CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`761180Orig1s000
`
`INTEGRATED REVIEW
`
`
`

`

`Review Memorandum: Adbry (Tralokinumab)
`
`BLA 761180, SDN 41
`
`Clinical Reviewer:
`Clinical Team Leader:
`Project Manager:
`Drug Product:
`Indication:
`Memorandum Date:
`
`Executive Summary
`
`Resubmission (7/2/2021) (Cycle #2)
`Following FDA Complete Response (4/23/2021) to Cycle #1
`review of BLA 761180, SDN 1 initial submission on 4/27/2020
`Hamid Tabatabai, M.D.
`David Kettl, M.D.
`Strother Dixon, Senior Regulatory Health Project Manager
`Adbry (Tralokinumab) injection (SC), 150 mg/mL
`Treatment of moderate to severe Atopic Dermatitis (AD)
`December 22, 2021
`
`This application is a Complete Response resubmission of BLA 761180 for tralokinumab-ldrm
`for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients whose disease is
`not adequately controlled with topical prescription therapies or when those therapies are not
`advisable. BLA 761180 was initially submitted by LEO Pharma A/S under regulatory pathway
`351(a) of the Public Health Service Act on 4/27/2020 and received a Complete Response (CR)
`letter on 4/23/2021 from the Agency.
`
`Tralokinumab is a new molecular entity, first-in-class, fully human immunoglobulin G4 (IgG4)
`monoclonal antibody. It is an immunomodulator/interleukin (IL) Inhibitor that neutralizes the
`cytokine IL-13 by inhibiting its interactions with IL-13 receptors α1 and α2. Other than
`corticosteroids, tralokinumab is the second systemic product (after dupilumab) to be approved
`for the treatment of moderate-to-severe AD.
`
`The Phase 3 program included two 52-week placebo-controlled monotherapy trials (ECZTRA-1,
`ECZTRA-2) and a 32-week trial (ECZTRA-3) evaluating the safety and effectiveness of
`tralokinumab in combination with topical corticosteroids. the results of the three Phase 3 trials
`showed statistically significant improvement in the primary endpoints (proportion of subjects
`with an Investigator’s Global Assessment [IGA] score of 0 [clear] or 1 [almost clear] [IGA 0/1]
`at Week 16 and proportion of subjects with at least 75% reduction in Eczema Area and Severity
`Index (EASI) score from baseline [EASI-75] at Week 16).
`
`Following completion of the Integrated Review of Marketing Application (Cycle #1), the review
`team concluded that there was substantial evidence to support the effectiveness of tralokinumab
`and did not identify safety issues that might impact approval of the application. Agreement on
`draft labeling was achieved with the sponsor as no safety or efficacy issues were identified by the
`review team, and no nonclinical or clinical pharmacology issues were identified which would
`preclude approval of the application.
`
`However, the initial BLA 761180 submission received a Complete Response action as
`recommended by the Center for Devices and Radiological Health (CDRH) review team, because
`it did not contain sufficient information regarding the needle-safety performance of the device.
`
`Reference ID: 4909926
`
`

`

`Since the Complete Response action, the applicant resubmitted BLA 761180 on 7/2/2021,
`including the following deficiencies outlined in the CR letter of 4/23/2021:
`
` Final finished combination product needle safety performance (testing results for the
`accessorized pre-filled syringe (APFS) needle safety performance using final finished
`product after preconditioning over the proposed shelf-life of month to the appropriate
`confidence and reliability of 95%/99%.
` Data supporting the combination product’s shelf-life at BLA approval (the APFS
`compressive override force testing using
`month real-time aged samples, and APFS
`needle safety activation testing using 24-month real-time aged samples), sequentially
`preconditioned and tested to ensure 95% confidence /99% reliability to support a shelf-
`life of months at BLA approval. The applicant plans to extend the shelf-life of
`tralokinumab to 36 months following further similar needle safety performance testing,
`and accelerated aging to simulate 36 months of real-time storage.
