● Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 2.1−4.9% of adults across North America, Europe, and Japan1 ● AD is characterized by excessive dryness, intense itching, inflamed skin, and open sores or oozing2-3 and has a significant impact on quality of life due to itch, sleep interference, and psychological distress4 ● Tralokinumab is a fully human monoclonal antibody which neutralizes interleukin-13, a key driver of the chronic inflammation underlying moderate-to-severe AD5-9 ● Primary analysis of the Phase 3 trials (ECZTRA 1 [NCT03131648] and ECZTRA 2 [NCT03160885]) demonstrated superiority of tralokinumab 300 mg every 2 weeks compared with placebo in all primary and secondary endpoints of the initial 16-week treatment period. Superiority of tralokinumab for the primary endpoint of Investigator’s Global Assessment (IGA) 0/1 was more pronounced in ECZTRA 2 than in ECZTRA 1 ● ECZTRA 1 and ECZTRA 2 followed an identical design, but recruited patients from different countries across Europe, North America, Asia, and Oceania. The randomization procedure stratified patients by geographical region and baseline IGA score (moderate or severe). Hence, an imbalance in baseline characteristics may be present within countries A B 0 10 20 30 40 50 60 70 80 90 100 North America (USA) (n=198) Europe (n=477) Asia (Japan) (n=127) All subjects (n=802) P a ti e n ts , % 0 10 20 30 40 50 60 70 80 90 100 North America (USA & Canada) (n=361) Europe (n=234) Asia (Korea) (n=78) Australia (n=121) All subjects (n=794) P a ti e n ts , % ECZTRA 2 ECZTRA 1 Moderate (IGA=3) Severe (IGA=4) Moderate (IGA=3) Severe (IGA=4) Figure 2. Proportion of patients with severe (baseline IGA=4) and moderate (IGA=3) AD by region in (A) ECZTRA 1 and (B) ECZTRA 2 A B 0 10 20 30 40 50 North America (USA) (n=198) Europe (n=477) Asia (Japan) (n=127) All subjects (n=802) M e a n b a se lin e E A S I 0 10 20 30 40 50 North America (USA & Canada) (n=361) Europe (n=234) Asia (Korea) (n=78) Australia (n=121) All subjects (n=794) M e a n b a se lin e E A S I ECZTRA 2 ECZTRA 1 Moderate (IGA=3) Severe (IGA=4) Moderate (IGA=3) Severe (IGA=4) Figure 3. Mean baseline EASI scores of patients by region and baseline IGA in (A) ECZTRA 1 and (B) ECZTRA 2 A 0 20 40 60 80 100 Wet wraps Phototherapy Antibiotics Other immunosuppressant Azathioprine Methotrexate Cyclosporine Mycophenolate Systemic steroids Calcineurin inhibitors Topical corticosteroid Any previous treatment Patients, % P ri o r A D t re a tm e n t North America (n=361) Europe (n=234) Asia (Korea) (n=78) Australia (n=121) ECZTRA 1 Wet wraps Phototherapy Antibiotics Other immunosuppressant Azathioprine Methotrexate Cyclosporine Mycophenolate Systemic steroids Calcineurin inhibitors Topical corticosteroid Any previous treatment P ri o r A D t re a tm e n t North America (n=198) Europe (n=477) Asia (Japan) (n=127) B ECZTRA 2 0 20 40 60 80 100 Patients, % Axis Axis Figure 4. Prior AD treatments in all randomized patients by region in (A) ECZTRA 1 and (B) ECZTRA 2 A B 0 20 40 60 80 100 P a ti e n ts , % 0 20 40 60 80 100 P a ti e n ts , % ECZTRA 2 ECZTRA 1 Topical corticosteroid potency Topical corticosteroid potency 37.4% 34.8% 15.2% 52.0% 45.7% 23.3% 50.1% 11.1% 12.8% 21.5% 49.6% 22.3%20.9% 33.8% 36.3% 19.9% 35.7% 29.9% 11.1% 23.1% 46.2% 10.3% North America (n=198) Europe (n=477) Asia (Japan) (n=127) North America (n=361) Europe (n=234) Asia (Korea) (n=78) Australia (n=121) Low Moderate Unknown High Ultra high Low Moderate Unknown High Ultra high Figure 5. Potency of prior TCS used in all randomized patients in (A) ECZTRA 1 and (B) ECZTRA 2 2020 Fall Clinical Dermatology Conference, October 29-November 1, 2020, Live Virtual Meeting ● In this post hoc analysis of the ECZTRA 1 and ECZTRA 2 studies, regional differences were observed in disease severity and prior AD treatment, despite identical inclusion criteria ● Japan and Australia enrolled a similarly high proportion of patients with severe AD (IGA-4); however, Australia had the highest levels of prior medication use, compared with low use