Schedule of PRO assessments in ECZTRA 1-3 Patient-reported outcome measure DLQI POEM Eczema-related sleep NRS (weekly average) Assessed daily with eDiary Assessed daily with eDiary Worst daily pruritus NRS (weekly average) Baseline X X Week 1 Week 2 X X Week 3 Week 4 X X Week 5 Week 6 X X Week 7 Week 8 X X Week 9 Week 10 Visit 5a Week 11 Week 12 X X Week 13 Week 14 Visit 7a Week 15 Week 16 Visit 1a Visit 2a Visit 3a Visit 4a Visit 6a Visit 8a X X Earliest possible time point for assessment Figure 1. Schedule of PRO measure assessments in initial 16-week period Introduction Methods Objective ● The objective of this analysis was to examine early changes in several PRO measures across the ECZTRA 1/2 and ECZTRA 3 trials Conclusions ● Tralokinumab, with or without concomitant TCS, led to early (within 1−3 weeks) improvements in patient-relevant endpoints compared to placebo across the three trials ● AD severely impacts a patient’s quality of life; interventions with the potential to provide such early improvements are highly desirable ● Concomitant use of TCS in ECZTRA 3 may explain why differences between tralokinumab and placebo were observed earlier in ECZTRA 1/2 ● The long-term resilience of PRO measure improvements is being assessed in the ongoing ECZTEND trial for tralokinumab (NCT03587805) ● These findings support the previously demonstrated superiority of tralokinumab 300 mg every two weeks when compared to placebo, over 16 weeks of treatment across multiple outcome measures, reflecting the signs and symptoms of AD ● Atopic dermatitis (AD) is a chronic, inflammatory skin disease, with an estimated prevalence of between 2.1% and 4.9% in adults across North America, Europe, and Japan1 ● Moderate-to-severe AD is characterized by symptoms including excessive dryness, scaling, red or inflamed skin, blisters or bumps, open sores or oozing, and intense itching.2 These symptoms can be severely debilitating to patients and their quality of life, resulting in sleep disturbance, pain, and depression2 ● The pathogenesis of AD is complex and multifactorial, combining skin barrier dysfunction and immune dysregulation, leading to chronic type 2 inflammation3,4 ● Interleukin (IL)-13, a key type 2 cytokine, has been identified as a key driver of the underlying inflammation of AD, with IL-13 levels within lesional skin correlating with AD severity5-8 ● Tralokinumab is a fully human monoclonal antibody which specifically neutralizes IL-139 - Recent Phase 3, placebo-controlled trials have investigated tralokinumab in the treatment of moderate-to- severe AD as a monotherapy (ECZTRA 1, NCT03131648; ECZTRA 2, NCT03160885) and in combination with topical corticosteroids (TCS) [ECZTRA 3, NCT03363854] - Efficacy results from these trials were promising, with significantly more patients achieving the primary endpoints of Investigator’s Global Assessment (IGA) score of 0 or 1 and Eczema Area and Severity Index (EASI) score of 75 (a 75% reduction in EASI score) at 16 weeks with tralokinumab versus placebo in all three studies ● It is important to assess the efficacy of tralokinumab in terms of patient-reported outcomes (PROs), which are vital for providing insight on the real-life value of treatments for AD10 Study design ● ECZTRA 1 and 2 were two identically designed, multinational, double-blind, randomized, placebo-controlled, 52-week trials ● ECZTRA 3 was a multinational, double-blind, randomized, placebo plus TCS-controlled 32-week trial ● All trials were conducted in adults with moderate-to-severe AD who were candidates for systemic therapy Patients ● Key inclusion criteria common for all trials were: 18 years of