`
`The CDRH review team (ICC review memorandum of 10/13/2021) recommended that the
`combination product was approvable and no outstanding unresolved information requests or CR
`deficiencies remained.
`
`Additionally, the Applicant included safety data update (data cut-off date of 3/31/2021) of their
`initial 120-day safety data update (data cut-off date of 4/30/2020) for the ISS-AD, which was
`consistent with the safety profile of tralokinumab from the safety review of the initial BLA
`submission and identified no new safety concerns.
`
`Pediatrics
`
`Clinical studies were conducted only in adults. Because tralokinumab is a new active ingredient,
`this BLA is required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication in pediatric patients, under the Pediatric Research Equity Act (PREA) (21
`U.S.C. 355c).
`
`On 6/28/2018, the Division agreed to the Agreed initial pediatric study plan (Agreed iPSP)
`submitted by the sponsor on 6/4/2018, which included the following:
` Partial waiver to conduct studies in pediatric patients less than 6 months of age (studies
`are impossible or highly impractical)
` Deferral of Phase 3 clinical trials in pediatric patients ages 6 months to < 18 years.
`
`On 2/18/2020, the Agency agreed with the sponsor’s submitted revised proposed timelines for
`the pediatric studies to harmonize with the PIP for EMA/PDCO.
`
`During the first review cycle of this BLA, the Pediatric Review Committee (PeRC) agreed to the
`pediatric study plan presented at the PeRC meeting on 10/27/2020.
`
`Postmarketing Requirements and Commitment (PMR/PMC)
`
`Reference ID: 4909926
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`The following 6 PMRs and 1 PMC were agreed to by the FDA and the Applicant, and will be
`issued with the following milestones:
`
`PMR - 1
`Trial LP0162-1334 (ECZTRA 6) Trial: Efficacy and safety (phase 3, randomized, DB, PC,
`parallel-group, monotherapy) trial in Adolescents (12 to <18 years of age) with moderate-to-
`severe atopic dermatitis (AD) who are candidates for systemic treatment.
`
`PMR – 1 Schedule Milestones:
`Final Protocol Submission: 06/15/2018
`Study/Trial Completion:
`03/30/2021
`Final Report Submission:
`03/30/2022
`
`PMR – 2
`Trial LP0162-1335: A PK and safety (randomized, single [observer] blinded, parallel-group,
`monotherapy) dose-ranging trial in pediatric subjects 2 to <12 years of age with moderate-to-
`severe atopic dermatitis (AD) who are candidates for systemic AD treatment (studied
`sequentially in 2 cohorts: 6 to <12 years and 2 to <6 years).
`
`PMR – 2 Schedule Milestones:
`Final Protocol Submission: 03/31/2022
`Study/Trial Completion:
`09/30/2025
`Final Report Submission:
`03/31/2026
`
`PMR – 3
`Trial LP0162-1336: An efficacy and safety (phase 3, randomized, double-blind, placebo-
`controlled, parallel-group) trial with tralokinumab and placebo in combination with topical
`corticosteroid [TCS] therapy in pediatric subjects 2 to <12 years of age with moderate-to-severe
`atopic dermatitis (AD) who are candidates for systemic AD treatment (studied simultaneously in
`2 cohorts: 6 to <12 years and 2 to <6 years).
`
`PMR – 3 Schedule Milestones:
`Draft Protocol Submission: 05/31/2023
`Final Protocol Submission: 09/30/2023
`Study/Trial Completion:
`03/31/2027
`Final Report Submission:
`09/30/2027
`
`PMR – 4
`Study LP0162-1381: An efficacy, safety, and pharmacokinetic (PK) (phase 2, single-arm, open-
`label, monotherapy) trial in infants and pediatric subjects (6 months to <2 years of age) with
`moderate-to-severe atopic dermatitis (AD) who are candidates for systemic AD treatment.
