MEDICAL REVIEW(S) Clinical Review Brenda Carr, MD BLA 761055 Dupixent (Dupilumab)

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 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 2 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 “A Phase 3 Confirmatory Study Investigating the Efficacy and Safety of Dupilumab 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

CDER Clinical Review Template 2015 Edition 3 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 4 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 5 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 Table 29. Proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 16*...... 81 Table 30. Proportion of Subjects with at least 4-point change from baseline Weeks 2, 4, 16 for Trials 1334* ...... 82 Table 31. IGA Responder by Baseline IGA Severity for Trial 1416* ...... 82

CDER Clinical Review Template 2015 Edition 6 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 Table 47. Proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 16*...... 108 Table 48. Proportion of Subjects with at least 4-point change from baseline Weeks 2, 4, 16 for 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

CDER Clinical Review Template 2015 Edition 7 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 8 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 during the 52-Week Treatment Period by AESI Category, High Level Term, and Preferred Term- Study 1224 – SAF* ...... 160 Table 85. 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 – 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 Table 87. 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 – SAF*...... 163 Table 88. 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* ...... 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 Table 96. Summary statistics for Hematology (White Blood Cells) values and changes from baseline by visit Eosinophils (Safety Analysis Set)* ...... 179

CDER Clinical Review Template 2015 Edition 9 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Table 97. Summary statistics for Hematology (Red Blood Cells and Platelets) values and changes from baseline by visit platelets*...... 181 Table 98. Summary statistics for Hematology (White Blood Cells) values and changes from 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 Table 111. Number of patients with treatment-emergent adverse events (TEAE) during the 52- week period by primary system organ class, high level term and preferred term (Safety Analysis 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 Table 114. 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)*...... 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

CDER Clinical Review Template 2015 Edition 10 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 11 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 12 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 13 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

1

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

CDER Clinical Review Template 2015 Edition 14 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

3 studies.

1.3. Benefit-Risk Assessment

Appears this way on original

CDER Clinical Review Template 2015 Edition 15 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 16 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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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Dimension Evidence and Uncertainties Conclusions and Reasons 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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Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Dimension Evidence and Uncertainties Conclusions and Reasons

• 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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Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Dimension Evidence and Uncertainties Conclusions and Reasons 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 CDER Clinical Review Template 2015 Edition 20 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Dimension Evidence and Uncertainties Conclusions and Reasons 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

CDER Clinical Review Template 2015 Edition 21 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Dimension Evidence and Uncertainties Conclusions and Reasons participation in the studies. Therefore, evaluations of patients in these categories will be conducted as postmarketing requirements.

Appears this way on original

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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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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. CDER Clinical Review Template 2015 Edition 24 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 25 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

Dupilumab is an NME. (b) (4)

12 Package inserts for tacrolimus ointment and pimecrolimus cream. CDER Clinical Review Template 2015 Edition 26 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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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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 the QW arm and 42% in the Q2W arm). (b) (5)

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 CDER Clinical Review Template 2015 Edition 29 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 The manufacture of dupilumab drug substance (b) (4)

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) CDER Clinical Review Template 2015 Edition 30 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 The manufacturing process of drug product consists of (b) (4)

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 shield and an (b) (4) plunger stopper with (b) (4)

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 were identified during inspection of the Le Trait filling facility (b) (4) . The Sanofi Le Trait manufacturing CDER Clinical Review Template 2015 Edition 31 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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(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 CDER Clinical Review Template 2015 Edition 32 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 33 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 Dupilumab (b) (4) is a (b) (4) 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 potential of dupilumab. (b) (4)

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 300 mg injections), followed by 300 mg given every other week. (b) (4)

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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 CDER Clinical Review Template 2015 Edition 36 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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. CDER Clinical Review Template 2015 Edition 37 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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:

Dupilumab drug substance (DS) contains (b) (4) . 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 CDER Clinical Review Template 2015 Edition 38 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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Regeneron has the ultimate responsibility for the overall combination product in the United States, which include auditing and other oversight activities (b) (4)

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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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 CDER Clinical Review Template 2015 Edition 41 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 CDER Clinical Review Template 2015 Edition 42 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 CDER Clinical Review Template 2015 Edition 43 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 44 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 45 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

Appears this way on original

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5.2. Review Strategy

The efficacy review will focus on the 3 pivotal Phase 3 studies, which are intended to establish efficacy and support proposed labeling of use of dupilumab “with and without topical (b) (4) .” 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