of medications (including systemic immunosuppressants) in Japan, most likely due to regional differences in AD treatment guidelines ● Regional differences in standard of care, in addition to differential assessment of study outcomes may, in part, explain the differences in therapeutic responses observed between ECZTRA 1 and ECZTRA 2. These analyses highlight the importance of stratification by region in the randomization procedure as performed in these trials Conclusions Characteristic ECZTRA 1 (n=802) ECZTRA 2 (n=794) Mean age, years (SD) 38.8 (14.1) 36.7 (14.6) Male, % 59.1 59.6 Severe disease (IGA-4), % 50.7 48.7 Mean EASI (SD) 32.4 (13.8) 32.2 (14.2) Mean SCORAD (SD) 70.6 (12.9) 70.1 (13.1) Mean DLQI (SD) 16.9 (7.0) 17.7 (7.1) Mean weekly average worst daily pruritus NRS (SD) 7.7 (1.4) 7.9 (1.4) Mean duration of AD, years (SD) 28.3 (14.7) 28.1 (15.6) Mean BSA involvement with AD, % (SD) 53.1 (24.5) 52.7 (25.4) Table 1. Demographics and baseline characteristics of all randomized patients DLQI, Dermatology Life Quality Index. Patient demographics and AD severity at baseline ● In total, 802 and 794 patients were randomized in ECZTRA 1 and 2, respectively. Overall the demographic and disease characteristics at baseline were similar across the trials (Table 1) ● Patients had a long mean duration of AD (28.3/28.1 years) and high body surface area (BSA) involvement (53.1/52.7%) Study design and patients ● ECZTRA 1 and ECZTRA 2 were identically designed, multinational, double-blind, randomized, placebo-controlled, 52-week clinical trials of tralokinumab monotherapy in patients with moderate-to-severe AD — In ECZTRA 1, patients were enrolled from Europe (Germany, France, Spain), North America (USA), and Asia (Japan) — In ECZTRA 2, patients were enrolled from Europe (UK, Italy, Denmark, Poland, and Russia), North America (USA and Canada), Asia (Korea), and Australia ● Based on the inclusion criteria, eligible patients were 18 years of age, with a confirmed diagnosis of AD for 1 year, Eczema Area and Severity Index (EASI) score of 16, IGA 3, pruritus Numeric Rating Scale (NRS) 4, and were candidates for systemic therapy due to a recent (within 1 year) history of inadequate response or intolerance to topical treatment ● Before treatment, patients underwent a washout period of 2 weeks for topical treatments including topical corticosteroids (TCS), 4 weeks for systemic medications, and 6 weeks for phototherapy (Figure 1) References 1. Barbarot S et al. Allergy 2018; 73: 1284−1293. 2. Nutten S. Ann Nutr Metab 2015; 66(Suppl 1): 8–16. 3. Weidinger S, Novak N. Lancet 2016; 387: 1109–1122. 4. Silverberg JI et al. Ann Allergy Asthma Immunol 2018; 121: 340–347. 5. Szegedi K et al. J Eur Acad Dermatol Venereol 2015; 29: 2136–2144. 6. Popovic B et al. J Mol Biol 2017; 429: 208–219. 7. Furue K et al. Immunology 2019; 158: 281–286. 8. Tsoi LC et al. J Invest Dermatol 2019; 139: 1480–1489. 9. Bieber T. Allergy 2020; 75: 54–62. Disclosures Eric Simpson reports grants and/or personal fees from AbbVie, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Forte Bio, Galderma, Incyte, Kyowa Hakko Kirin, LEO Pharma, Lilly, MedImmune, Menlo Therapeutics, Merck, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron, Sanofi, Tioga, and Valeant. Thomas Werfel has received honoraria for invited talks or scientific advice and research grants from Astellas, Galderma, Janssen/JNJ, LEO Pharma, Lilly, Novartis, Pfizer, and Sanofi/Regeneron. Thomas Bieber has been a lecturer and/or consultant for AbbVie, Almiral, AnaptysBio, Arena, Asana Biosciences, Astellas, BioVersys, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Davos Biosciences, Dermavant/Roivant, Dermtreat, DS Pharma, Evaxion, FLX Bio, Galapagos/MorphoSys, Galderma, GlaxoSmithKline, Glenmark, Incyte, Kymab, LEO Pharma, Lilly, L´Oréal, Menlo Therapeutics, Novartis, Pfizer, Pierre Fabre, Sanofi/Regeneron, UCB, and Vectans. Louise Abildgaard Steffensen, Alexandra Kuznetsova, and Marie Louise Østerdal are employees of LEO Pharma. Hidehisa Saeki is an advisor to LEO