`
`PMR – 4 Schedule Milestones:
`Draft Protocol Submission: 02/28/2027
`Final Protocol Submission: 06/30/2027
`Study/Trial Completion:
`12/31/2028
`
`Reference ID: 4909926
`
`

`

`Final Report Submission:
`
`06/30/2029
`
`PMR – 5
`A prospective, pregnancy exposure registry based observational exposure cohort study that
`compares the maternal, fetal, and infant outcomes of women exposed to tralokinumab during
`pregnancy to an unexposed control population.
`
`PMR – 5 Schedule Milestones:
`Draft Protocol Submission: 06/01/2022
`Final Protocol Submission: 10/31/2022
`Study/Trial Completion:
`09/30/2034
`Interim/Other:
`Not applicable
`Final Report Submission:
`09/30/2035
`
`PMR – 6
`An additional pregnancy study that uses a different design from the Pregnancy Registry (for
`example a retrospective cohort study using claims or electronic medical record data with
`outcome validation or a case control study) to assess major congenital malformations,
`spontaneous abortions, stillbirths, and small for gestational age and preterm birth in women
`exposed to tralokinumab during pregnancy compared to an unexposed control population.
`
`PMR – 6 Schedule Milestones:
`Draft Protocol Submission: 06/01/2022
`Final Protocol Submission: 10/31/2022
`Study/Trial Completion:
`06/30/2030
`Interim/Other:
`06/30/2027
`Final Report Submission:
`12/30/2030
`
`PMC – 7
`The applicant commits to conduct a real-time shipping study of commercial product as a Post
`Marketing Commitment (PMC).
`
`PMC – 7 Schedule Milestones:
`Final Report Submission:
`07/2022
`
`Labeling:
`Draft labeling has been agreed to by the Applicant, and the final approved labeling will be
`attached to the action letter.
`
`Hamid Tabatabai, M.D.
`Clinical Reviewer
`Division of Dermatology and Dentistry (DDD)
`Office of Immunology and Inflammation (OII)
`OND/CDER
`
`Reference ID: 4909926
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`HAMID N TABATABAI
`12/22/2021 03:22:19 PM
`Clinical Review Memo. for Cycle #2 Approval
`
`DAVID L KETTL
`12/22/2021 03:24:37 PM
`
`Reference ID: 4909926
`
`

`

`BLA 761180
`tralokinumab injection, 150 mg/mL
`
`Integrated Review
`Table 1. Administrative Application Information
`Category
`Application Information
`Application type
`BLA
`Application number(s)
`761180
`Priority or standard
`Standard
`Submit date(s)
`4/27/2020
`Received date(s)
`4/27/2020
`PDUFA goal date
`4/27/2021
`Division/office
`Division of Dermatology and Dentistry (DDD)
`Review completion date
`4/19/2021
`Established/proper name
`tralokinumab
`(Proposed) proprietary name
`Pharmacologic class
`
`Code name
`Applicant
`Dosage form(s)/formulation(s)
`Dosing regimen
`
`Applicant proposed
`indication(s)/ population(s)
`
`IgG4 monoclonal antibody that neutralizes IL-13 cytokine by
`inhibiting interactions with IL-13 receptors α1 and α2
`Click or tap here to enter name.
`LEO Pharma A/S
`Injection
`An initial dose of 600 mg (four 150 mg injections), followed by
`300 mg (two 150 mg injections) administered every other week.
`At prescriber’s discretion, a dosage of 300 mg every 4 weeks may
`be considered for patients who achieve clear or almost clear skin
`after 16 weeks of treatment
`For the treatment of moderate-to-severe atopic dermatitis in adult
`patients whose disease is not adequately controlled with topical
`prescription therapies or when those therapies are not advisable.
`TRADENAME can be used with or without topical
`corticosteroids.