“A Phase 3 Confirmatory Study Investigating the Efficacy and Safety of Dupilumab 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. CDER Clinical Review Template 2015 Edition 47 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 48 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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. CDER Clinical Review Template 2015 Edition 49 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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), CDER Clinical Review Template 2015 Edition 50 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 51 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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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Table 4. Table of Schedule of Events

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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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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. 6 To be collected before the injection of study drug. CDER Clinical Review Template 2015 Edition 55 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 • Proportion of patients with improvement (reduction) of weekly average of peak daily pruritus NRS ≥3 from baseline to week 16 • Percent change from baseline to week 16 in weekly average of peak daily pruritus NRS • Proportion of patients with improvement (reduction) of weekly average of peak daily pruritus NRS ≥4 from baseline to week 4 • Proportion of patients with improvement (reduction) of weekly average of peak daily pruritus NRS ≥4 from baseline to week 2

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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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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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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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:

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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, CDER Clinical Review Template 2015 Edition 60 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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, the Applicant disclosed financial interests for one clinical investigator: (b) (6) , who was a principal investigator at Site(b) (6) in(b) (6) . He received $33,678 for “consulting services and steering committee member from Regeneron from (b) (6) .” Dr. (b) (6) was also a principal investigator in the covered (b) (6) .

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 42 3 Lack of efficacy 41 2 Lost to follow-up 00 0

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Physician decision 00 1 Protocol violation 21 0 Withdrawal by subject 56 14 Death 00 0 Other 11 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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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 Randomized 223 224 224 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 CDER Clinical Review Template 2015 Edition 63 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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baseline disease characteristics is presented in Table 10.

Table 10. Baseline Disease Characteristics*

Trial 1334 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo Randomized 223 224 224 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 *Source: Table 9 of statistical review

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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*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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Table 12. Atopic/Allergic Disease History – SAF*

*Source: Table 10 of study report

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 Randomized 223 224 224 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 CDER Clinical Review Template 2015 Edition 66 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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

*Source: Table 11 of study report

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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*

Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo 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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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.

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Table 16. Proportion of subjects with EASI75 (≥75% improvement from baseline) at Week 16*

Trial 1334 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo FAS 223 224 224 EASI 75 117 (53%) 114 (51%) 33 (15%) *Source: Table 1 from statistical review

Both dupilumab dosing regimens were superior to placebo treatment at Week 16 for the 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 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo 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%) *Source: Statistical review Table 13

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. CDER Clinical Review Template 2015 Edition 71 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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

Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W

Randomized 223 224 224 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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6.2. R668-AD-1416 (1416); SOLO 2

“A Phase 3 Confirmatory Study Investigating the Efficacy and Safety of Dupilumab 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.

6.2.2. Study Results

Compliance with Good Clinical Practices

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.

Financial Disclosure

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 “steering committee member” from Regeneron from (b) (6) until (b) (6) . Dr. (b) (6) was also a principal investigator in the covered (b) (6)

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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Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Table 20. Initial Treatment Period Subject Disposition for Trials 1416*

Study 1416 Placebo Dupilumab Dupilumab 300 mg Q2W 300 mg QW Randomized 236 233 239 Discontinued 15 (6%) 10 (4%) 17 (7%) Reasons for discontinuation Adverse events 311 Lack of efficacy 002 Lost to follow-up 335 Physician decision 121 Protocol violation 211 Withdrawal by subject 626 Death 100 Other 010 Subjects who used at least one topical corticosteroids (TCS; dermatological preparations)(1) TCS 67 (28%) 24 (11%) 24 (10%) *Source: Table 6 of statistical review 1 Subjects who used topical corticosteroids within the initial treatment period were considered as nonresponders for the efficacy analyses.

Protocol Violations/Deviations

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.

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Table 21. Summary of Protocol Deviations – All Randomized Patients*

*Source: Table 5 of the study report

Table of Demographic Characteristics

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 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo Randomized 239 233 236 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%) CDER Clinical Review Template 2015 Edition 75 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Black 15 (6%) 13 (6%) 20 (9%) Asian 45 (19%) 44 (19%) 50 (21%) Other* 11 (5%) 11 (5%) 10 (4%) *Source: Table 8 of statistical review

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 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo Randomized 239 233 236 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 Weekly Average Peak Pruritus NRS score 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 *Source: Table 9 of statistical review

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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 CDER Clinical Review Template 2015 Edition 77 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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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Treatment Compliance, Concomitant Medications, and Rescue Medication Use

Treatment Compliance

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.