age; confirmed diagnosis of AD for 1 year; inadequate response to topical medications 1 year prior to screening; IGA score of 3; and EASI score of 12 at screening and 16 at baseline ● Patients were randomized 3:1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (ECZTRA 1/2) or 2:1 to subcutaneous tralokinumab 300 mg plus TCS or placebo every 2 weeks plus TCS (ECZTRA 3) for an initial 16 weeks ● Rescue treatment in the form of topical and systemic medications was permitted in all trials to control intolerable AD symptoms Patient-reported outcomes ● A series of PRO measures were assessed in the three trials (Figure 1) - Numeric Rating Scale (NRS) for worst daily pruritus (11-point scale with 0 being “no itch” and 10 being “worst itch imaginable”) [Daily via an eDiary] - NRS for eczema-related sleep interference (11-point scale with 0 indicating that it “did not interfere” and 10 indicating that it “completely interfered”) [Daily via an eDiary] - Dermatology Life Quality Index (DLQI): 10 items addressing a patient’s perception of the impact of their skin disease on different aspects of their daily life over the last week – patients scored the impact on each activity on a 4-point scale (where 0 is “not at all, not relevant” to 3 for “very much”) [bi-weekly to week 8, then at weeks 12 and 16] - Patient-Orientated Eczema Measure (POEM): consisting of seven items eac addressing a specific AD symptom over the last week (itching, sleep, bleeding, weeping, cracking, flaking, and dryness) – patients indicated the frequency of each experienced in the previous week to generate a total score (bi-weekly to week 8, then at weeks 12 and 16) - DLQI and POEM were answered electronically at the study site and all PRO measures were reported prior to clinician assessments 2020 Fall Clinical Dermatology Conference, October 29-November 1, 2020, Live Virtual Meeting Early changes in patient-relevant endpoints in three tralokinumab pivotal Phase 3 trials (ECZTRA 1−3) in adult patients with moderate-to-severe atopic dermatitis Jonathan I. Silverberg,1 Michael Cork,2 Andreas Wollenberg,3 Norito Katoh,4 Louise Abildgaard Steffensen,5 Azra Kurbasic,5 Christina Kurre Olsen,5 Alexandra Kuznetsova,5 Marie Louise Østerdal,5 Andreas Westh Vilsbøll,5 Mette Deleuran6 1Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; 2Sheffield Dermatology Research, Department of Infection, Immunity & Cardiovascular Disease, Faculty of Medicine, Dentistry & Health, The University of Sheffield, Sheffield, UK; 3Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany; 4Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 5LEO Pharma A/S, Ballerup, Denmark; 6Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark Safety ● Adverse events were assessed at baseline and at each subsequent visit Statistical analysis ● The changes in worst daily pruritus, eczema-related sleep interference, DLQI, and POEM were assessed by a repeated measurements model, including baseline IGA, region, and treatment-by-week interaction as factors and interaction between week and baseline value as covariates — Change = Treatment*Week + Baseline*Week + Region + Baseline IGA — Data collected after permanent discontinuation or initiation of rescue medication were excluded Patient-reported outcomes ● Tralokinumab improved weekly average NRS worst daily pruritus from baseline compared with placebo by week 1 in ECZTRA 1 (–0.7 vs. –0.2; P0.001) and ECZTRA 2 (–0.7 vs. –0.3; P0.001), and week 3 in ECZTRA 3 (–2.6 vs. –2.0; P=0.003) (Figure 2) ● Tralokinumab reduced weekly mean eczema-related sleep interference from baseline compared with placebo by week 1 in ECZTRA 1 (–0.6 vs. –0.2; P0.001) and