`Proposed SNOMED indication 24079001 |Atopic dermatitis (disorder)
`Regulatory action
`Complete response
`Approved dosage
`NA
`(if applicable)
`Approved indication(s)/
`population(s) (if applicable)
`Approved SNOMED term for
`indication (if applicable)
`
`NA
`
`NA
`
`
`
`
`
`
`Integrated Review Template, version 2.0 (04/23/2020)
`
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`Reference ID: 4784656
`
` 4)
`
`(b) (4)
`
`

`

`BLA 761180
`tralokinumab injection, 150 mg/mL
`
`Table of Contents
`Table of Tables ............................................................................................................ vi
`Table of Figures ........................................................................................................... xi
`Glossary ......................................................................................................................1
`I. Executive Summary ....................................................................................................3
`1. Summary of Regulatory Action .............................................................................3
`2. Benefit-Risk Assessment ........................................................................................5
`2.1. Benefit-Risk Framework .................................................................................5
`2.2. Conclusions Regarding Benefit-Risk ..............................................................8
`II. Interdisciplinary Assessment...................................................................................10
`3. Introduction ..........................................................................................................10
`3.1. Review Issue List ...........................................................................................10
`3.1.1. Key Review Issues Relevant to Evaluation of Benefit ...........................10
`3.1.1.1. Key Benefit Review Issue #1 ...........................................................10
`3.1.2. Key Review Issues Relevant to Evaluation of Risk ................................11
`3.1.2.1. Key Risk Review Issue #1 ................................................................11
`3.2. Approach to the Review ................................................................................11
`4. Patient Experience Data .......................................................................................15
`5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology ............16
`5.1. Clinical Pharmacology Executive Summary .................................................16
`5.1.1. Recommendations ...................................................................................18
`5.1.2. Postmarketing Requirement and Commitments .....................................18
`5.2. Summary of Clinical Pharmacology Assessment ..........................................18
`5.2.1. Pharmacology and Clinical Pharmacokinetics ........................................18
`5.2.2. Clinical Pharmacology Questions ...........................................................21
`6. Assessment of Effectiveness ................................................................................31
`6.1. Dose and Dose Responsiveness .....................................................................31
`6.2. Clinical Trials Intended to Demonstrate Efficacy .........................................31
`6.2.1. Trial Design .............................................................................................31
`6.2.2. Eligibility Criteria ...................................................................................34
`6.2.3. Endpoints ................................................................................................36
`6.2.4. Statistical Analysis Plan ..........................................................................37
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`BLA 761180
`tralokinumab injection, 150 mg/mL
`6.2.5. Results of Analyses .................................................................................41
`7. Risk and Risk Management ..................................................................................51
`7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ....................51
`7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-
`Specific Factors ..............................................................................................51
`7.3. Potential Safety Concerns Identified Through Postmarket Experience ........52
`7.4. FDA Approach to the Safety Review ............................................................52
`7.5. Adequacy of Clinical Safety Database ..........................................................53
`7.6. Safety Findings and Concerns Based on Review of Clinical Safety
`Database ..........................................................................................................55
`7.6.1. Safety Findings and Concerns, Trials ECZTRA-1, ECZTRA-2, and
`ECZTRA-3 ..................................................................................................55
`8. Therapeutic Individualization ..............................................................................96