Table 26. Compliance with Background Moisturizer (Emollient)*

Trial 1416 Dupilumab 300 Dupilumab 300 Placebo mg QW mg Q2W Randomized 239 233 236 Compliance 76% 74% 71% *Source: Table 12 of statistical review

Concomitant Medications

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

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Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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*

Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo FAS+ 239 233 236 IGA 0 or 1 86 (36%) 83 (36%) 20 (9%) *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 4 presents the IGA successes over time.

Figure 4. Success on the IGA(1) for the initial treatment period for Trial 1416*

*Source: Figure 1 Statistical Review

Data Quality and Integrity - Reviewers' Assessment

The data quality was adequate.

Efficacy Results - Secondary and other relevant endpoints CDER Clinical Review Template 2015 Edition 80 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 28.

Table 28. Proportion of subjects with EASI75 (≥75% improvement from baseline) at Week 16*

Trial 1416 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo FAS 239 233 236 EASI 75 113(47%) 102 (44%) 28 (12%) *Source: Table 1 statistical review

Both dupilumab dosing regimens were superior to placebo treatment at Week 16 for the secondary endpoint, proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 16 (p<0.0001). See Table 29.

Table 29. Proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 16*

Trial 1416 Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo FAS 239 233 236 Pruritus FAS 228 225 221 (Baseline NRS≥4) Reduction of at least 4- point change from 87 (38%) 79 (35%) 21 (10%) baseline+ *Source: Table 1 statistical review +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. 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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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%) *Source: Table 13 statistical review

Dose/Dose Response

See Section 7.1.4

Durability of Response

The study was not designed to assess durability of response.

Persistence of Effect

The study was not designed to assess the persistence of treatment effect. See discussion in Section 6.1.2.

Additional Analyses Conducted on the Individual Trial

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

Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W

Randomized 239 233 236

53/127 (42%) 53/118 (45%) 17/121 (14%) Moderate=3 33/112 (29%) 30/115 (26%) 3/115 (3%) Severe=4 *Source: Table 26 statistical review

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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. CDER Clinical Review Template 2015 Edition 83 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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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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 CDER Clinical Review Template 2015 Edition 85 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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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*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. 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 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). 8 To be collected before the injection of study drug. 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 13 Includes: antigen-specific IgE (region-specific allergen panels).

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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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3 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 4 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 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. 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 Includes: antigen-specific IgE (region-specific allergen panels). 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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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. 3 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). 4 Select US sites only. If the photograph is not taken at the recommended visit, it should be taken at the next visit. 5 Includes: antigen-specific IgE (region-specific allergen panels). CDER Clinical Review Template 2015 Edition 91 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 • Proportion of patients with improvement (reduction) in weekly average of peak daily Pruritus NRS ≥3 from baseline to Week 16 • 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) • Proportion of patients with improvement (reduction) in weekly average of peak daily Pruritus NRS ≥3 from baseline to Week 52 • Proportion of patients with improvement (reduction) in weekly average of peak daily Pruritus NRS ≥4 from baseline to Week 52 • 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) CDER Clinical Review Template 2015 Edition 92 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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• 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 ≥3 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 24 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 CDER Clinical Review Template 2015 Edition 93 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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.

6.3.2. Study Results

Compliance with Good Clinical Practices

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).

Financial Disclosure

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.

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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 Randomized 319 106 315 Discontinued 17 (5%) 6 (6%) 25 (8%) Reasons for discontinuation Adverse Events 405 Lack of efficacy 003 Lost to follow-up 201 Physician Decision 423 Protocol violation 312 Withdrawal by subject 4311 Death 000 Other 000 Subjects with at least one rescue(1) medication Rescue 35 (11%) 10 (9%) 116 (37%) *Source: Table 7 from statistical review

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

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*Source: Table 5 of study report

Protocol Violations/Deviations

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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Table 37. Summary of Major Protocol Deviations – All Randomized Patients*

*Source: Table 7 study report

Table of Demographic Characteristics

Most subjects were white and male, and the mean age was approximately 38 years. Demographic and baseline characteristics were similar among the treatment groups.

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Table 38. Baseline Demographics for Trial 1224*

Trial 1224 Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W + + + TCS TCS TCS Randomized 319 106 315 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%) *Source: Table 9 from statistical review

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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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 300 mg QW 300 mg Q2W + + + TCS TCS TCS Randomized 319 106 315 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 Weekly Average Peak Pruritus NRS score 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 *Source: Table 10 of statistical review

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.

