# Safety of tralokinumab in patients with moderate-to-severe atopic dermatitis followed for up to 4.5 years: an integrated analysis of 8 clinical trials

Kristian Reich, Richard G. Langley, Juan Francisco Silvestre Salvador, Delphine Staumont-Sallé, Antonio Costanzo, Andrew E. Pink, Amy S. Paller, Norito Katoh, Andreas Wollenberg, Richard B. Warren, et al.

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## To cite this version:

Kristian Reich, Richard G. Langley, Juan Francisco Silvestre Salvador, Delphine Staumont-Sallé, Antonio Costanzo, et al. Safety of tralokinumab in patients with moderate-to-severe atopic dermatitis followed for up to 4.5 years: an integrated analysis of 8 clinical trials. British Journal of Dermatology, 2025, Br J Dermatol, pp.1-11. 10.1093/bjd/ljaf309. hal-05348273

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Distributed under a Creative Commons Attribution 4.0 International License
1 Safety of tralokinumab in patients with moderate-to-severe atopic dermatitis
2 followed for up to 4.5 years: an integrated analysis of 8 clinical trials
3 Running head: Integrated safety of up to 4.5 years tralokinumab in patients with AD

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5 Kristian Reich,¹ Richard G Langley,² Juan Francisco Silvestre Salvador,³ Delphine Staumont-Sallé,⁴ Antonio Costanzo,⁵ Andrew E Pink,⁶ Amy S Paller,⁷ Norito Katoh,⁸ Andreas
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7 Wollenberg,⁹,¹⁰,¹¹ Richard B Warren,¹²,¹³ Andrew Blauvelt,¹⁴ Christian Bjerregård Øland,¹⁵ Ann-Marie Tindberg,¹⁵ Le Gjerum¹⁵ and Eric L Simpson¹⁶

9 ¹Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg,
10 11 Germany
12 ¹²Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, Nova
13 Scotia, Canada
14 ¹³Dermatology Department, Hospital General Universitario Dr Balmis, ISABIAL, Alicante, Spain
15 ¹⁴Department of Dermatology, University Hospital of Lille, INFINITE (Institute for Translational Research) U1286 Inserm, University of Lille, Lille, France
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17 ¹⁵Dermatology Unit Department of Biomedical Sciences, Humanitas University, Milano, Italy;
18 Skin Pathology Laboratory, Humanitas Research Hospital IRCCS, Milano, Italy
19 ¹⁶St John's Institute of Dermatology, Guy's and St Thomas' Hospitals, London, UK
20 ¹⁷Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago,
21 IL, USA
22 ¹⁸Kyoto Prefectural University of Medicine Graduate School of Medical Science, Japan
23 ¹⁹Department of Dermatology and Allergy, University Hospital Augsburg, Augsburg, Germany
24 ¹⁰Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany
25 ¹¹Comprehensive Center for Inflammation Medicine, University of Luebeck, Luebeck, Germany
26 ¹²Dermatology Centre, Northern Care Alliance NHS Foundation Trust, Manchester, UK
27 ¹³NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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29 ¹⁴Blauvelt Consulting, LLC, Annapolis, MD, USA
30 ¹⁵LEO Pharma A/S, Ballerup, Denmark
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¹⁶Department of Dermatology, Oregon Health & Science University, Portland, OR, USA

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**Corresponding author:** Kristian Reich

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**Email:** k.reich@uke.de

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**ORCID:** 0000-0001-5248-4332

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**Acknowledgements:** The authors thank Jens-Kristian Slott Jensen for assistance with the statistical analyses. Medical writing and editorial support, under the direction of the authors, was provided by Krista Mills, PhD of Alphabet Health and was funded by LEO Pharma A/S, Ballerup, Denmark. This manuscript was developed in accordance with Good Publication Practice Guidelines (https://www.ismpp.org/gpp-2022). Authors had full control of the content and made the final decision on all aspects of this publication.

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**Funding sources:** This study was funded by LEO Pharma A/S and supported by the NIHR Manchester Biomedical Research Centre (NIHR203308).

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**Conflicts of interest:** Kristian Reich has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Forward Pharma, Gilead, Galderma, Janssen-Cilag, Kyowa Kirin, LEO Pharma, Lilly, Medac, Novartis, Ocean Pharma, Pfizer, Sanofi, UCB; Professor Reich is co-founder of Moonlake Immunotherapeutics. Richard G Langley has served and received compensation in the form of grants and/or honoraria as principal investigator for and is on the scientific advisory board or has served as a speaker for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, Novartis, Pfizer, UCB, and UNION. Juan Francisco Silvestre has served as an investigator and/or speaker and/or advisor for following pharmaceutical companies: AbbVie, Almirall-Hermal, Amgen, Astra Zeneca, Eli-Lilly, Galderma, LEO Pharma, Incyte, Novartis, Pfizer, Regeneron, and Sanofi-Genzyme. Delphine Staumont-Salle has been a speaker, consultant and/or investigator for AbbVie, Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi Genzyme, and UCB. Antonio Costanzo has received research grants or consulting fees from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, and UCB. Andrew Pink has acted as investigator, speaker or advisor or received research or educational funding from LEO Pharma, Novartis, UCB, AbbVie, Almirall, Amgen,
1 BMS, Boehringer Ingelheim, Janssen, La Roche-Posay, Lilly, Pfizer, Galderma, and Sanofi.
2 Amy S Paller has been an investigator for AbbVie, Applied Pharma Research, Dermavant, Eli
3 Lilly, Incyte, Janssen, Krystal, Regeneron, Timber, and UCB, a consultant for AbbVie, Abeona,
4 Apogee, Arcutis, Aslan, BioCryst, Boehringer-Ingelheim, Bristol-Myers-Squibb, Dermavant,
5 Incyte, Johnson and Johnson, Krystal Biotech, LEO Pharma, Mitsubishi Tanabe, Nektar,
6 Primus, Procter and Gamble, Regeneron, Sanofi, Seanergy, TWI Biotech, and UCB, and on the
7 Data Safety Monitoring Board for AbbVie, Abeona, and Galderma. Norito Katoh has received
8 honoraria as a speaker/consultant for Sanofi, Maruho, Abbvie, Ely-Lilly Japan, Taiho
9 Pharmaceutical, Jansen Pharma, Mitsubishi Tanabe Pharma, Abbvie, Kyowa Kirin, Celgene
10 Japan, LEO Pharma, and Otsuka Pharmaceutical, and has received grants as an investigator
11 from Sanofi, Maruho, Abbvie, Mitsubishi Tanabe Pharma, Ely-Lilly Japan, Kyowa Kirin, Sun
12 Pharma, Taiho Pharmaceutical, and LEO Pharma. Andreas Wollenberg has received grants,
13 personal fees, or nonfinancial support from AbbVie, Almirall, Aileens, Alentis, Beiersdorf,
14 Bioderma, Bioproject, BMS, Chugai, Galapagos, Galderma, GSK, Hans Karrer, Janssen, LEO
15 Pharma, Lilly, L'Oreal, Maruho, MedImmune, Merck, MSD, Novartis, Pfizer, Pierre Fabre,
16 Regeneron, Santen, Sanofi-Aventis, and UCB. Richard B Warren has received research grants
17 or consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim,
18 Bristol Myers Squibb, Celgene, DiCE, Eli Lilly, GSK, Janssen, LEO Pharma, Medac, Novartis,
19 Pfizer, Sanofi, Sun Pharma, UCB, and UNION. He is supported by the Manchester NIHR
20 Biomedical Research Centre. Andrew Blauvelt has served as a speaker (received honoraria)
21 for Eli Lilly and Company and UCB, has served as a scientific adviser (received honoraria) for
22 AbbVie, Almirall, Alumis, Amgen, Anaptysbio, Apogee, Arcutis, Boehringer Ingelheim, Bristol
23 Myers Squibb, Dermavant, Eli Lilly and Company, Galderma, GlaxoSmithKline, Incyte, IQVIA,
24 Janssen, LEO Pharma, Lipidio, Merck, Novartis, Oruka, Paragon, Pfizer, Regeneron, Sanofi,
25 Spherix Global Insights, Sun Pharma, Takeda, UCB Pharma, and Union, has acted as a clinical
26 study investigator (institution has received clinical study funds) for AbbVie, Acelyrin, Almirall,
27 Alumis, Amgen, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly and
28 Company, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron,
29 Sanofi, Sun Pharma, Takeda, and UCB Pharma, and owns stock in Lipidio and Oruka. Ann-
30 Marie Tindberg and Le Gjerum are employees and shareholders of LEO Pharma. Christian
31 Bjerregård Øland is a former employee of LEO Pharma. Eric Simpson reports grants and/or
32 personal fees from AbbVie, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly,
33 FortéBio, Galderma, Incyte, Kyowa Kirin, LEO Pharma, MedImmune, Menlo Therapeutics,
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Merck, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron,