`8.1. Intrinsic Factors .............................................................................................96
`8.2. Drug Interactions ...........................................................................................96
`8.3. Plans for Pediatric Drug Development ..........................................................97
`8.4. Pregnancy and Lactation................................................................................97
`8.4.1. Animal Data ............................................................................................97
`9. Product Quality ....................................................................................................98
`9.1. Device or Combination Product Considerations ...........................................99
`10. Human Subjects Protections/Clinical Site and Other Good Clinical Practice
`Inspections/Financial Disclosure ........................................................................99
`11. Advisory Committee Summary ........................................................................100
`III. Appendices ...........................................................................................................101
`12. Summary of Regulatory History ......................................................................101
`13. Pharmacology Toxicology: Additional Information and Assessment .............103
`13.1. Summary Review of Studies Submitted Under the Investigational New
`Drug ..............................................................................................................103
`13.1.1. Pharmacology (Primary and Secondary) ............................................104
`13.1.2. Safety Pharmacology ..........................................................................105
`13.1.3. Absorption, Distribution, Metabolism, Excretion/Pharmacokinetics .106
`13.1.4. Toxicology ..........................................................................................112
`13.1.4.1. General Toxicology ......................................................................112
`13.1.4.2. Genetic Toxicology ......................................................................115
`
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`BLA 761180
`tralokinumab injection, 150 mg/mL
`13.1.4.3. Reproductive Toxicology .............................................................116
`13.1.5. Excipients/Impurities ..........................................................................124
`13.1.6. Extractables/Leachables ......................................................................127
`13.1.7. Referenced NDAs, BLAs, Drug Master Files .....................................127
`13.2. Individual Reviews of Studies Submitted to the NDA ..............................127
`13.2.1. Pharmacology ......................................................................................127
`13.2.2. Extractables/Leachables ......................................................................128
`13.3. Labeling .....................................................................................................133
`13.3.1. Multiple of Human Exposure Calculations .........................................133
`14. Clinical Pharmacology: Additional Information and Assessment ...................137
`14.1. Individual Study Review ...........................................................................137
`14.1.1. Summary of Bioanalytical Method Validation and Performance of
`the Assays for Measuring Tralokinumab Serum Concentrations .............137
`14.1.2. Study CAT-354-0703 ..........................................................................141
`14.1.3. Study MI-CP224 .................................................................................143
`14.1.4. Study CAT-354-0602 ..........................................................................145
`14.1.5. Study MI-CP199 .................................................................................148
`14.1.6. Study CD-RI-CAT-354-1049 .............................................................149
`14.1.7. Study D2213C00001 ...........................................................................151
`14.1.8. Study ECZTRA-1 (LP0162-1325) ......................................................153
`14.1.9. Study ECZTRA-2 (LP0162-1326) ......................................................158
`14.1.10. Study ECZTRA-3 (LP0162-1339) ....................................................160
`14.1.11. Study ECZTRA-5 (LP0162-1341) ....................................................163
`14.1.12. Population Pharmacokinetic Analysis of Tralokinumab in Patients
`with Moderate-to-Severe Atopic Dermatitis .............................................165
`14.1.13. Exposure–Response Analysis of Tralokinumab in Moderate-to-
`Severe Atopic Dermatitis ..........................................................................173
`14.1.14. Summary of Biomarker Analysis for Pivotal Study LP0162-1325
`(ECZTRA-1) .............................................................................................178
`14.2. In Vivo Studies ..........................................................................................182
`15. Trial Design: Additional Information and Assessment ....................................183