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Table 40. Medical History Findings (≥5% of Patients in Any Treatment Group) by Primary System Organ Class and Preferred Term– SAF*

*Source: study report

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Table 41. Atopic/Allergic Disease History – SAF*

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*Source: Table 12 study report

Treatment Compliance, Concomitant Medications, and Rescue Medication Use

Treatment Compliance

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.

Table 42. Compliance with Background Moisturizer (Emollient)*

Trial 1224 Dupilumab 300 Dupilumab 300 mg QW mg Q2W Placebo + TCS + TCS + TCS Randomized 319 106 315 Compliance 37% 37% 39% *Source: Table 12 of statistical review

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Concomitant Medications

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.

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Table 43. Rescue Medication Taken during the 16-Week Period – SAF*

*Source: Table 13 of study report

A generally similar pattern to use of rescue medications was noted during the 52-Week period.

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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 300 mg QW 300 mg Q2W + + + 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.

IGA assessments were performed Weeks 1, 2, 4, 6, 8, 12, and 16. Figure 6 presents the IGA successes over time.

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Figure 6. Success on the IGA(1) for the initial treatment period for Trial 1224*

*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

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 46.

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Table 46. Proportion of subjects with EASI75 (≥75% improvement from baseline) at Week 16*

Trial 1224 Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W + + + TCS TCS TCS FAS 319 106 315 EASI 75 204 (64%) 73 (69%) 73 (23%) *Source: Table 2 from the statistical review

Both dupilumab dosing regimens were superior to placebo treatment at Week 16 for the secondary endpoint, proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 16 (p<0.0001). See Table 47.

Table 47. Proportion of subjects with improvement (reduction) of weekly average of peak daily pruritus ≥4 from baseline to Week 16*

Trial 1224 Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W + + + TCS TCS TCS FAS 319 106 315 Pruritus FAS 295 102 299 (Baseline NRS≥4) Reduction of at least 4- point change from 150 (51%) 60 (59%) 59 (20%) baseline+ *Source: Table 2 of statistical review +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. 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.

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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 300 mg QW 300 mg Q2W 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%) *Source: Table 14 of statistical review +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

Durability of Response

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 300 mg QW 300 mg Q2W + + + 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.

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Persistence of Effect

The study was not designed to evaluate persistence of effect.

Additional Analyses Conducted on the Individual Trial

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 300 mg QW 300 mg Q2W Placebo + TCS+ + TCS + TCS

Randomized 319 106 315

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 CDER Clinical Review Template 2015 Edition 110 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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%) *Source: Statistical review Table 1 +Full analysis set

Table 52. Proportion of Subjects Achieving Treatment Success at Week 16 for Combination Study 1224*

Study 1224 Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W + 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%) *Source: Statistical review Table 2 +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. CDER Clinical Review Template 2015 Edition 111 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 Dupilumab Dupilumab Dupilumab Dupilumab Placebo Placebo 300 mg QW 300 mg Q2W 300 mg QW 300 mg Q2W 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) test stratified by baseline disease severity and region as the primary analysis method. *Source: Statistical review Table 1

Table 54. Proportion of Subjects Achieving Treatment Success at Week 16 for Study 1224*

Study 1224 Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W + TCS + TCS + TCS Pruritus FAS (Baseline NRS≥4) 295 102 299 Reduction of at least 4- point change from 150 (51%) 60 (59%) 59 (20%) 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) test stratified by baseline disease severity and region as the primary analysis method. *Source: Statistical review Table 2

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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*

Study 1334 Study 1416 Dupilumab Dupilumab Dupilumab Dupilumab Placebo Placebo 300 mg QW 300 mg Q2W 300 mg QW 300 mg Q2W 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%) *Source: Table 18 of statistical review

Table 56. Efficacy (IGA 0 or 1) by Baseline Demographics for Trial 1224*

Study 1224 Randomized 319 106 315 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%) CDER Clinical Review Template 2015 Edition 113 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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*Source: Table 19 of statistical review

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 frequency. (b) (4)

Table 57. IGA Responder by Baseline IGA Severity for Studie 1334 and 1416*

Study 1334 Study 1416 Dupilumab Dupilumab Dupilumab Dupilumab Placebo Placebo 300 mg QW 300 mg Q2W 300 mg QW 300 mg Q2W 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%) *Source: Statistical review Table 26

Table 58. Success on the IGA at Week 16 by Baseline IGA Severity for Study 1224*

Study 1224 Dupilumab Dupilumab Placebo 300 mg QW 300 mg Q2W + + + TCS TCS TCS Randomized 319 106 315 IGA 0/1 2 N/A N/A (0%)

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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.