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Sanofi, Tioga, and Valeant.

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**Data availability:** Data will be made available, upon request to the study sponsor, following
review by the external Patient and Scientific Review Board.

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**Ethics statement:** All trials were conducted in accordance with the ethical principles derived
from the Declaration of Helsinki and Good Clinical Practice guidelines and were approved by
the local institutional review board or ethics committee of each institution.

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**Patient consent:** All patients provided written informed consent.

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**What is already known about this topic?**

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* For patients with chronic, moderate-to-severe atopic dermatitis (AD) who require long-term systemic treatments to control their disease, drug safety is a top priority

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* Tralokinumab, a monoclonal antibody that specifically targets interleukin-13, is indicated for the treatment of patients ≥12 years of age with moderate-to-severe AD

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* A previous pooled analyses of phase II and III trials showed that tralokinumab was well-tolerated for up to 1 year of treatment

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**What does this study add?**

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* Here, a large integrated safety analysis of tralokinumab is reported, including 2693 patients ≥12 years of age with moderate-to-severe AD treated with tralokinumab in 7 placebo-controlled clinical trials and an open-label extension

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* No new safety signals were observed through 4.5 years of tralokinumab treatment, and the rates of adverse events (AEs) and AEs of special interest remained consistent or decreased with longer tralokinumab exposure

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* Long-term use of tralokinumab was well-tolerated

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1 Abstract

2 **Background:** Patients with moderate-to-severe atopic dermatitis (AD) require long-term
3 management, and understanding the long-term safety of new treatments is a top priority for
4 patients and healthcare professionals.

5 **Objectives:** To evaluate the safety of tralokinumab in adults and adolescents with moderate-to-
6 severe AD by conducting an integrated safety analysis of 7 placebo-controlled trials and the
7 ongoing, open-label extension study ECZTEND.

8 **Methods:** An initial 16-week placebo-controlled (PBO-CTRL) safety set and an all-tralokinumab
9 (ALL-TRALO) safety set combining the placebo-controlled trials and ECZTEND (data cut-off 30
10 April, 2022) were analyzed. All treatment-emergent adverse events (AEs) were recorded. AEs
11 of special interest (AESIs) were pre-defined. Safety areas of clinical interest for advanced
12 systemic AD treatments were captured retrospectively. Proportions of patients with events and
13 incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated. PYE was defined
14 as the time until the first event or exposure end, whichever came first, and incidence was
15 defined as the first event.

16 **Results:** Safety results were similar between the PBO-CTRL safety set and ALL-TRALO safety
17 set. In the latter, 2693 patients received tralokinumab for up to 238.5 weeks (≈4.5 years,
18 PYE=5320.2). Most AEs were nonserious, mild or moderate in severity, and occurred with
19 similar frequencies between tralokinumab and placebo in the PBO-CTRL safety set. The most
20 common AEs that occurred at higher rates for tralokinumab vs. placebo were nasopharyngitis
21 (IR ratio [IRR] comparing tralokinumab vs. placebo=1.26), conjunctivitis (IRR=3.11), and
22 injection site reaction (IRR=19.57). Dermatitis atopic and asthma occurred at lower rates with
23 tralokinumab vs. placebo (IRR=0.51 and 0.57, respectively). AESI eye disorders occurred at
24 higher rates with tralokinumab vs. placebo (IRR=2.43), and 98% were mild to moderate. AESIs
25 that were less frequent with tralokinumab vs. placebo included skin infections requiring systemic
26 treatment (IRR=0.43) and eczema herpeticum (IRR=0.32). Rates of AEs of clinical interest
27 (related to other approved systemic AD treatments) were low and similar between treatment
28 groups. IRs of AEs did not increase with longer exposure in the ALL-TRALO safety set.

29 **Conclusions:** Long-term use of tralokinumab in adults and adolescents with moderate-to-
30 severe AD was well-tolerated and consistent with the initial placebo-controlled treatment period,
31 with no new safety signals identified.
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**Clinical trial registration:** ECZTRA 1 (NCT03131648), ECZTRA 2 (NCT03160885), ECZTRA 3 (NCT03363854), ECZTRA 5 (NCT03562377), ECZTRA 6 (NCT03526861), ECZTRA 7 (NCT03761537), ECZTRA 8 (NCT04587453), and ECZTEND (NCT03587805; data cut-off 30 April, 2022).

