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Revolutionizing Atopic Dermatitis (RAD) Conference, 13 June 2021 Introduction Objective Methods Results ● Baseline characteristics were similar between the two treatment arms (Table 1) ● Tralokinumab treatment led to a greater shift towards a non-lesional profile at 16 Weeks relative to placebo (Figure 2) ● Tralokinumab modified epidermal barrier characteristics through Week 16 (Figure 5) Neutralizing interleukin-13 with tralokinumab shifts the molecular phenotype of lesional skin towards that of non-lesional skin and restores barrier abnormalities Emma Guttman-Yassky1, Matthew Zirwas2, Kenji Kabashima3, Delphine Staumont-Sallé4, Petra Amoudruz5, Mads Røpke5, Ana Pavel1 1Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Dermatology, Ohio State University, Columbus, OH, USA; 3Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4Department of Dermatology, University Hospital of Lille, University of Lille, Lille, France; 5LEO Pharma A/S, Ballerup, Denmark ● To measure the impact of IL-13 cytokine neutralization using transcriptomic analysis of biopsies taken from patients enrolled in the ECZTRA 1 trial ● Skin biopsy samples were taken at Baseline, Week 4, and Week 16 from patients (n=50) enrolled in the ECZTRA 1 trial for both transcriptomic analyses and immunohistochemistry (Figure 1) ● Gene expression levels of biomarkers related to inflammation and skin barrier were assessed by RNA sequencing and validated by quantitative polymerase chain reaction (qPCR) Conclusions ● Treatment with tralokinumab shifted the AD transcriptome towards that of non-lesional skin ● Neutralization of the IL-13 cytokine significantly modulated key AD immune and barrier abnormalities in skin lesions Figure 1. ECZTRA 1 trial design and skin biopsy sampling schedule All statistics presented are for Week 16. * P<0.05 vs Baseline; ** P<0.01 vs Baseline; *** P<0.001 vs Baseline. Blue asterisk indicates significance vs placebo. Abbreviations: yc, common gamma chain; AD, atopic dermatitis; BL, baseline; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment IL, interleukin; JAK, Janus kinase; NRS, numerical range scale; Q2W, every 2 weeks; Q4W, every 4 weeks; qPCR, quantitative polymerase chain reaction; SCORAD, SCORing Atopic Dermatitis; STAT, signal transducer and activator of transcription; TCS, topical corticosteroid TYK, tyrosine kinase. ● Tralokinumab treatment modulated key immune pathways/markers over 16 Weeks (Figures 3, 4) Table 1. Baseline demographics and clinical characteristics for randomized subjects in parent study (ECZTRA 1) and in the biopsy biomarker subgroup Characteristic All randomized (N=802) Biopsy subgroup (N=50) Age, years Mean (SD) 38.8 (14.1) 39.4 (13.9) Sex, n (%) Male 474 (59.1) 29 (58.0) Female 328 (40.9) 21 (42.0) Race, n (%) White 564 (70.3) 37 (74.0) Black 59 (7.4) 3 (6.0) Asian 160 (20.0) 10 (20.0) IGA, n (%) Moderate Disease 391 (48.8) 26 (52.0) Severe Disease 407 (50.7) 24 (48.0) EASI Mean (SD) 32.4 (13.8) a 33.8 (14.2) SCORAD Mean (SD) 70.6 (12.9) a 73.1 (12.8) DLQI Mean (SD) 16.9 (7.0) b 17.4 (5.4) d Worst Daily Pruritus NRS (weekly average) Mean (SD) 7.7 (1.4) c 8.0 (1.2) Figure 5. Immunohistochemistry images of the epidermal barrier with quantification at baseline, Week 4, and Week 16. Change from Baseline (%) Epidermal thickness *** Week 4 Week 16 LOR % coverage ** S100A7 intensity in epidermis * 60 40 20 0 -20 -40 * Ki-67 cells in epidermis * * CK16 intensity in epidermis ** * CK16 LOR S100A7 Ki-67 Week 0 Week 4 Week 16 Non-lesional . Figure 4. Levels of key AD-related immune and barrier genes over 16 Weeks measured by A. transcriptomics and B. validated by qPCR + P<0.1, *P<0.05, **P<0.01, ***P<0.001 -1.5 -1 -0.5 0 0.5 1 1.5 Row Z-Score A. B. Disclosures Emma Guttman-Yassky has received honoraria for consultant services from AbbVie, Almirall, Amgen, Asana