ECZTRA 2 (–0.7 vs. –0.2; P0.001) and week 2 in ECZTRA 3 (–2.3 vs. –1.9; P=0.037) (Figure 3) Characteristic ECZTRA 1 ECZTRA 2 ECZTRA 3 Table 1. Demographics and clinical characteristics of randomized patients at baseline q2w, every 2 weeks; SCORAD, SCORing Atopic Dermatitis; SD, standard deviation. aIncluding American Indian or Alaska native and Native Hawaiian or other Pacific Islander; bn=197; cn=195; dn=194; en=601; fn = 598; gn=591; hn=589; in=200; jn=592; kn=591; ln=584; mn=587; nn=586; on=126; pn=125; qn=252; rn=251; sn=250. Week C h a n g e in w o rs t d a ily p ru ri tu s N R S Tralokinumab q2w (n=601) Placebo (n=197) 0 -2 -1 -3 -4 -5 0 2 3 4 5 6 7 8 9 10 11 12 13 15 1614 Week C h a n g e in w o rs t d a ily p ru ri tu s N R S Tralokinumab q2w (n=591) Placebo (n=201) 0 -4 -2 -5 -3 -1 0 0 1 1 2 3 4 5 6 7 8 9 10 11 12 13 15 1614 Week ECZTRA 3 C h a n g e in w o rs t d a ily p ru ri tu s N R S Tralokinumab q2w + TCS (n=252) Placebo + TCS (n=126) 0 A B C -2 -1 -4 -3 -5 1 2 3 4 5 6 7 8 9 10 11 12 13 15 1614 ** ** * * ** *** *** *** *** *** *** *** ****** ECZTRA 1 *** *** *** *** *** *** *** *** *** ** *** *** *** ****** *** ECZTRA 2 *** *** *** *** *** *** *** *** *** *** *** *** *** ****** *** Figure 2. Changes in worst daily pruritus NRS in ECZTRA 1, 2, and 3 A B C C ha ng e in ec ze m a -r el a te d s le ep N RS Tralokinumab q2w (n=601) Placebo (n=197) 0 -4 -2 -3 -1 -5 0 -2 -4 -3 -1 -5 0 ECZTRA 1 *** *** *** *** *** *** *** *** ** ** ** ** ** **** ECZTRA 2 C ha ng e in ec ze m a -r el a te d s le ep N RS Tralokinumab q2w (n=591) Placebo (n=201) 0 *** *** *** *** *** *** *** *** *** *** *** *** *** *** ****** ECZTRA 3 C ha ng e in ec ze m a -r el a te d s le ep N RS 0 -2 -4 -5 -3 -1 Week 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 1614 Week 1 2 3 4 5 6 7 8 9 10 11 12 13 15 1614 Week 1 2 3 4 5 6 7 8 9 10 11 12 13 15 1614 *** ** ** *** *** *** *** *** *** *** *** *** ****** Tralokinumab q2w + TCS (n=252) Placebo + TCS (n=126) *** Figure 3. Changes in daily eczema-related sleep NRS in ECZTRA 1, 2, and 3 in ECZTRA 1, 2, and 3 P0.05; **P0.01; ***P0.001. Data collected after permanent discontinuation of investigational medicinal product or initiation of rescue medication not included. In case of no post-baseline assessments before initiation of rescue medication, the week 2 change will be imputed as 0. ECZTRA 2 B C h a n g e in D LQ I Tralokinumab q2w (n=591) Placebo (n=201) 0 2 4 6 8 10 12 1614 ****** ****** *** *** 0 -2 -4 -8 -12 -14 -6 -10 A Week C h a n g e in D LQ I Tralokinumab q2w (n=601) Placebo (n=197) 0 2 4 6 8 10 12 1614 *** *** *** *** *** ** 0 -2 -4 -8 -12 -14 -6 -10 ECZTRA 1 Week C ****** ****** ** * Week ECZTRA 3 C h a n g e in D LQ I Tralokinumab q2w + TCS (n=252) Placebo + TCS (n=126) 0 -2 -4 -8 -12 -14 -6 -10 0 2 4 6 8 10 12 1614 Figure 4. Changes in DLQI in ECZTRA 1, 2, and 3 *P0.05; **P0.01; ***P0.001. Data collected after permanent discontinuation of investigational medicinal product or initiation of rescue medication not included. In case of no post-baseline assessments before initiation of rescue medication, the week 1 change will be imputed as 0. *P<0.05; **P<0.01; ***P<0.001. Data collected after permanent discontinuation of investigational medicinal product or initiation of rescue medication not included. In case of no post- baseline assessments before initiation of rescue medication, the week 1 change will be imputed as 0. *P0.05; **P0.01; ***P0.001. Data collected after permanent discontinuation of investigational medicinal product or initiation of rescue medication not included. In case of no post- baseline assessments before initiation of rescue medication, the