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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.

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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 dosing. (b) (4)

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. CDER Clinical Review Template 2015 Edition 117 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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 CDER Clinical Review Template 2015 Edition 118 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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. CDER Clinical Review Template 2015 Edition 119 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 demonstrate additional treatment benefit than DUPIXENT 300 mg Q2W. (b) (4)

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. CDER Clinical Review Template 2015 Edition 120 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 intended to assess the long-term safety and efficacy (b) (4) of SC dupilumab, CDER Clinical Review Template 2015 Edition 121 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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. CDER Clinical Review Template 2015 Edition 123 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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*

*Source: Table 27 Summary of Clinical Safety 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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*Source: Table 23 study report

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 CDER Clinical Review Template 2015 Edition 128 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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 conclusion. The proposed labeling language (b) (4) 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 Q2W): A 64-year-old male received dupilumab 600 mg loading dose on (b) (6) , followed by dupilumab 300 mg Q2W. On (b) (6) (Day 188), 18 days after the last dose of the study drug, he experienced severe peripheral cancer of the upper lobe of the right lung with multiple brain metastases. On (b) (6) (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.

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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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*Source: Table 47 Summary of Clinical Safety 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 CDER Clinical Review Template 2015 Edition 139 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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

Primary Safety Pool (16-Week-Monotherapy)

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*

*Source: Table 49 Summary of Clinical Safety 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 CDER Clinical Review Template 2015 Edition 141 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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*

*Source: Table 50 Summary of Clinical Safety 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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*Source: Table 44 of study report

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.

Primary Safety Pool (16-Week-Monotherapy)

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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*Source: Table 43 Summary of Clinical Safety

Study 1224 (Dupilumab + TCS): 16-Week Data

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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*Source: Table 86 study report Study 1224 (Dupilumab + TCS): 52-Week Data

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.

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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*

*Source: Table 51 Summary of Clinical Safety

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*

*Source: Table 52 Summary of Clinical Safety

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*

*Source: Table 95 study report

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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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*Source: Table 97 study report

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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

*

*Source: Table 32 study report 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*

*Source: Table 53 Summary of Clinical Safety 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*

*Source: Table 97 study report

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.

Table 85. 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 – SAF*

*Source: Table 97 study report

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*

*Source: Table 55 Summary of Clinical Safety

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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Table 87. 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 – SAF*

*Source: Table 97 study report

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 placebo + TCS group.

Table 88. 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*

*Source: Table 97 study report

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. CDER Clinical Review Template 2015 Edition 165 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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*

*Source: Table 56 Summary of Clinical Safety

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 placebo + TCS group.

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.

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Table 90. Summary of Treatment-Emergent Adverse Events of Special Interest Suicidal Behavior by HLT and PT – 16-Week Treatment Period - Primary Safety Pool*

*Source: Table 57 Summary of Clinical Safety

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.”

Primary Safety Pool (16-Week-Monotherapy)

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.

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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.

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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*

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*Source: Table 39 Summary of Clinical Safety

Study 1224 (Dupilumab + TCS): 16-Week Data

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.

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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*

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*Source: Table 40 Summary of Clinical Safety

Study 1224 (Dupilumab + TCS): 52-Week Data

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.

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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*

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*Source: Table 41 Summary of Clinical Safety

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.

Primary Safety Pool (16-Week-Monotherapy) Red Blood Cells and Platelets

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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

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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.

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Table 95. Summary statistics for Hematology (White Blood Cells) values and changes from baseline by visit (Safety Analysis Set)*

Mean (SD) Mean (SD) Mean Change Mean (SD) Mean 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 **EOT= end of treatment +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

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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.

Table 96. Summary statistics for Hematology (White Blood Cells) values and changes from baseline by visit 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 **EOT= end of treatment +EOS= end of study

Figure 9. Mean Change (+/-SE) of Hematology (White Blood Cells) From Baseline (Safety Analysis Set)*

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*Source: Post-Text Table 9.1.1.1/2; Pool 2

Study 1224 (Dupilumab + TCS): 52-Week Data

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)].

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Table 97. 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 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 **EOT= end of treatment +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.

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Table 98. Summary statistics for Hematology (White Blood Cells) values and changes from baseline by visit (Safety Analysis Set)*

Mean (SD) Mean (SD) Mean Change Mean (SD) Mean 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 **EOT= end of treatment +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

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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 (Safety Analysis Set)*

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

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Study 1224 (Dupilumab + TCS): 52-Week Data

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 CDER Clinical Review Template 2015 Edition 185 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

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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

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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.