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## Introduction

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Atopic dermatitis (AD) is a chronic skin disease characterized by dysregulated type 2 immune response, impaired skin-barrier function, itch, and skin microbial dysbiosis with increased *Staphylococcus aureus* colonization.¹ Interleukin (IL)-13 has been identified as a dominant cytokine in AD pathogenesis.²⁻⁴ Of note, improved understanding of AD immunopathogenesis has led to development of new systemic treatment options, such as biologics targeting type 2 cytokines (including IL-13) and small molecules targeting the Janus kinase (JAK) and signal transducer and activator of transcription pathways.⁵⁻⁷

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Tralokinumab is a fully human, high-affinity, monoclonal antibody that specifically targets IL-13 and is indicated for the treatment of patients ≥12 years of age with moderate-to-severe AD.⁸ In phase III clinical trials for up to 1 year, tralokinumab improved signs and symptoms of AD both as monotherapy and in combination with topical corticosteroids (TCS) in adults and adolescents.⁶,⁹⁻¹¹ Interim analyses of the ongoing long-term tralokinumab extension trial, ECZTEND, showed that clinical improvements were sustained for up to 4 years.¹²,¹³

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Studies assessing patient preferences for the most important attributes of systemic treatments show that safety is a top priority.¹⁴,¹⁵ Previous integrated safety analyses of phase II and III placebo-controlled clinical trials demonstrated similar frequency and severity of adverse events (AEs) between tralokinumab and placebo during the initial 16-week treatment period.¹⁶ Common AEs that occurred more frequently with tralokinumab vs. placebo were upper respiratory tract infection (mainly symptoms related to common cold), conjunctivitis, and injection-site reactions. As patients with moderate-to-severe AD often require long-term treatment, it is important to continuously monitor and assess the safety profile of systemic treatments with cumulative exposure over time. Here, updated integrated safety data of tralokinumab treatment from 8 clinical trials in AD are presented, including data from 2693 adolescent and adult patients treated for up to 4.5 years, representing 5320.2 patient-years of exposure (PYE).
# 1 Patients and methods

# 2 Studies

This integrated safety analysis of tralokinumab included 7 double-blinded, randomized, placebo-controlled clinical trials of up to 52 weeks duration (parent trials): the 2, 52-week phase III monotherapy studies ECZTRA 1 (NCT03131648) and ECZTRA 2 (NCT03160885), the 32-week phase III TCS-combination trial ECZTRA 3 (NCT03363854), the 16-week phase II vaccine response trial ECZTRA 5 (NCT03562377), the 52-week phase III monotherapy trial in adolescents ECZTRA 6 (NCT03526861), the 26-week phase III TCS combination trial in cyclosporin failures ECZTRA 7 (NCT03761537), the 16-week phase III TCS combination study in Japanese patients ECZTRA 8 (NCT04587453), and an ongoing up to 5-year open-label extension study ECZTEND (NCT03587805) with a data cut-off of 30 April, 2022 (Figure 1).

Individual trial designs and eligibility criteria have been previously described<sup>6,9-12,17-19</sup> and are summarized in Appendix S1 (see Supporting Information). All trials were conducted in accordance with the ethical principles derived from the Declaration of Helsinki and Good Clinical Practice guidelines and were approved by the local institutional review board or ethics committee of each institution. All patients, or their legal representatives, provided written informed consent.

# 18 Patients

The parent trials ECZTRA 1-3 and ECZTRA 5-8 enrolled adolescent (12-17 years of age) and adult patients (≥18 years of age) with moderate-to-severe AD for whom topical treatment was inadequate or inadvisable (Figure 1 and Appendix S1; see Supporting Information). Patients who completed the 7 parent trials were invited to enroll in ECZTEND.<sup>12</sup> All patients who received at least one dose of subcutaneous tralokinumab or placebo with or without TCS were included in the analyses.

# 25 Analysis sets

This analysis examined 2 pooled datasets. A placebo-controlled (PBO-CTRL) safety set assessed the profile of placebo vs. tralokinumab 300 mg (or 150 mg in 98 adolescent patients) every 2 weeks (Q2W) during the initial 16 weeks in the 7 parent trials ECZTRA 1-3 and ECZTRA 5-8. The PBO-CTRL safety set included both monotherapy and combination studies
1 with TCS. An all-tralokinumab (All-TRALO) safety set assessed the long-term safety profile of
2 tralokinumab and included data for all patients who received at least 1 dose of tralokinumab
3 (300 mg or 150 mg Q2W, or 300 mg or 150 mg every 4 weeks [Q4W]) while on active treatment
4 in any of the 7 placebo-controlled parent trials (ECZTRA 1-3 and ECZTRA 5-8) and the open-
5 label study ECZTEND (tralokinumab 300 mg Q2W) until data cut-off.

## Endpoints

7 All AEs, including serious adverse events (SAEs) and AEs leading to discontinuation of
8 study drug, were treatment-emergent and reported after the first dose of study drug.
9 Investigators recorded AEs during the treatment period, which were coded using the Medical
10 Dictionary for Regulatory Activities (MedDRA®) version 24.0. AEs of special interest (AESIs)
11 were predefined based on areas of safety and regulatory interest for biologics in AD: eye
12 disorders, skin infections requiring systemic treatment, eczema herpeticum, and malignancies
13 diagnosed after dosing (excluding basal cell carcinoma, localized squamous cell carcinoma of
14 the skin, and carcinoma in situ of the cervix). These AEs were captured using an electronic case
15 report form questionnaire.

16 For other safety areas of clinical interest, the cluster analyses grouped the preferred
17 terms (PTs) and terms associated with related clinical disease presentations retrospectively
18 using Standardized or Customized MedDRA® Queries based on: known adverse drug reactions
19 (ADRs) and precautions listed in the tralokinumab Summary of Product Characteristics/United
20 States Prescribing Information, AEs of interest for targeted immunomodulatory therapies in AD,
21 and inclusion of any system organ classes (SOC) or preferred terms (PTs) reported in the PBO-
22 CTRL safety set (using a flagging nominal P-value ≤0.05 between tralokinumab and placebo to
23 avoid potential reporting bias). The clusters are described in Table S1 (see Supporting
24 Information).

## Statistical analyses

26 Statistical analyses were based on pooled safety information from individual trials; no
27 sample size calculation was performed. Incidence was reported as the percentage of patients
28 with at least 1 event. Only AEs occurring while on active treatment were included, and PYE was
29 defined as the sum of the exposure while on active treatment. 'PYE at risk' was defined as PYE
30 or PYE up until an event (whichever came first). Periods of safety follow up were disregarded in
31 both safety sets. Marginal incidence rates (IRs) for AEs were calculated using Poisson
regression and g-computation<sup>20</sup> for both safety sets with incidence rate ratios (IRRs) estimated if at least one patient in both treatment groups experienced an event. The regression was adjusted for treatment (PBO-CTRL safety set only) and parent trial with an offset of log (PYE at risk), and used the HC3 robust covariance matrix ('sandwich' R package).<sup>21</sup> The delta method was used to calculate IRs (log-scale), IRRs (log-scale), and incidence rate differences (IRD).

Model assumptions were not checked. Adjustment for parent trials was performed to mitigate potential issues due to differing randomization ratios across parent trials (Simpson's paradox).

Further details on the methodology can be found in Appendix S2 (see Supporting Information).

Presentations are made using the safety analysis set, which comprised all dosed patients.

Estimates used in figures, additional analyses, and corresponding presentations as per the United States Prescribing Information population are provided in Tables S1-S11 and Figures S1-S5 (see Supporting Information).

