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King’s Research Portal DOI: 10.1016/j.jaad.2018.01.017 Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Simpson, E. L., Flohr, C., Eichenfield, L. F., Bieber, T., Sofen, H., Taïeb, A., Owen, R., Putnam, W., Castro, M., DeBusk, K., Lin, C-Y., Voulgari, A., Yen, K., & Omachi, T. A. (2018). Efficacy and safety of lebrikizumab (an anti- IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE). Journal of the American Academy of Dermatology , 863-871.e11. https://doi.org/10.1016/j.jaad.2018.01.017 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. 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Oct. 2021 ORIGINAL ARTICLES Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE) Eric L. Simpson, MD,a Carsten Flohr, MD, PhD,b Lawrence F. Eichenfield, MD,c Thomas Bieber, MD, PhD, MDRA,d Howard Sofen, MD,e Alain Ta€ıeb, MD,f Ryan Owen, PhD,g Wendy Putnam, PhD,g Marcela Castro, MD,g Kendra DeBusk, PhD,g Chin-Yu Lin, PhD,g Athina Voulgari, PhD,h Karl Yen, MD,i and Theodore A. Omachi, MDg Portland, Oregon; London and Welwyn Garden City, United Kingdom; San Diego, Los Angeles, and South San Francisco, California; Bonn, Germany; Bordeaux, France; and Basel, Switzerland Background: Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). Objective: Weinvestigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. From the Department of Dermatology, School of Medicine, following activities: Sanofi Regeneron (investigator, consultant, Oregon Health & Science University, Portlanda; St. John’s speaker); Cutanea (consultant); Dermavant (investigator); Eli Lilly Institute of Dermatology, King’s College London and Guy’s & (consultant); Galderma (investigator, consultant); Anacor/Pfizer St Thomas’ NHS Foundation Trust, Londonb; Department of (investigator, consultant); Novartis (consultant); LEO (investigator, Dermatology, University of California San Diegoc; Department consultant); Medimetriks (consultant); and Valeant (investigator, of Dermatology and Allergy, University Medical Center, Bonn, consultant). Dr Bieber has the following declaration of interests: Germanyd; University of California Los Angeles School of Roche (consultant); Sanofi Regeneron (investigator, consultant, Medicinee; Department of Dermatology and Pediatric Derma- speaker); Eli Lilly (investigator, consultant, speaker); Galderma tology, Bordeaux Hospital University Center, Francef; Genen- (investigator, consultant); Pfizer (investigator, consultant); Novartis tech, South San Franciscog; Global Product Development (investigator, consultant); GlaxoSmithKline (consultant, speaker); Clinical Science, Roche Products Limited, Welwyn Garden Cityh; LEO (investigator, consultant, speaker); and AbbVie (consultant). and Roche, Grenzacherstrasse, Basel, Switzerland.i Dr Sofen reports personal fees from Genentech during the Drs Simpson and Flohr contributed to this manuscript equally. conduction of the study and personal fees from Regeneron and Funding sources: Funded by Genentech, a member of the Roche LEO outside the submitted work. Dr Ta€ıeb has nothing to disclose. Group. Editorial assistance was provided by Wemimo Omotosho, Drs Owen, Putnam, DeBusk, Lin, and Omachi are employees of PhD, of MediTech Media, funded by Genentech. Dr Flohr is funded Genentech, a member of the Roche group, and have a patent through a National Institute for Health Research (NIHR) Career pending. Dr Yen is an employee of Roche and has a patent Development Fellowship (CDF-2014-07-037), and also supported pending. Dr Voulgari is an employee of Roche Products Ltd. by the NIHR Biomedical Research Centre based at Guy’s and St Previously presented: Data from this study were presented at the Thomas’ NHS Foundation Trust and King’s College London. European Academy of Dermatology and Venereology in Conflicts of interest: Dr Simpson reports grants, personal fees, and Vienna, Austria on October 1, 2016. nonfinancial support from Roche-Genentech during the conduct Accepted for publication January 9, 2018. of the study; personal fees from AbbVie, Celgene, Dermira, Reprints not available from the authors. Galderma, LEO Pharma, Menlo Therapeutics, Sanofi Genzyme, Correspondence to: Theodore A. Omachi, MD, Genentech, Inc, and Valeant Pharmaceutical; grants and personal fees from Anacor 1 DNA Way, MS 452a, South San Francisco, CA 94080. E-mail: Pharma, GlaxoSmithKline, and Regeneron Pharmaceuticals; grants [email protected]. from MedImmune, Novartis, Roivant Sciences, Tioga Pharmaceu- Published online January 15, 2018. ticals, and Vanda Pharmaceuticals; and grants and personal fees 0190-9622 from Eli Lilly outside the submitted work. Dr Flohr reports personal Ó 2018 by the American Academy of Dermatology, Inc. This is an fees from Sanofi Regeneron outside the submitted work. The open access article under the CC BY-NC-ND license (http:// views expressed are those of the author(s), and not necessarily creativecommons.org/licenses/by-nc-nd/4.0/). those of the UK NIHR or the UK Department of Health. Dr https://doi.org/10.1016/j.jaad.2018.01.017 Eichenfield reports personal fees and nonfinancial support from Roche-Genentech during the conduction of the study and the 863 864 Simpson et al JAM ACAD DERMATOL MAY 2018 Methods: A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. Results: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. Limitations: Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. Conclusion: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD. ( J Am Acad Dermatol 2018;78:863-71.) Key words: anti-IL-13; atopic dermatitis; EASI; lebrikizumab; pruritus; topical corticosteroids. Atopic dermatitis (AD) is a skin barrier components.10,11 chronic skin disorder charac- CAPSULE SUMMARY Treatment of AD with sys- terized by intensely pruritic, temic agents such as cyclo- eczematous lesions accompa- d Interleukin 13 (IL-13) is overexpressed in sporine can decrease skin nied by a disrupted skin bar- patients with atopic dermatitis (AD). IL-13 levels,12 and recent tri- rier and type 2 inflammation.1 als have reported improved d Lebrikizumab, a monoclonal antibody AD is one of the most com- against IL-13, was superior to placebo in clinical responses in patients mon dermatologic diagnoses patients with AD when administered with moderate-to-severe AD worldwide and its burden is subcutaneously every 4 weeks along treated with dupilumab, a multidimensional, impacting with topical corticosteroids. monoclonal antibody against sleep, psychosocial activities, IL-4Ra, which inhibits IL-13/ and health-related quality of d IL-13 inhibition with lebrikizumab could IL-4 signaling.13,14 Together, life.2-4 In moderate-to-severe reduce the need for oral these data support IL-13 as a AD, potent topical corticoste- immunosuppressive
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