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Primary Safety Pool (16-Week-Monotherapy)

Table 101. Shift Table for Electrocardiogram (ECG) status by Visit(Safety Analysis Set)*

*Source: Post-text Table 10.1.2/2; Pool 2

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Study 1224 (Dupilumab + TCS): 52-Week Data

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.

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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% ADA+ Combined AD- (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)

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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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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*

*Source: Table 3 Summary of Clinical Safety

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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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“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*

*Source: Table 58 Summary of Clinical Safety

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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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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Table 107. Number of Patients with Broad Conjunctivitis CMQ by PT Primary Safety Pool- Treatment Period - SAF Dupilumab*

*Source: Table 61 Summary of Clinical Safety

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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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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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 High Level Term Placebo QW 300 mg Q2W 300 mg QW Combined 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.

Table 111. Number of patients with treatment-emergent adverse events (TEAE) during the 52-week period by primary system organ class, high level term and preferred term (Safety Analysis Set)*

Dupilumab High Level Term Placebo QW 300 mg Q2W 300 mg QW Combined Preferred Term + TCS + TCS + TCS + TCS (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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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 High Level Term Placebo QW 300 mg Q2W 300 mg QW Combined Preferred Term + TCS + TCS + TCS + TCS (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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Primary Safety Pool (16-Week-Monotherapy)

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 *Source: Post-Text Table 7.2.1.6/1; Pool 2

Study 1224 (Dupilumab + TCS): 16-Week Data

Table 114. 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 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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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 vaccinated with a Tdap vaccine ( (b) (4) Adacel®) and a meningococcal polysaccharide vaccine ( (b) (4) Menomune®) (b) (4) responses were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-

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treated and placebo-treated patients. (b) (4) .

(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 vaccines were not assessed. (b) (4)

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.

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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.

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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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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 2. A randomized, double-blind, placebo-controlled phase 3 study to investigate the efficacy 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

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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.

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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.

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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

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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

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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:

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 2. A randomized, double-blind, placebo-controlled phase 3 study to investigate the efficacy 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

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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

CDER Clinical Review Template 2015 Edition 211 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125

Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

from Applicant)

Appears this way on original

Attachment A: Narratives of Serious Adverse Events from Primary Safety Pool

1334/SOLO 1

CDER Clinical Review Template 2015 Edition 215 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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.

CDER Clinical Review Template 2015 Edition 216 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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.

Comment: I assess this event as being unrelated to dupilumab.

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

CDER Clinical Review Template 2015 Edition 217 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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).

Comment: I assess this event as being unrelated to dupilumab.

1416/SOLO 2

Dupilumab 300 mg Q2W 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.

Comment: I assess this event as being unrelated to dupilumab.

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

CDER Clinical Review Template 2015 Edition 218 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 219 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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

CDER Clinical Review Template 2015 Edition 220 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

(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.

Comment: I assess this event as being unrelated to dupilumab.

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 on (b) (6) (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.

CDER Clinical Review Template 2015 Edition 221 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Comment: I assess this event as being unrelated to dupilumab.

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.

4. 002017005: Atopic dermatitis This 49 y/o Caucasian male was received his first dose of study product on 18 Nov 2013. He presented with “suberythrodermia, severe pruritus, and excoriations” on (b) (6) 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.

Dupilumab 300 mg Q2W 1. 000031005: Syncope This 46 y/o Caucasian male received his first dose of study treatment on 01 Oct 2013 and the last dose prior to the event on 25 Nov 2013. He suffered a seizure on (b) (6) and fell,

CDER Clinical Review Template 2015 Edition 222 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

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.

Comment: I assess this event as being unrelated to dupilumab.

2. 007003001: Atopic dermatitis This 30 y/o Caucasian male received his first dose of study treatment on 16 Oct 2013 and the last dose prior to the event on 13 Nov 2013. He was hospitalized on (b) (6) 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 “resolved” on (b) (6) , 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 etiology with “bandemia” (values not provided) on (b) (6) . 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 resolved, and he was discharged feeling “well” on (b) (6) , 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.

CDER Clinical Review Template 2015 Edition 223 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)

Reference ID: 4075125 Clinical Review Brenda Carr, MD BLA 761055 Dupixent (dupilumab)

Appears this way on original

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Reference ID: 4075125 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------BRENDA CARR 03/24/2017

SNEZANA TRAJKOVIC 03/24/2017

Reference ID: 4075125