# Results

## Patient disposition and baseline characteristics

A total of 2852 patients comprised the PBO-CTRL safety set (tralokinumab, n=1939; placebo, n=913), and 2693 patients comprised the ALL-TRALO safety set (Table 1). In the ALL-TRALO safety set, 30.6% (n=824) of patients had ≥3 years of tralokinumab exposure with a median and maximum treatment exposure of approximately 1.5 years and 4.5 years, respectively (Table S12; see Supporting Information). The frequencies of discontinuations due to treatment failure (AEs or lack of efficacy) were low (5.3% and 9.0%, respectively) (Figure S6; see Supporting Information). Baseline characteristics were similar between the tralokinumab and placebo-treated groups in the PBO-CTRL safety set, and with the ALL-TRALO safety set (Table 1). Additional information on atopy and skin disease history at baseline is included in Tables S13 and S14 (see Supporting Information).
# 1 Treatment-Emergent Adverse Events

During Weeks 0-16 in the PBO-CTRL safety set, the overall frequency of patients reporting ≥1 AE was similar between the placebo (68.1%) and tralokinumab (67.5%) groups, and most AEs were mild or moderate in severity (Figure 2). The frequency of SAEs in both groups was low, with lower IR for tralokinumab vs. placebo (IRR=0.60), and the frequencies of AEs leading to drug withdrawal were similar between the tralokinumab and placebo groups in the PBO-CTRL safety set (IRR=0.94) (Figure 2). Among the commonly reported AEs (≥2% in any treatment group of the PBO-CTRL safety set), those with higher IRs for tralokinumab vs. placebo were the PTs nasopharyngitis (IRR=1.26), conjunctivitis (IRR=3.11), and injection site reaction (IRR=19.57) (Figure 3). Common AEs with lower IRs for tralokinumab vs. placebo included the PTs dermatitis atopic (worsening of AD; IRR=0.51) and asthma (IRR=0.57).

The IRs of AEs, SAEs, and AEs leading to drug withdrawal did not increase with increased exposure time in the ALL-TRALO safety set vs. the PBO-CTRL safety set (Figure 2). In the ALL-TRALO safety set, the most common SOC of SAEs were infections and infestations (n=51; IR=0.94); injury, poisoning, and procedural complications (n=26; IR=0.48); and skin and subcutaneous tissue disorders (n=26; IR=0.47). Most SAEs were reported as single events without any clustering. SAEs reported in >0.1% of tralokinumab-treated patients at the PT level were dermatitis atopic (n=18; IR=0.33) and asthma (n=5; IR=0.09). In the ALL-TRALO safety set, the most common AEs leading to drug withdrawal included the PTs dermatitis atopic (n=29; IR=0.57), injection site reaction (n=13; IR=0.25), conjunctivitis (n=5; IR=0.09), eosinophilia (n=5; IR=0.08), conjunctivitis allergic (n=3; IR=0.06), and ulcerative keratitis (n=3; IR=0.05). Consistent results for treatment-emergent AEs (TEAEs) were found in the United States Prescribing Information population (Figures S1 and S2; see Supporting Information).

# 25 Overall summary of AESIs

AESI eye disorders—classified by the investigator as conjunctivitis, keratoconjunctivitis, or keratitis—occurred in more patients receiving tralokinumab than placebo (IRR=2.43) in the PBO-CTRL safety set (Figure 4). This difference between tralokinumab and placebo was largely driven by the higher IR for the AESI conjunctivitis category. AESIs with a lower IR for tralokinumab vs. placebo in the PBO-CTRL safety set included AESI skin infections requiring systemic treatment (IRR=0.43) and AESI eczema herpeticum (IRR=0.32). In the ALL-TRALO
safety set 98% of AESI eye disorder events were mild-to-moderate, and only 0.4% lead to permanent discontinuation of study drug. AESI malignancy was reported in 20 patients (0.7%; IR=0.35) in the ALL-TRALO safety set, with the PTs reported by more than one patient being prostate cancer (n=4; IR=0.07), invasive breast carcinoma (n=3; IR=0.05), invasive ductal breast carcinoma (n=2; IR=0.04), and breast cancer (n=2; IR=0.03) (Table S6; see Supporting Information). The rates of all AESIs except for malignancy did not increase over time with tralokinumab treatment in the ALL-TRALO safety set. Consistent results for AESIs were found in the United States Prescribing Information population (Figure S3; see Supporting Information).

## Safety areas of interest for targeted immunomodulatory therapies in AD

The known tralokinumab ADRs (other than the above-mentioned AESIs conjunctivitis and keratitis) of injection site reactions, upper respiratory tract infections, and eosinophilia were all reported at higher IRs for tralokinumab vs. placebo in the PBO-CTRL safety set (Figure 5). IRs for all ADRs did not increase over time in the ALL-TRALO safety set. While not an ADR, there is a special warning and precaution for use of tralokinumab in patients with helminth infections, as the influence of tralokinumab on the immune response against helminth infections is unclear;²² in this analysis there were no cases of helminth infections.

IRs for AEs of interest for targeted immunomodulatory therapies in AD, including serious infections, herpes viral infections, arthralgia, nausea, major adverse cardiovascular events, and malignancies were low and did not differ between tralokinumab and placebo (P≤0.05) for the PBO-CTRL safety set (Figure 6). Skin infections demonstrated a lower IR for tralokinumab vs. placebo, including the PTs dermatitis infected (IRR=0.29) and staphylococcal skin infection (IRR=0.12). IRs for the majority of the safety areas of interest for targeted immunomodulatory therapies in AD did not increase over time in the ALL-TRALO safety set. Consistent results for ADRs and safety areas of interest for targeted immunomodulatory therapies in AD were found in the United States Prescribing Information population (Figures S4 and S5; see Supporting Information).
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Discussion

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This analysis represents the largest integrated safety data set published for biologics indicated for the treatment of moderate-to-severe AD to date, including data from 2693 patients ≥12 years of age treated with tralokinumab for up to 4.5 years, with a total of 5320.2 PYE. This analysis expands upon and demonstrates a pattern of AEs generally consistent with previously reported results, with no new safety signals identified.¹⁶ Most AEs for tralokinumab were non-serious and mild or moderate in severity, and the IRs did not increase with increasing duration of treatment (i.e., entire period vs. initial 16-week period). The most commonly reported AE, both here and in previous studies, was related to symptoms of common cold, with specific differences between previous results and the present analysis related to differences between MedDRA® versions used (i.e., AEs related to symptoms of common cold were coded as PT viral upper respiratory tract infection in MedDRA® 20.0 used by Simpson et al. 2022¹⁶ and as PT nasopharyngitis in MedDRA® 24.0 used in the present analysis). The lower IRs for the PTs dermatitis atopic and dermatitis infected for tralokinumab vs. placebo (49% and 71% lower rate, respectively) further support the efficacy of tralokinumab. The most frequently reported AEs in the adolescent ECZTRA 6 study and among adolescents in ECZTEND were consistent with the present integrated data set, with overall lower rates in ECZTEND.¹⁰,²³

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Informal comparisons with safety analyses for other oral and biologic medications utilized to treat patients with moderate-to-severe AD suggest a favorable safety profile for tralokinumab. Ocular surface diseases, including various forms of conjunctivitis, are commonly present in patients with AD and have been reported to increase with baseline AD disease severity.²⁴⁻²⁶ In the present analysis, frequency of the AESI 'conjunctivitis' during the initial 16 weeks of treatment was 7.4% for tralokinumab Q2W and 3.1% for placebo, i.e., risk ratio of 2.4 (7.4/3.1) comparing tralokinumab to placebo. These results are consistent with a previous analysis of a smaller patient pool in 5 clinical trials characterizing the occurrence of conjunctivitis with up to 16 weeks of tralokinumab treatment,²⁶ and lower than reported for 16 weeks of dupilumab (9.7% for dupilumab Q2W vs. 2.2% for placebo; risk ratio ≈ 9.3/2.1 = 4.4),²⁵,²⁷ and lebrikizumab (8.5% for lebrikizumab vs. 2.5% for placebo; risk ratio ≈ 8.5/2.5 = 3.4 or 10.0/2.7 = 3.7).²⁸,²⁹