Pharma. The tralokinumab ECZTRA 1 and 2 studies were sponsored by LEO Pharma ● Of the patients with severe AD (IGA-4) at baseline, higher mean baseline EASI was observed in Japan (46.3 and Australia (48.0), compared with Europe (37.9/40.9), North America (37.6/34.9), and Korea (42.3) (Figure 3) Prior treatment for AD ● The trial population was heavily pretreated for AD. Almost all patients across all regions had received prior TCS (96−100%) (Figure 4) — The proportion of patients who had received ultra-high potency TCS was highest in Japan, whereas in Korea the majority of TCS used was of low and moderate potency (Figure 5) ● Prior systemic steroid treatment was highest in Australia (80.2%) and Korea (79.5%) ● There was high variability in prior use of systemic immunosuppressants. Cyclosporine was the most commonly used systemic immunosuppressant, used by 40% of patients in Japan, Europe, Korea, and Australia. Use of mycophenolate, methotrexate, and azathioprine was less common, in ,22% of patients, except in Australia where methotrexate and azathioprine were used by 33.9% and 28.9%, respectively ● More patients in Europe and Australia had received phototherapy for AD compared with Asia and North America, and use of wet wraps was also higher in Australia compared with other regions Tralokinumab 300 mg q2w Tralokinumab 300 mg q2w Placebo q2w Placebo q2w Tralokinumab 300 mg q4w Alternating with placebo Open-label treatment Tralokinumab 300 mg q2w Optional TCS and optional home use Placebo q2w 3:1 randomization Washout of TCS and other AD medication 300 mg q2w after initial loading dose (600 mg) Patient with clinical response of IGA-0/1 or EASI-75 2:2:1 randomization ECZTRA 1 (n=603) ECZTRA 2 (n=593) ECZTRA 1 (n=199) ECZTRA 2 (n=201) Screening Initial treatment Maintenance treatment Safety follow-up 66 weeks52 weeks16 weeks0-6 weeks Key inclusion criteria • Diagnosis of AD for �1 year • BSA involvement �10% • EASI score �12 at screening and 16 at baseline • IGA score �3 at screening and at baseline • Worst daily pruritus NRS average score ≥4 prior to baseline • Patients not achieving IGA-0/1 or EASI-75 at week 16 • Patients transferred from maintenance treatment Secondary endpoints • Reduction of worst daily pruritus NRS (weekly average) �4 from baseline to week 16 • Change in SCOring Atopic Dermatitis (SCORAD) from baseline to week 16 • Change in DLQI score from baseline to week 16 Maintenance endpoints • IGA-0/1 at week 52 • EASI-75 at week 52 Primary endpoints • IGA-0/1 at week 16 • EASI-75 at week 16 Figure 1. ECZTRA 1 and ECZTRA 2 trial design Introduction Results Methods Objective ● The objective of this post hoc analysis was to evaluate whether there were meaningful regional differences in baseline characteristics and prior AD treatment in the large cohort of patients with moderate-to-severe AD from the Phase 3 tralokinumab studies (ECZTRA 1 and ECZTRA 2) Tralokinumab monotherapy in adult patients with moderate-to-severe atopic dermatitis: regional differences in baseline disease characteristics and prior treatment in the ECZTRA 1 and ECZTRA 2 trials 1Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 2Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany; 3Department of Dermatology and Allergy, University Medical Center, Bonn, Germany; 4LEO Pharma A/S, Ballerup, Denmark; 5Department of Dermatology, Nippon Medical School, Tokyo, Japan Eric Simpson,1 Thomas Werfel,2 Thomas Bieber,3 Louise Abildgaard Steffensen,4 Alexandra Kuznetsova,4 Marie Louise Østerdal,4 Hidehisa Saeki5 Post hoc analysis ● This analysis compared patient demographics, disease characteristics, and prior use of AD treatments in all randomized patients by region in the ECZTRA 1 and ECZTRA 2 trials ● The proportion of patients with severe AD (IGA-4) was 50.7% and 48.7% for the overall study populations in ECZTRA 1 and 2, respectively. Japan (66.1%) and Australia (63.6%) had the highest proportions of patients with severe AD (IGA-4) compared with Europe (52.6/51.3%), North America (36.4/43.2%), and Korea (43.6%) (Figure 2)