`16. Efficacy: Additional Information and Assessment ..........................................185
`16.1. Different Approaches for Handling Missing Data .....................................187
`16.2. Additional Analyses—EASI-90 ................................................................193
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`BLA 761180
`tralokinumab injection, 150 mg/mL
`16.3. Efficacy Over Time During the Initial Treatment Period ..........................193
`16.4. Disposition During the Maintenance Treatment Period ............................197
`16.5. Efficacy Over Time During the Maintenance Treatment Period ...............198
`16.6. Findings in Special/Subgroup Populations ................................................203
`17. Clinical Safety: Additional Information and Assessment ................................212
`17.1. Death Narratives ........................................................................................213
`17.2. SAE Narratives: Initial Treatment Period—Tralokinumab Group ............215
`17.3. SAE Narratives: Maintenance Treatment Period, Tralokinumab Group ...222
`17.4. SAE Narratives: Open-Label Treatment Period, Tralokinumab
`Q2W+Optional TCS Group ..........................................................................225
`17.5. TEAEs by Subgroup-Initial Treatment Period, Monotherapy Trials
`ECZTRA-1 and ECZTRA-2 .........................................................................236
`18. Mechanism of Action/Drug Resistance: Additional Information and
`Assessment .......................................................................................................241
`19. Other Drug Development Considerations: Additional Information and
`Assessment .......................................................................................................241
`20. Data Integrity-Related Consults (Office of Scientific Investigations, Other
`Inspections) ......................................................................................................241
`21. Labeling Summary of Considerations and Key Additional Information .........242
`22. Postmarketing Requirements and Commitments .............................................243
`23. Financial Disclosure .........................................................................................244
`24. References ........................................................................................................245
`25. Review Team ....................................................................................................246
`
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`BLA 761180
`tralokinumab injection, 150 mg/mL
`
`Table of Tables
`Table 1. Administrative Application Information ............................................................... i
`Table 2. Benefit-Risk Framework........................................................................................5
`Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety
`Determinations1 for Tralokinumab ..............................................................................12
`Table 4. Patient Experience Data Submitted or Considered ..............................................15
`Table 5. Key Review Issues ...............................................................................................17
`Table 6. Summary of General Clinical Pharmacology and Pharmacokinetics ..................18
`Table 7. Proportion of Subjects who Maintained a Response at Week 52 by Weight
`Category in the Pivotal Phase 3 Studies (ECZTRA-1, ECZTRA-2, and
`ECZTRA-3) .................................................................................................................27
`Table 8. Investigator’s Global Assessment (IGA) Scale ...................................................35
`Table 9. Eczema Area and Severity Index (EASI) ............................................................35
`Table 10. Methods for Handling the Missing Data for the Primary and Binary
`Secondary Endpoints ...................................................................................................40
`Table 11. Subject Disposition to Week 16—ECZTRA-1, ECZTRA-2, and
`ECZTRA-3 (FAS1) ......................................................................................................42
`Table 12. Demographics—Trials ECZTRA-1, ECZTRA-2, and ECZTRA-3 (FAS1) ......43
`Table 13. Baseline Disease Characteristics—ECZTRA-1, ECZTRA-2, and
`ECZTRA-3 (FAS1) ......................................................................................................45
`Table 14. Rescue Medication During Initial Treatment Period—ECZTRA-1,
`ECZTRA-2, and ECZTRA-3 (FAS1) ...........................................................................46
`Table 15. Rescue Medication During Maintenance Period—ECZTRA-1 and
`ECZTRA-2 (MAS1) .....................................................................................................46
`Table 16. Rescue Medication During Continuation Period—ECZTRA-3
`(Continuation Treatment Analysis Set1) ......................................................................46
`Table 17. Results for the Primary and Secondary Endpoints at Week 16—ECZTRA-1
`and ECZTRA-2 (FAS; Primary Analysis; Primary Estimand1) ..................................47