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The IRs related to safety areas of interest for targeted immunomodulatory therapies in AD were low. Arthralgia has been added as a listed ADR for dupilumab due to post-marketing
reports.³⁰ The IR for arthralgia in the present analysis was low and similar between tralokinumab and placebo (IRR=1.02) in the PBO-CTRL safety set and did not increase with additional exposure time. It has been suggested that arthralgia reported in the literature for dupilumab could be explained by the importance of IL-4 for balancing Th2 (IL-4/IL-13) vs. Th17 (IL-17/IL-23) polarization;³¹ it remains to be determined whether tralokinumab, which only targets IL-13, will be associated with this rare AE over time in post-marketing data.

In AD, the combination of skin barrier defects, immune dysregulation, and alteration in the skin microbiome results in an increased risk for viral and bacterial skin infections, including eczema herpeticum and S. aureus.³² Additionally, there is a potential increased risk of infections associated with immunomodulating systemics, such as herpes viral infection.¹⁶,²⁷,³³⁻³⁶ In the PBO-CTRL safety set of the present analysis, the rate of serious infections was 58% lower, AESI eczema herpeticum was 68% lower, and herpes zoster was 14% lower with tralokinumab vs. placebo. Similarly, local skin infections were reduced by 58%, mainly driven by an 88% reduction in staphylococcal skin infections. This is consistent with previous studies showing that biologics such as tralokinumab and dupilumab significantly reduce S. aureus abundance in patients with moderate-to-severe AD.²,³⁷⁻⁴⁰

An increased risk of malignancy has been reported in patients treated with immunomodulatory systemics, particularly JAK inhibitors.³³⁻³⁵ In the present analysis, malignancies (Standardized MedDRA® Query) were reported in 0.4% of both tralokinumab- and placebo-treated patients in the PBO-CTRL safety set, and the IR did not increase with additional exposure time in the ALL-TRALO safety set. Among the 20 AESI malignancies (IR=0.35) reported in the present analysis (diagnosed among 2693 patients over a total exposure time of 5320 PYE), the occurrence of 4 prostate cancer events and 7 events related to breast cancer was consistent with previous data. Both are common forms of cancer occurring with a rate of 0.2-0.3 events per 100 PYE in adult men and women with AD.⁴¹

A limitation of the study is that the short 16-week placebo-controlled period limits the assessment of AEs with tralokinumab vs. the underlying disease, especially for uncommon or rare events. When comparing the IRs between the PBO-CTRL and ALL-TRALO safety sets, it is important to consider that risk over time may not be constant and can change for reasons other than treatment exposure. For example, disease severity improves over time due to treatment effect, thus leading some AEs to become less frequent (e.g., eczema herpeticum). Additionally, selection and survival biases may have been possible, as patients with more AEs may not have
elected to, or been eligible for, participation in ECZTEND. Potential observational biases due to the lower visit frequency in ECZTEND compared with the parent trials may have resulted in patients not accurately remembering safety concerns, causing lower rates of AEs. These biases are likely smaller for the pre-defined AESIs, severe AEs, and SAEs due to the special focus and remembrance of these events as compared to, for example, headache and symptoms of common cold. Comparisons of AE frequencies from this study with the current literature are for context only.

In summary, this integrated safety analysis in adolescent and adult patients with moderate-to-severe AD is consistent with the previously published safety profile of tralokinumab and demonstrates that long-term use of tralokinumab for up to 4.5 years was well-tolerated with no new safety signals.

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## 13 References

14 1 Stander S. Atopic Dermatitis. *N Engl J Med* 2021;**384**:1136-1143.

15 2 Sander N, Stolzl D, Fonfara M *et al*. Blockade of IL-13 signaling improves skin barrier function and biology in patients with moderate to severe atopic dermatitis. *Br J Dermatol* 2024;**191**:344-350.

18 3 Simpson EL, Guttman-Yassky E, Eichenfield LF *et al*. Tralokinumab therapy for moderate-to-severe atopic dermatitis: Clinical outcomes with targeted IL-13 inhibition. *Allergy* 2023;**78**:2875-2891.

21 4 Tsoi LC, Rodriguez E, Degenhardt F *et al*. Atopic Dermatitis Is an IL-13-Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis. *J Invest Dermatol* 2019;**139**:1480-1489.

24 5 Davis DMR, Drucker AM, Alikhan A *et al*. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. *J Am Acad Dermatol* 2024;**90**:e43-e56.

27 6 Wollenberg A, Blauvelt A, Guttman-Yassky E *et al*. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). *Br J Dermatol* 2021;**184**:437-449.

31 7 Wollenberg A, Kinberger M, Arents B *et al*. European guideline (EuroGuiDerm) on atopic eczema: part I - systemic therapy. *J Eur Acad Dermatol Venereol* 2022;**36**:1409-1431.
1 8 Simpson EL, Blauvelt A, Silverberg JI et al. Tralokinumab Provides Clinically MeaningFUL Responses at Week 16 in Adults with Moderate-to-Severe Atopic Dermatitis Who Do NOT Achieve IGA 0/1. Am J Clin Dermatol 2024;25:139-148.

4 9 Gutermuth J, Pink AE, Worm M et al. Tralokinumab plus topical corticosteroids in adults with severe atopic dermatitis and inadequate response to or intolerance of ciclosporin A: a placebo-controlled, randomized, phase III clinical trial (ECZTRA 7). Br J Dermatol 2022;186:440-452.

8 10 Paller AS, Flohr C, Cork M et al. Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial. JAMA Dermatol 2023;159:596-605.

11 11 Silverberg JI, Toth D, Bieber T et al. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol 2021;184:450-463.

15 12 Blauvelt A, Langley RG, Lacour JP et al. Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial. J Am Acad Dermatol 2022;87:815-824.

18 13 Gooderham M et al. In submission. Br J Dermatol. 2024.

19 14 Feldman SR, Guerin A, Gauthier-Loiselle M et al. Patient preferences for treatment attributes in moderate-to-severe atopic dermatitis: a discrete choice experiment. J Dermatolog Treat 2024;35:2345739.

22 15 Schaarschmidt ML, Kromer D, Wellmann P et al. Patients' preferences for systemic treatment of atopic dermatitis: safety and efficacy count the most. J Dermatolog Treat 2024;35:2308682.

25 16 Simpson EL, Merola JF, Silverberg JI et al. Safety of tralokinumab in adult patients with moderate-to-severe atopic dermatitis: pooled analysis of five randomized, double-blind, placebo-controlled phase II and phase III trials. Br J Dermatol 2022;187:888-899.

