PowerPoint Presentation Objective Rapid and sustained improvements in itch and sleep with tralokinumab treatment in patients with moderate-to-severe Atopic Dermatitis, a post hoc analysis of pooled data from ECZTRA 1 and 2 Eric Simpson1, Andreas Wollenberg2, Weily Soong3, Thomas Mark4, Alexandra Kuznetsova4, Louise Abildgaard Steffensen4, Jonathan I Silverberg5 • Atopic dermatitis (AD) is a chronic skin disease associated with significant itch and sleep disturbances that profoundly affect patients’ daily lives • Tralokinumab is a fully human, high-affinity, monoclonal antibody that specifically neutralizes the interleukin-13 cytokine, a key driver of AD signs and symptoms • In two pivotal phase 3 trials (ECZTRA 1, NCT03131648; ECZTRA 2, NCT03160885) in adults with moderate-to-severe AD, tralokinumab monotherapy demonstrated superiority compared to placebo for each primary and secondary endpoint at Week 16 and was well tolerated up to 52 weeks of treatment1 Trial design To evaluate the timing and effect of tralokinumab on itch and sleep in adult patients with moderate-to-severe AD pooled from two identical Phase 3 trials. 1Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 2Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany; 3Alabama Allergy & Asthma Center and Clinical Research Center of Alabama, Birmingham, AL, United States; 4LEO Pharma A/S, Ballerup, Denmark; 5George Washington University School of Medicine and Health Sciences, Washington, DC Introduction Methods • ECZTRA 1 and 2 were two identically designed, multinational, double-blind, randomized, placebo-controlled, 52-week trials (Figure 1) • Patients were randomized 3:1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks for an initial 16 weeks • Prior to randomization, AD treatments were washed out: 4 weeks for systemic treatments and 2 weeks for TCS and other topical treatments • Rescue treatment could be used at the discretion of the investigator to control intolerable symptoms Figure 1. ECZTRA 1 and 2 trial design. Table 1. Baseline demographics and clinical characteristics. Patients, demographics, and clinical characteristics References Disclosures Conclusions Tralokinumab monotherapy showed rapid and sustained improvements from baseline in itch and sleep interference relative to placebo, starting from Day 2 after the first dose. 1.. Wollenberg A et al. Br J Dermatol. 2020 Sep 30. doi: 10.1111/bjd.19574. Online ahead of print. Eric Simpson is a consultant and investigator for Regeneron/Sanofi, Dermira, Menlo Pharmaceuticals, Lilly, Abbvie, Genentech, Medimmune, GSK, LEO Pharma, Celgene, and Pfizer. 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. Weily Soong has served on the advisory board and received research grants from Genentech, Inc., Teva, Novartis, and Pfizer; served on the advisory board, received research grants, and was a speaker for AstraZeneca, Regeneron, Sanofi, and GlaxoSmithKline; received research grants and was a speaker for Optinose; received research grants from Avillion, Gossamer Bio, 3M, and LEO Pharma. Thomas Mark, Alexandra Kuznetsova, and Louise Abildgaard Steffensen are employees of LEO Pharma A/S. Jonathan I. Silverberg reports honoraria as a consultant/advisory board member from LEO Pharma and has acted as a consultant for, and/or received grants/honoraria from, AbbVie, AnaptysBio, Asana Biosciences, Galderma Research and Development, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Lilly, MedImmune, Menlo Therapeutics, Pfizer, PuriCore, Regeneron, and Sanofi. Acknowledgements • The ECZTRA 1 and 2 clinical trials were sponsored by LEO Pharma A/S • Editorial support was provided by Clair Geary, PhD of Alphabet Health (New York, NY), supported by LEO Pharma A/S, according to Good Publication Practice guidelines (https://www.ismpp.org/gpp3). Figure 2. Percent improvement from baseline in weekly average over 16 weeks in: A. worst daily pruritus NRS B. eczema related sleep NRS Results All randomized (N=1596) Tralokinumab Q2W (n=1196) Placebo (n=400) Mean age in years (SD) 37.8 (14.4) 37.9 (14.2) 37.2 (14.8) Male, n (%) 947 (59.3) 710 (59.4) 237 (59.3) Region, n (%) North America 559 (35.0) 419 (35.0) 140 (35.0) Europe 711 (44.5) 533 (44.6) 178 (44.5) Australia 121 (7.6) 90 (7.5) 31 (7.8) Asia 205 (12.8) 154 (12.9) 51 (12.8) Mean affected BSA, % 52.9 (24.9), n=1595 52.7 (24.8) 53.6 (25.3), n=399 Mean disease duration, years (SD) 28.2 (15.2), n=1594 28.1 (15.2), n=1195 28.5 (14.9), n=399 Severe Disease (IGA 4), n (%) 794 (49.7) 591 (49.4) 203 (50.8) Mean EASI (SD) 32.3 (14.0), n=1590 32.2 (14.0), n=1192 32.7 (13.9), n=398 Mean total SCORAD (SD) 70.4 (13.0), n=1590 70.2 (13.2), n=1192 71.1 (12.4), n=398 Mean DLQI (SD) 17.3 (7.1), n=1572 17.2 (7.1), n=1178 17.5 (7.0), n=394 Mean weekly average worst daily pruritus NRS (SD) 7.8 (1.4), n=1577 7.8 (1.4), n=1182 7.8 (1.4), n=395 Mean weekly average eczema related sleep NRS (SD) 7.0 (2.0), n=1577 7.0 (2.0), n=1182 7.0 (2.0), n=395 • At Week 16, tralokinumab had a greater adjusted mean percentage improvement from baseline in weekly average of worst daily pruritus NRS (tralokinumab 35.5%, placebo 21.4%; p<0.001) and eczema-related