`Table 18. Results for the Primary and Secondary Endpoints at Week 16—ECZTRA-3
`(FAS; Primary Analysis; Primary Estimand1) .............................................................47
`Table 19. Proportion of Subjects who Maintained their Response at Week 52—
`ECZTRA-1 and ECZTRA-2 (Composite Estimand; MAS; NRI1) ..............................49
`Table 20. Proportion of Subjects Who Maintained a Response at Week 32—
`ECZTRA-3 (Composite Estimand; Continuation Treatment Analysis Set; NRI1) ......50
`Table 21. Duration of Exposure, Safety Population, Initial Treatment Period (Weeks 0
`to 16)—ECZTRA-1, ECZTRA-2, and ECZTRA-3 .....................................................54
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`BLA 761180
`tralokinumab injection, 150 mg/mL
`Table 22. Duration of Exposure, Safety Population, Maintenance Period—
`ECZTRA-1, ECZTRA-2 (Weeks 16 to 52), and ECZTRA-3 (Weeks 16 to 32) .........54
`Table 23. Duration of Exposure, Safety Population—ECZTRA-1 and ECZTRA-2
`(Open-Label Period (Weeks 16 to 52) .........................................................................55
`Table 24. Overview of Adverse Events, Safety Population, Trials ECZTRA-1 and
`ECZTRA-2, and ECZTRA-3 (Initial Treatment Period) .............................................56
`Table 25. Overview of Adverse Events, Safety Population, Trials ECZTRA-1,
`ECZTRA-2, and ECZTRA-3 (Maintenance Period) ...................................................56
`Table 26. Overview of Adverse Events, Safety Population, Trials ECZTRA-1 and
`ECZTRA-2 (Open-Label Period) ................................................................................57
`Table 27. Serious Adverse Events, Safety Population, ECZTRA-1+2, ECZTRA-3
`(Initial Treatment Period) ............................................................................................58
`Table 28. SAEs, Safety Population, Trials ECZTRA-1, ECZTRA-2, and ECZTRA-3
`(Maintenance Treatment Period) .................................................................................60
`Table 29. Adverse Events Leading to Discontinuation (in at Least One Subject),
`Safety Population, Trials ECZTRA-1, ECZTRA-2, and ECZTRA-3 (Initial
`Treatment Period) ........................................................................................................61
`Table 30. Adverse Events Leading to Discontinuation (in at Least One Subject) by
`FDA Medical Query (Narrow), Safety Population, ECZTRA-1, -2, and -3 (Initial
`Treatment Period) ........................................................................................................62
`Table 31. AEs Leading to Discontinuation, Safety Population, Trials ECZTRA-1,
`ECZTRA-2, and ECZTRA-3 (Maintenance Treatment Period) ..................................63
`Table 32. Grouped Queries by Preferred Term, Safety Population, ECZTRA-1,
`ECZTRA-2, and ECZTRA-3 (Initial Treatment Period) .............................................65
`Table 33. Adverse Events Assessed by Investigator as Treatment-Related, Safety
`Population, ECZTRA-1, ECZTRA-2, and ECZTRA-3 (Maintenance/Continuation
`Treatment Period) ........................................................................................................67
`Table 34. Summary of Eye Disorders by SOC and PT, Initial Treatment Period, AD
`Pool, Adjusted Pooling, Safety Analysis Set ...............................................................69
`Table 35. Frequency of Skin Infections Requiring Systemic Treatment per 100 PYE
`or Incidence (%) ...........................................................................................................71
`Table 36. Frequency of Eczema Herpeticum per 100 PYE or Incidence (%) ...................71
`Table 37. Summary of Malignancies (SMQ) by SOC and PT, Entire Trial Period, AD
`Pool, Simple Pooling, Safety Analysis Set ..................................................................72
`Table 38. Summary of Treatment-Emergent Severe or Serious Infection, Initial
`Treatment Period and Follow-up, AD Pool, Safety Analysis Set ................................75
`Table 39. Summary of Serious Allergic Reactions by SOC and PT, Initial Treatment
`Period, AD Pool, Adjusted Pooling, Safety Analysis Set ............................................78
`
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`BLA 761180
`tralokinumab injection, 150 mg/mL
`Table 40. AEs within the SOC Psychiatric Disorders by PT, Initial Treatment Period,
`AD Pool, Adjusted Pooling, Safety Analysis Set ........................................................80
`Table 41. Summary of Cardiovascular Events of Interest, AD Pool (All Doses), Entire
`Trial Period ..................................................................................................................81
`Table 42. Summary of Rare Events by SOC and PT, Entire Trial Period, AD Pool
`(All Doses), Safety Analysis Set ..................................................................................82
`Table 43. Summary of Subjects With Potentially Clinically Significant Hematology
`Values, Initial Treatment Period, AD Pool (ECZTRA Trials Only), Safety
`Analysis Set .................................................................................