28 17 Blauvelt A, Langley R, Peris K et al. 551 - Continuous tralokinumab treatment over 4 years in adults with moderate-to-severe atopic dermatitis provides long-term disease control. Br J Dermatol 2024;190:ii48-ii49.

31 18 Merola JF, Bagel J, Almgren P et al. Tralokinumab does not impact vaccine-induced immune responses: Results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis. J Am Acad Dermatol 2021;85:71-78.
19 Tralokinumab in Combination With Topical Corticosteroids in Japanese Subjects With
2 Moderate-to-severe Atopic Dermatitis (ECZTRA 8). ClinicalTrials.gov identifier:

3 NCT04587453. Sponsored by LEO Pharma A/S. Updated September 22, 2022.

20 Bartlett JW. Covariate adjustment and estimation of mean response in randomised trials.
5 *Pharm Stat* 2018;17:648-666.

21 Zeileis A, Köll S, Graham N. Various Versatile Variances: An Object-Oriented
7 Implementation of Clustered Covariances in R. *J Stat Softw* 2020;95:1-36.

22 Adtralza® (tralokinumab): EPAR - Product Information [EMA Summary of Product
9 Characteristics]. LEO Pharma A/S, Ballerup, DK, 2023.

23 Simpson E, Paller A, Wollenberg A et al. 43997 Long-term safety and efficacy of tralokinumab in adolescents with moderate to severe atopic dermatitis: an interim analysis of ECZTEND. *J Am Acad Dermatol* 2023;89:AB190.

24 Ravn NH, Ahmadzay ZF, Christensen TA et al. Bidirectional association between atopic
14 dermatitis, conjunctivitis, and other ocular surface diseases: A systematic review and
15 meta-analysis. *J Am Acad Dermatol* 2021;85:453-461.

25 Akinlade B, Guttman-Yassky E, de Bruin-Weller M et al. Conjunctivitis in dupilumab
17 clinical trials. *Br J Dermatol* 2019;181:459-473.

26 Wollenberg A, Beck LA, de Bruin Weller M et al. Conjunctivitis in adult patients with
19 moderate-to-severe atopic dermatitis: results from five tralokinumab clinical trials. *Br J
20 Dermatol* 2022;186:453-465.

27 Thaci D, E LS, Deleuran M et al. Efficacy and safety of dupilumab monotherapy in adults
22 with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized
23 trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2). *J Dermatol Sci* 2019;94:266-
24 275.

28 Stein Gold L, Thaci D, Katoh N et al. 52041 Safety of Lebrikizumab in Adults and
26 Adolescents With Moderate-to-Severe Atopic Dermatitis: Integrated Analysis From 10
27 Clinical Trials. *J Am Acad Dermatol* 2024;91:AB307.

29 Stein Gold L, Thaci D, Thyssen JP et al. Safety of Lebrikizumab in Adults and
29 Adolescents with Moderate-to-Severe Atopic Dermatitis: An Integrated Analysis of Eight
30 Clinical Trials. *Am J Clin Dermatol* 2023;24:595-607.

30 Dupixent® (dupilumab): EPAR - Product Information [EMA Summary of Product
32 Characteristics]. Sanofi and Regeneron Pharmaceuticals, Inc., Tarrytown, New York,
33 US, 2024.
1 31 Bridgewood C, Newton D, Bragazzi N et al. Unexpected connections of the IL-23/IL-17 and IL-4/IL-13 cytokine axes in inflammatory arthritis and enthesitis. *Semin Immunol* 2021;**58**:101520.

4 32 Wang V, Boguniewicz J, Boguniewicz M et al. The infectious complications of atopic dermatitis. *Ann Allergy Asthma Immunol* 2021;**126**:3-12.

6 33 Bieber T, Katoh N, Simpson EL et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 years and up to 3.9 years of treatment: an updated integrated analysis of eight clinical trials. *J Dermatol Treat* 2023;**34**:2161812.

9 34 Guttman-Yassky E, Jacob P. Thyssen, Silverberg JI et al. Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies. *JACI* 2023;**151**:172-181.

12 35 Simpson EL, Silverberg JI, Nosbaum A et al. Integrated Safety Update of Abrocitinib in 3802 Patients with Moderate-to-Severe Atopic Dermatitis: Data from More than 5200 Patient-Years with Up to 4 Years of Exposure. *Am J Clin Dermatol* 2024;**25**:639-654.

15 36 Manzar D, Nair N, Suntres E et al. Systematic review and network meta-analysis of the risk of Herpes zoster with biological therapies and selective Janus kinase-1 inhibitors in atopic dermatitis. *Postepy Dermatol Alergol* 2024;**41**:72-77.

18 37 Beck LA, Bieber T, Weidinger S et al. Tralokinumab treatment improves the skin microbiota by increasing the microbial diversity in adults with moderate-to-severe atopic dermatitis: Analysis of microbial diversity in ECZTRA 1, a randomized controlled trial. *J Am Acad Dermatol* 2023;**88**:816-823.

22 38 Guttman-Yassky E, Kabashima K, Staumont-Salle D et al. Targeting IL-13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years. *Allergy* 2024;**79**:1560-1572.

25 39 Olesen CM, Ingham AC, Thomsen SF et al. Changes in Skin and Nasal Microbiome and Staphylococcal Species Following Treatment of Atopic Dermatitis with Dupilumab. *Microorganisms* 2021;**9**:1487.

28 40 Simpson EL, De Benedetto A, Boguniewicz M et al. Phenotypic and Endotypic Determinants of Atopic Dermatitis Severity From the Atopic Dermatitis Research Network (ADRN) Registry. *J Allergy Clin Immunol Pract* 2023;**11**:2504-2515.

31 41 Mansfield KE, Schmidt SAJ, Darvalics B et al. Association Between Atopic Eczema and Cancer in England and Denmark. *JAMA Dermatol* 2020;**156**:1086-1097.
# Figure legends

**Figure 1** Integrated safety analysis study design. Patients with AD who had an Eczema Area and Severity Index (EASI) of ≥16, Investigator's Global Assessment (IGA) score of ≥3, ≥10% of the total body surface area affected, a history of chronic AD for ≥1 year, and for whom topical treatment was inadequate or inadvisable were eligible for enrollment into the parent trials.

Patients who completed the parent trials were invited to enroll in ECZTEND.

AD, atopic dermatitis; JP, Japan; n, number of included patients from the indicated trial; N, number of patients in indicated treatment set; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; TCS, topical corticosteroids; TRALO, tralokinumab.

