depression and a family history of suicide (grandmother) He
died from an intentional overdose on Day 93. The most recent dose of IP before the event was
(b) (6)
on (Study Day 85). At that time, the patient had received a total of 13 doses of 300
mg dupilumab once weekly (qw).
Comment: This subject is discussed in the body of the review. See Section 8.4.2.
8. 840040014: Mental status changes p. 879

This 74 y/o white female (US) with a history of dementia was admitted on Day 161 (55 days
after the final dose of study drug) for altered mental status, noted at her nursing home
residence. She had received 16 doses of IP. The event was resolved at discharge on Day 163,
with etiology unreported.

Clinical Review
Brenda Carr, MD
BLA 761055
9. 840084002: Delirium; Erysipelas

This 72 y/o white female (United States) was admitted on Day 29 for delirium, with onset 3 days
prior to admission. The event was described as coinciding with increased use of systemic
antipruritic medications and sleep medications (for her AD). The symptoms resolved with
discontinuation of these four medications, and she was discharged on Day 31. On Day 78, she
was hospitalized for erysipelas. The most recent dose of IP before the event was on Day 71; at
that time, she had received a 11 doses of IP. She was treated with IV antibiotics. On Day 83, she
was considered to have recovered from erysipelas and discharged on that day. She received her
next dose of study treatment on Day 84 and completed study treatment.
Comment: I assess this event as being unrelated to dupilumab….mental status issues resolved
with withdrawal of certain meds…Erysipelas resolved and she continued study treatment…
1021-Phase 2b (relevant arms): Formatting of the narrative information was different for this
trial, relative to the presentation of information from the Phase 3 trials.
placebo
1. 000018001: Osteonecrosis
This 46 y/o Caucasian male was was found to have avascular necrosis of the left hip and was
hospitalized for elective total hip arthroplasty. Study dosing was maintained.
2. 000018002: Abortion induced

This 19 y/o Black female was found to have a positive pregnancy test on the last study visit and
went on to have an induced abortion.
3. 002105005: Developmental hip dysplasia

This 43 y/o Caucasian male was hospitalized for surgery related to his congenital hip dysplasia.
He received his last dose of study treatment on an unspecified date prior to the event.

This 49 y/o Caucasian male was received his first dose of study product on 18 Nov 2013. He
(b) (6)
presented with “suberythrodermia, severe pruritus, and excoriations” on and was
hospitalized (date not specified) for worsening of atopic dermatitis. Treatment included a
topical corticosteroid and calcineurin inhibitor and ultraviolet B light therapy. The event was
resolved on 19 Dec 2013. Study treatment was permanently withdrawn.

1. 000031005: Syncope
This 46 y/o Caucasian male received his first dose of study treatment on 01 Oct 2013 and the
(b) (6)
last dose prior to the event on 25 Nov 2013. He suffered a seizure on and fell,

Clinical Review
Brenda Carr, MD
BLA 761055
striking his head and injuring his elbows. He was admitted to the emergency room, where he
was reported to have been “in and out of consciousness.” He had no previous history of
seizures, but had a history of “falling” in the 3 preceding months. He was discharged on the
same day, with a discharge diagnosis of syncope. He continued IP as planned.

This 30 y/o Caucasian male received his first dose of study treatment on 16 Oct 2013 and the
(b) (6)
last dose prior to the event on 13 Nov 2013. He was hospitalized on due to a
severe exacerbation of atopic dermatitis: “confluent inflammatory erythematous lesions along
with numerous oozing erosions, partially covered with scabs and accompanying skin itching of
the trunk, neck, face, and upper and lower extremities.” Treatment included topical
corticosteroids, “anti-inflammatory,” and “greasing agents.” The flare was considered to be
(b) (6)
“resolved” on , and he was apparently discharged the same day. Study treatment
was permanently withdrawn.
Comment: In the list of narratives, the subject’s number is as above. However, there is no such
subject number among the actual narratives. The closest number isn 703-001, and this subject’s
history is presented above. A role for dupilumab cannot be excluded.
Dupilumab 300 mg QW
000017004: Viral infection
This 19 y/o Caucasian male received his first dose of study treatment on 26 Jul 2013 and the
last dose prior to the event on 09 Aug 2013. He developed a fever of 38.8°C of unknown
(b) (6)
etiology with “bandemia” (values not provided) on . He was hospitalized for
further investigation (date not specified). Workup (including blood culture, echocardiogram and
magnetic resonance imaging) was negative. Treatment included one dose of intravenously
administered antibiotics (infection prophylaxis) and pain medications. The fever and bandemia
(b) (6)
resolved, and he was discharged feeling “well” on , i.e. the following day, with a
final diagnosis of “viral infection.” Study dosing was maintained.
Comment: I do not strongly suspect a role for dupilumab here.

Clinical Review
Brenda Carr, MD
BLA 761055

---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
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/s/
----------------------------------------------------
BRENDA CARR
03/24/2017
SNEZANA TRAJKOVIC
03/24/2017

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CENTER FOR DRUG EVALUATION AND

Submit Date(s) July 28, 2016

Reviewer Name(s) Brenda Carr, MD

Established Name Dupilumab

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1 Executive Summary ...............................................................................................................14

3 Regulatory Background .........................................................................................................26

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on

5 Sources of Clinical Data and Review Strategy .......................................................................40

6 Review of Relevant Individual Trials Used to Support Efficacy .............................................47

6.1. R668-AD-1334 (1334); SOLO 1 .......................................................................................47

7 Integrated Review of Effectiveness.....................................................................................110

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8.3.1. Issues Regarding Data Integrity and Submission Quality......................................129

9 Advisory Committee Meeting and Other External Consultations .......................................209

10 Labeling Recommendations ................................................................................................209

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10.1. Prescribing Information............................................................................................209

11 Risk Evaluation and Mitigation Strategies (REMS) ..............................................................210

12 Postmarketing Requirements and Commitments...............................................................210

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Figure 1. Study Flow Diagram .......................................................................................................50

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IVRS interactive voice response system

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1.1. Product Introduction

Dupilumab is a recombinant human immunoglobulin-G4 (IgG4) monoclonal antibody (mAb) that

Dupilumab belongs to the pharmacological class of immunomodulators, interleukin inhibitors. It

1.2. Conclusions on the Substantial Evidence of Effectiveness

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1.3. Benefit-Risk Assessment

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Benefit-Risk Summary and Assessment

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Dimension Evidence and Uncertainties Conclusions and Reasons

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Dimension Evidence and Uncertainties Conclusions and Reasons

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Dimension Evidence and Uncertainties Conclusions and Reasons

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Dimension Evidence and Uncertainties Conclusions and Reasons

Dimension Evidence and Uncertainties Conclusions and Reasons

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Dimension Evidence and Uncertainties Conclusions and Reasons

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2.1. Analysis of Condition

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory cutaneous disorder, which is

AD is clinically diagnosed and relies principally on disease pattern (morphology and

Patients with AD are predisposed to colonization or infection by microbes, particularly

demographic factors: A US population–based study. J Allergy Clin Immunol 2013;132:1132-8.

Invest Dermatol (2017) 137, 26-30.

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Reference ID: 4075125

The pathogenesis involves a complex interplay of genetic, immunological and environmental

2.2. Analysis of Current Treatment Options

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