Biosciences, Boerhinger Ingelhiem, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Lilly, EMD Serono, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Sienna Biopharma, and Union Therapeutics and received research grants for investigator services from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boerhinger Ingelhiem, Celgene, Concert, Dermavant, Dermira, DS Biopharma, Lilly, Glenmark, Galderma, Innovaderm, Janssen, Kiniska, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, Regeneron, Sienna Biopharma, UCB, and Union Therapeutics. Matthew Zirwas has acted as a consultant for AbbVie, Aclaris, Arcutis, Asana, Aseptic MD, Avillion, DS Biopharma, Fitbit, Foamix, Genentech, Incyte, Janssen, LEO Pharma, Lilly, L’Oreal, Menlo, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, and UCB. Kenji Kabashima has received consulting fees or advisory board honoraria from Japan tobacco Inc., Chugai Pharmaceutical, Maruho, and Pola Pharma, and has received research grants from LEO Pharma, Japan tobacco Inc., P&G Japan, Eli Lilly Japan, Tanabe Mitsubishi, Ono Pharmaceutical, Kyowa Hakko Kirin, Pola Pharma, AbbVie, Sanofi, and Kyorin Pharmaceutical. Delphine Staumont-Sallé has served as an investigator for Abbvie, Amgen/Celgène, Galderma, Eli Lilly, Leo Pharma, Novartis, Sanofi-Regeneron, has received consulting fees from Abbvie, Astra-Zeneca, Eli Lilly, Leo Pharma, Janssen, Novartis, Sanofi, Pfizer, and has received speaker fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, and Sanofi. Petra Amoudruz and Mads Røpke are employees of LEO Pharma. Ana Pavel has received research support from Mount Sinai Hospital, New York, USA and The University of Mississippi, MS, USA. Acknowledgements The ECZTRA 1 clinical trial was sponsored by LEO Pharma. This poster was previously presented at the American Academy of Dermatology Association Virtual Meeting Experience (AAD VMX), April 23-25, 2021. References 1. Bieber T. Allergy. 2020;75:54-62; 2. Furue K et al. Immunology. 2019; 158: 281-286; 3. Szegedi K et al. JEADV. 2015;29:2136–2144; 4. Tsoi LC et al. J Invest Dermatol. 2019;139:1480-1489; 5. Popovic B et al. J Mol Biol. 2017; 429: 208–219; 6. May RD et al. Br J Pharmacol 2012; 166:177–93; 7. Weidinger S et al. SKIN J Cutan Med 2019; 3 (Suppl.):S42; 8. Wollenberg A et al. Br J Dermatol. 2020 Sep 30. doi: 10.1111/bjd.19574; 9. Silverberg et al. Br J Dermatol. 2020 Sep 30. doi: 10. 1111/bjd.19573. 10. Guttman-Yassky E, et al. Poster presentation at AAD VMX 2021; 11. Bieber T, et al. Poster presentation at AAD VMX 2021. All statistics presented are for Week 16. * P<0.05 vs Baseline; ** P<0.01 vs Baseline; *** P<0.001 vs Baseline, *P<0.05 vs placebo. Figure 3. Levels of skin biomarkers in the following immune pathways were reduced over 16 Weeks of tralokinumab treatment: A. Th2, B. Th22, IL22, C. Th17, and D. Th1-specific Placebo (n=15) Tralokinumab (n=35) + P<0.1 *P<0.05 **P<0.01 ***P<0.00 1 A. B. C. D. ● The interleukin (IL)-13 cytokine is a key driver of the skin inflammation seen in patients with atopic dermatitis (AD) 1–4 ● By binding to the IL-13 cytokine with high affinity, tralokinumab prevents the receptor interaction and IL-13 signaling 5–7 ● Tralokinumab demonstrated efficacy and safety in three Phase 3 trials for the treatment of AD 8,9 No IL-13 signaling Figure 2. Transcriptome analyses depicting A. Direction of dysregulation in AD; B. Improvements towards non-lesional transcriptome profiles for tralokinumab and placebo groups Tralokinumab Placebo BL W4 W16 NL BL W4 W16 NL Direction of Dysregulation in AD Up- Regulated Down-Regulated Tralokinumab Placebo Log2(FCH) 2 0 -2 BL W4 W16 BL W4 W16 Lesional vs Non-lesional Transcriptome (1908 genes, |FCH|>2, FDR<0.05) *** P<0.001 Tralokinumab vs Placebo ** 46.6 16.4 13.7 -3.9 *** *** Tralokinumab Placebo W4 W16 W4 W16 Improvement (%) A B a n=798; b n=785; c n=793; d n=49