**Figure 2** Overall summary of TEAEs. Details on represented data in the figures are provided in Tables S2 and S3 (see Supporting Information). <sup>a</sup>Study size-adjusted % and IR; <sup>b</sup>All Safety Sets Adj IR plot: X-axis transformed to a pseudo-log10 scale in two segments. Dotted line represents the breakpoint of the X-axis segments. Error bars represent 95% CI; <sup>c</sup>PBO-CTRL Safety Set IRR plot: IRR only calculated if at least one patient in both treatment groups experienced the event(s). X-axis transformed to a log10 scale. <sup>*</sup>P-value ≤0.05. Error bars represent 95% CI. <sup>d</sup>The reported death occurred after the patient discontinued treatment in the initial period of the vaccine study (ECZTRA 5) trial. The cause of death was noted as due to septic shock and respiratory failure, caused by suppurative pneumonia, as well as pulmonary embolism, caused by underlying emphysema with liver disease and malnutrition as contributing factors. These were assessed by the investigator as not related to study drug (tralokinumab and vaccines).<sup>18</sup>

%, percentage of patients; Adj, adjusted; AE, adverse event; CI, confidence interval; IR, Incidence rate (n/100PYE), for IR calculations, patient exposure was censored at the time of first event; IRR, incidence rate ratio; n, number of patients achieving the indicated metric, or with ≥1 event; N, number of patients with recorded observation; PBO-CTRL, placebo-controlled; PYE, patient-years of exposure; TEAE, treatment-emergent AE; TRALO, tralokinumab.

**Figure 3** Most frequently reported TEAEs (≥2% in any treatment group of the placebo-controlled safety set). Details on represented data in the figures are provided in Tables S4 and S5 (see Supporting Information). <sup>a</sup>Study size-adjusted % and IR; <sup>b</sup>All Safety Sets Adj IR plot: X-axis transformed to a pseudo-log10 scale in two segments. Dotted line represents the breakpoint of the X-axis segments. Error bars represent 95% CI; <sup>c</sup>PBO-CTRL Safety Set IRR plot: IRR only
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calculated if at least one patient in both treatment groups experienced the event(s). X-axis
transformed to a log10 scale. *P-value ≤0.05. Error bars represent 95% CI.

%, percentage of patients; Adj, adjusted; AE, adverse event; CI, confidence interval; IR, incidence rate (n/100PYE), for IR calculations; IRR, incidence rate ratio; patient exposure was censored at the time of first event; n, number of patients achieving the indicated metric, or with ≥1 event; N, number of patients with recorded observation; PBO-CTRL, placebo-controlled; PYE, patient-years of exposure; TEAE, treatment-emergent AE; TRALO, tralokinumab.

**Figure 4** Overall summary of AESIs. Definitions of Customized MedDRA® Queries, Standardized MedDRA® Queries, and other cluster terms used are provided in Table S1; details on represented data in the figures are provided in Tables S6 and S7 (see Supporting Information). <sup>a</sup>Study size-adjusted % and IR; <sup>b</sup>All Safety Sets Adj IR plot: X-axis transformed to a pseudo-log10 scale in two segments. Dotted line represents the breakpoint of the X-axis segments. Error bars represent 95% CI; <sup>c</sup>PBO-CTRL Safety Set IRR plot: IRR only calculated if at least one patient in both treatment groups experienced the event(s). X-axis transformed to a log10 scale. *P-value ≤0.05. Error bars represent 95% CI; <sup>d</sup>Conjunctivitis category includes several PTs, such as conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial, and conjunctivitis viral; <sup>e</sup>Keratitis category includes several PTs, such as keratitis, keratitis viral, and ulcerative keratitis; <sup>f</sup>Keratoconjunctivitis category includes the LLT atopic keratoconjunctivitis, and PT keratitis or vernal keratoconjunctivitis; <sup>g</sup>Eczema herpeticum category includes PTs such as eczema herpeticum and Kaposi's varicelliform eruption; <sup>h</sup>Malignancies diagnosed after dosing, excluding basal cell carcinoma, localized squamous cell carcinoma of the skin, and carcinoma in situ of the cervix; the malignancies diagnosed after randomization in the ALL-TRALO safety analysis set include prostate cancer (n=4), invasive breast carcinoma (n=3), breast cancer (n=2), invasive ductal breast carcinoma (n=2), adenoid cystic carcinoma, angiosarcoma, cutaneous T-cell lymphoma, keratoacanthoma, malignant melanoma in situ, malignant melanoma, ovarian cancer, papillary thyroid cancer, and tonsil cancer.

%, percentage of patients; Adj, adjusted; AE, adverse event; AESI, adverse event of special interest; CI, confidence interval; IR, incidence rate (n/100PYE), for IR calculations, patient exposure was censored at the time of first event; IRR, incidence rate ratio; LLT, low level term; n, number of patients achieving the indicated metric, or with ≥1 event; N, number of patients with recorded observation; PBO-CTRL, placebo-controlled; PT, preferred term; PYE, patient-years of exposure; TRALO, tralokinumab.
**Figure 5** Overall summary of ADRs. Definitions of Customized MedDRA® Queries, Standardized MedDRA® Queries, and other cluster terms used are provided in Table S1; details on represented data in the figures are provided in Tables S8 and S9 (see Supporting Information). <sup>a</sup>Study size-adjusted % and IR; <sup>b</sup>All Safety Sets Adj IR plot: X-axis transformed to a pseudo-log10 scale in two segments. Dotted line represents the breakpoint of the X-axis segments. Error bars represent 95% CI; <sup>c</sup>PBO-CTRL Safety Set IRR plot: IRR only calculated if at least one patient in both treatment groups experienced the event(s). X-axis transformed to a log10 scale. *P-value ≤0.05. Error bars represent 95% CI; <sup>d</sup>ADR eosinophilia category includes eosinophilia and eosinophil count increased; <sup>e</sup>ADR upper respiratory tract infections category includes upper respiratory tract infection, pharyngitis, and nasopharyngitis.

%, percentage of patients; Adj, adjusted; ADR, adverse drug reaction; AE, adverse event; CI, confidence interval; CMQ, Customized MedDRA® Query; HLT, high level term; IR, incidence rate (n/100PYE), for IR calculations, patient exposure was censored at the time of first event; IRR, incidence rate ratio; n, number of patients achieving the indicated metric, or with ≥1 event; N, number of patients with recorded observation; NEC, not elsewhere classified; PBO-CTRL, placebo-controlled; PYE, patient-years of exposure; TRALO, tralokinumab.

**Figure 6** Safety areas of interest for targeted immunomodulatory therapies in AD. Definitions of Customized MedDRA® Queries, Standardized MedDRA® Queries, and other cluster terms used are provided in Table S1; details on represented data in the figures are provided in Tables S10 and S11 (see Supporting Information). <sup>a</sup>Study size-adjusted % and IR; <sup>b</sup>All Safety Sets Adj IR plot: X-axis transformed to a pseudo-log10 scale in two segments. Dotted line represents the breakpoint of the X-axis segments. Error bars represent 95% CI; <sup>c</sup>PBO-CTRL Safety Set IRR plot: IRR only calculated if at least one patient in both treatment groups experienced the event(s). X-axis transformed to a log10 scale. *P-value ≤0.05. Error bars represent 95% CI; <sup>d</sup>SOC: Infections and Infestations + Serious AE = Yes. <sup>e</sup>CMQ for skin infections involves selecting relevant preferred terms related to skin infections to accurately identify and classify instances of skin infections within the dataset. <sup>f</sup>Defined as the SMQ: 'Malignant or unspecified tumors (narrow scope)'. <sup>g</sup>Non-melanoma skin cancer identified by HLT = "Skin neoplasms malignant and unspecified (excl melanoma)."