week 2 change will be imputed as 0. Week C h a n g e in P O EM Tralokinumab q2w (n=591) Placebo (n=201) 0 -2 -4 -6 -10 -14 -8 -12 0 2 4 6 8 10 12 1614 *** *** ****** *** *** ECZTRA 2 A Week C h a n g e in P O EM Tralokinumab q2w (n=601) Placebo (n=197) -14 0 2 4 6 8 10 12 1614 ECZTRA 1 *** *** ****** *** *** Week ECZTRA 3 C h a n g e in P O EM Tralokinumab q2w + TCS (n=252) Placebo + TCS (n=126) 0 -4 -10 -14 -12 -8 -2 -6 0 2 4 6 8 10 12 1614 ** *** ****** *** *** Figure 5. Changes in POEM score in ECZTRA 1, 2, and 3 Patient characteristics ● 802, 794, and 380 patients were randomized in ECZTRA 1, 2, and 3, respectively. ● Patient demographics were well balanced between randomized groups (Table 1) Results Safety ● In the 16-week period, the overall safety of tralokinumab was comparable to placebo ● The incidence of 1 adverse event was similar between tralokinumab and placebo patients in all three trials (76.4% vs. 77.0% in ECZTRA 1, 61.5% vs. 66.0% in ECZTRA 2, and 71.4% vs. 66.7% in ECZTRA 3) ● The majority of adverse events were mild or moderate in severity ● Tralokinumab reduced mean DLQI compared with placebo in ECZTRA 1 (–4.4 vs. –2.5; P0.001), ECZTRA 2 (–4.7 vs. –2.2; P0.001), and ECZTRA 3 (–8.9 vs. –7.3; P=0.011) by week 2 (Figure 4) aVisit with efficacy assessment after baseline. ● Tralokinumab reduced mean POEM compared with placebo in ECZTRA 1 (–4.0 vs. –1.3; P0.001), ECZTRA 2 (–4.6 vs. –1.6; P0.001), and ECZTRA 3 (–7.9 vs. –5.9; P=0.006) by week 2 (Figure 5) ● Mean improvements from baseline for DLQI and POEM reached minimally clinical important difference of 4 at week 2 for tralokinumab Disclosures Jonathan I. Silverberg has received grants, personal fees, or nonfinancial support from AbbVie, AnaptysBio, Arena, Asana, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Lilly, Galderma, GlaxoSmithKline, Kiniksa, LEO Pharma, MedImmune, Menlo, Novartis, Pfizer, Regeneron, and Sanofi. Michael Cork is an investigator and/or consultant for Astellas, Boots, Dermavant, Galapagos, Galderma, Hyphens, Johnson & Johnson, LEO Pharma, L’Oréal, Menlo Therapeutics, Novartis, Oxagen, Pfizer, Procter & Gamble, Reckitt Benckiser, Regeneron, and Sanofi Genzyme. Andreas Wollenberg has received grants, personal fees, or nonfinancial support from AbbVie, Almirall, Beiersdorf, Bioderma, Chugai, Galapagos, Galderma, Hans Karrer, LEO Pharma, Lilly, L’Oreal, Maruho, MedImmune, Novartis, Pfizer, Pierre Fabre, Regeneron, Santen, and Sanofi-Aventis Norito Katoh is an advisor, speaker, or investigator for AbbVie, Lilly, LEO Pharma, Maruho, Mitsubishi Tanabe, Kyowa Kirin, Taiho, Regeneron, and Sanofi. Louise Abildgaard Steffensen, Azra Kurbasic, Christina Kurre Olsen, Alexandra Kuznetsova, Marie Louise Østerdal, and Andreas Westh Vilsbøll are employees of LEO Pharma. Mette Deleuran has received research support, consulting/advisory board agreements, and/or honoraria for lecturing from AbbVie, Almirall, Galapagos, LEO Pharma, Lilly, Meda, Novartis, Pfizer, Pierre Fabre, Regeneron, and Sanofi Gen. The tralokinumab ECZTRA 1, 2, and 3 studies were sponsored by LEO Pharma. References 1. Barbarot S et al. Allergy 2018; 73: 1284–1293. 2. Silverberg JI et al. Ann Allergy Asthma Immunol 2018; 121: 340–347. 3. Guttman-Yassky E et al. Semin Cutan Med Surg 2017; 36: 100–103. 4. Czarnowicki T et al. J Allergy Clin Immunol 2019; 143: 1–11. 5. Szegedi K et al. J Eur Acad Dermatol Venereol 2015; 29: 2136–2144. 6. Tsoi LC et al. J Invest Dermatol 2019; 139: 1480–1489. 7. Bieber T. Allergy 2020; 75: 54–62. 8. Pavel AB et al. J Am Acad Dermatol 2020; 82: 690–699. 9. Popovic B et al. 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