%, percentage of patients; Adj, adjusted; AE, adverse event; CI, confidence interval; CMQ, Customized MedDRA® Query; HLT, high level term; IR, incidence rate (n/100PYE), for IR calculations, patient exposure was censored at the time of first event; IRR, incidence rate ratio; MACE, major adverse cardiovascular event; n, number of patients achieving the indicated metric, or with ≥1 event; N, number of patients with recorded observation; NMSC, non-
1 melanoma skin cancer; PBO-CTRL, placebo-controlled; PYE, patient-years of exposure; SMQ,

2 Standardized MedDRA® Query; SOC, system organ class; TRALO, tralokinumab.
<table><caption>1 Table 1 Baseline parent trial demographics and characteristics</caption><thead><tr><th rowspan="2"></th><th colspan="2">PBO-CTRL Safety Set (Week 0-16)</th><th>ALL-TRALO</th></tr><tr><th>Tralokinumab<br>N=1939,<br>PYE=587.2</th><th>Placebo<br>N=913,<br>PYE=271.3</th><th>Safety Set<br>N=2693<br>PYE=5320.2</th></tr></thead><tbody><tr><td>Median age, years (min; max)</td><td>33.0 (12.0; 92.0)</td><td>32.0 (12.0; 82.0)</td><td>33.0 (12.0; 92.0)</td></tr><tr><td>Age group, n (%)</td><td></td><td></td><td></td></tr><tr><td>12-17</td><td>195 (10.1)</td><td>94 (10.3)</td><td>280 (10.4)</td></tr><tr><td>≥18</td><td>1744 (89.9)</td><td>819 (89.7)</td><td>2413 (89.6)</td></tr><tr><td>Female, n (%)</td><td>836 (43.1)</td><td>395 (43.3)</td><td>1155 (42.9)</td></tr><tr><td>Race, n (%)</td><td></td><td></td><td></td></tr><tr><td>White</td><td>1307 (67.4)</td><td>587 (64.3)</td><td>1802 (66.9)</td></tr><tr><td>Asian</td><td>409 (21.1)</td><td>210 (23.0)</td><td>588 (21.8)</td></tr><tr><td>Black or African American</td><td>153 (7.9)</td><td>84 (9.2)</td><td>211 (7.8)</td></tr><tr><td>BMI (kg/m²), N</td><td>1934</td><td>910</td><td>2687</td></tr><tr><td>Median (Q1; Q3)</td><td>24.8 (21.8; 29.0)</td><td>25.2 (21.9; 29.1)</td><td>24.9 (21.8; 29.0)</td></tr><tr><td>Current medical history, n (%)</td><td></td><td></td><td></td></tr><tr><td>Asthma</td><td>769 (39.7)</td><td>368 (40.3)</td><td>1085 (40.3)</td></tr><tr><td>Allergic conjunctivitis</td><td>401 (20.7)</td><td>207 (22.7)</td><td>583 (21.6)</td></tr><tr><td>Atopic keratoconjunctivitis</td><td>60 (3.1)</td><td>26 (2.8)</td><td>84 (3.1)</td></tr><tr><td>Median duration of AD, years (min; max)</td><td>24.0 (1.0; 77.0)</td><td>23.0 (1.0; 77.0)</td><td>24.0 (1.0; 77.0)</td></tr><tr><td>Median BSA, % (Q1; Q3)</td><td>49.0 (31.0; 70.0)</td><td>50.0 (31.0; 72.0)</td><td>50.0 (32.0; 70.0)</td></tr><tr><td>Median EASI (Q1; Q3)<sup>a</sup></td><td>27.6 (20.6; 39.3)</td><td>27.9 (20.8; 40.0)</td><td>27.8 (20.8; 39.5)</td></tr><tr><td>Median SCORAD score (Q1; Q3)<sup>a</sup></td><td>68.3 (60.0; 78.5)</td><td>68.9 (60.6; 79.2)</td><td>68.5 (60.2; 78.7)</td></tr><tr><td>IGA, n (%)<sup>a</sup></td><td></td><td></td><td></td></tr><tr><td>3</td><td>1005 (51.8)</td><td>475 (52.0)</td><td>1391 (51.7)</td></tr><tr><td>4</td><td>934 (48.2)</td><td>438 (48.0)</td><td>1302 (48.3)</td></tr></tbody></table>

aFull analysis set.

, percentage of patients; AD, atopic dermatitis; BMI, body mass index; BSA, body surface area; EASI, Eczema Area and Severity Index; IGA, Investigator's Global Assessment; n, number of patients with recorded observation; N, number of patients in indicated data set; PBO-CTRL, placebo-controlled; PYE, patient-years of exposure; Q1, first quartile (25th percentile); Q3, third quartile (75th percentile); SCORAD, SCORing Atopic Dermatitis; TRALO, tralokinumab.

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# Safety of tralokinumab in patients with moderate-to-severe atopic dermatitis followed for up to 4.5 years: an integrated analysis of 8 clinical trials

## Studies and analysis sets

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

2693 patients ≥12 years with moderate-to-severe AD from:

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

Integrated safety analysis of 2 data sets:

<figure><img src="image_7.png" /></figure>

## Results

### Most commonly reported AEs (≥2% in any treatment group of the PBO-CTRL safety set)

* The most common AEs that occurred at higher rates for tralokinumab vs. placebo were: nasopharyngitis, conjunctivitis, and injection site reaction

<figure><img src="image_8.png" /></figure>

#### Nasopharyngitis

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

#### Conjunctivitis

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

#### Injection site reaction

<figure><img src="image_13.png" /></figure>

* Most AEs were non-serious, mild, or moderate in severity with similar frequencies between tralokinumab and placebo in the PBO-CTRL safety set

* Dermatitis atopic and asthma occurred at lower rates with tralokinumab vs. placebo (IRR = 0.51 and 0.57, respectively)

* The incidence rate of AEs did not increase with longer exposure in the ALL-TRALO safety set

### Selected AEs of special interest

<figure><img src="image_14.png" /></figure>

#### AESI eye disorders

* Occurred at higher rates with tralokinumab vs. placebo (IRR = 2.43)

* 98% were mild-to-moderate

<figure><img src="image_15.png" /></figure>

#### AESIs less frequent with tralokinumab vs. placebo

* Eczema herpeticum (IRR = 0.32)

* Skin infections requiring systemic treatment (IRR = 0.43)

### Rates of AEs of clinical interest (related to other approved systemic AD treatments) were low and similar between treatment groups.

## Conclusions

Long-term use of tralokinumab in adult and adolescent patients was well tolerated and consistent with the initial placebo-controlled treatment period with no new safety signals identified

## Graphical Abstract

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<footnote>*incidence rate defined as 1/100PYR; number of patients with an event per 100 PYR or risk. AD, atopic dermatitis; AE, adverse event; AESI, AE of special interest; ALL-TRALO, all tralokinumab; IRR, incidence rate ratio; PBO-CTRL, placebo-controlled; PYR, patient years of exposure; PYE, PYR at risk; TRALO, tralokinumab.</footnote>
<figure><img src="image_16.png" /><figcaption>Figure 2
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<figure><img src="image_20.png" /><figcaption>Figure 6
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