sleep interference (tralokinumab 39.7%, placebo 18.4%; p<0.001) compared to placebo (Figure 2) Effect on itch and sleep over 16 weeks Figure 3. Percent improvement from baseline by day in: A. worst daily pruritus NRS B. eczema related sleep NRS • Relative to the placebo group, a significantly greater proportion of patients in the tralokinumab group achieved ≥2 or ≥4 point improvement after:† o 3 days for worst daily pruritus NRS ≥2 (at Day 3, tralokinumab: 29.7%, placebo: 20.0%; difference [95% CI]: 11.9 % [7.4%, 16.4%]; p<0.001) o 4 days for worst daily pruritus NRS ≥4 (at Day 4, tralokinumab: 10.1%, placebo: 7.5%; difference: 3.7 % [1.5%, 6.0%]; p=0.008) o 2 days for eczema related sleep NRS ≥2 (Day 2, tralokinumab: 29.7%, placebo: 24.0%; difference: 6.2 % [1.3%, 11.2%]; p=0.018) o 3 days for eczema related sleep NRS ≥4 (at Day 3, tralokinumab: 11.0%, placebo: 8.2%; difference: 4.3 % [1.8%, 6.8%]; p=0.005) ECZTRA 1 & 2: Phase 3, randomized, double-blind, placebo-controlled trials AD, atopic dermatitis; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; Q2W, every 2 weeks; Q4W, every 4 weeks; TCS, topical corticosteroid. Wollenberg A et al. Br J Dermatol 2020. 16 weeks0–6 weeks 52 weeks 66 weeks Tralokinumab 300 mg Q2W Placebo Q2W Tralokinumab 300 mg Q2W Tralokinumab 300 mg Q4W Placebo Q2W Placebo Q2W Tralokinumab 300 mg Q2W Optional TCS and optional home use Initial treatmentScreening Maintenance treatment Patients with clinical response IGA-0 / 1 or EASI-75 Safety follow-up ECZTRA 1 (n=603) and 2 (n=593) ECZTRA 1 (n=199) and 2 (n=201) 3:1 randomization Patients not achieving IGA=0/1 or EASI 75 at 16 weeks Up to 6 weeks washout of AD medication (2 weeks for TCS) 300 mg Q2W after initial loading dose (600 mg) 2:2:1 randomization Patients with clinical response criteria IGA 0/1 or EASI-75 Patients not achieving IGA 0/1 or EASI-75 at 16 weeks Open-label tralokinumab 300 mg Q2W + optional TCS (n=686) Key eligibility criteria • ≥18 years of age • Confirmed diagnosis of atopic dermatitis for ≥1 year • EASI score ≥12 at screening and ≥16 at baseline • IGA score ≥3 • AD involvement of ≥10% body surface area • Worst daily pruritus numeric rating scale (NRS) average score ≥4 during week prior to baseline • Candidates for systemic therapy due to a recent (within 1 year) history of inadequate response or intolerance to topical treatment Outcomes • EASI and IGA were assessed at baseline and at scheduled biweekly visits throughout the trials • Itch and sleep interference were recorded daily by patients using: o Numeric Rating Scale (NRS) for worst daily pruritus (11-point scale with 0 being “no itch” and 10 being “worst itch imaginable”) o NRS for eczema-related sleep interference (11-point scale with 0 indicating that it “did not interfere” and 10 indicating that it “completely interfered”) Analyses • This post hoc analysis was conducted of pooled data from ECZTRA 1 and ECZTRA 2 trials through Week 16 • Statistical analyses followed pre-specifications: o Difference in IGA 0/1 and EASI-75 response rates were assessed at Week 16 in a pre-specified pooled analysis of the primary endpoints using the Cochran- Mantel-Haenszel stratified by region, baseline Investigator’s Global Assessment (IGA) and trial. Missing data or data after rescue medication (including TCS) were imputed as non-response o Change from baseline in worst daily pruritus, eczema-related sleep interference were assessed both as weekly averages of worst daily measures (Baseline to Week 16) as well as the single worst daily measures (Baseline to Day 6) in post-hoc analyses using a mixed model for repeated measures with fixed effects of planned treatment, region, baseline IGA, trial and interactions between treatment and visit and baseline value and visit. Data collected after permanent discontinuation or initiation of rescue medication (including TCS) were set to missing o Difference in worst daily pruritus and eczema-related sleep interference response rates (NRS ≥2 and NRS≥4) were assessed using the single worst daily measures (Baseline to Day 12) in post-hoc analyses using the Cochran- Mantel-Haenszel stratified by region, baseline Investigator’s Global Assessment (IGA), and trial. Missing data or data after rescue medication (including TCS) were imputed as non-response o p values are nominal without multiplicity adjustment • 802 and 794 patients were randomized in ECZTRA 1 and 2, respectively (tralokinumab, n=1196; placebo, n=400) • Baseline demographics and clinical characteristics were well balanced between treatment groups (Table 1) IGA 0/1 and EASI-75 at Week 16 • Significantly more patients achieved the primary endpoints of IGA 0/1 (tralokinumab 19.0%, placebo 9.0%; p<0.001) and a 75% reduction in Eczema Area and Severity Index (EASI-75; tralokinumab 29.0%, placebo 12.1%; p<0.001) at Week 16 with tralokinumab versus placebo† 0 2 4 6 8 10 12 14 16 0 10 20 30 40 % Improvement in worst daily prurit us NRS from baseline (weekly average) Weeks post - baseline % Im p ro ve m en t ov er t im e *** *** *** *** *** *** *** *** *** *** *** *** ****** ****** 2 4 6 8 10 12 14 16 - 10 0 10 20 30 40 50 % Improvement in eczema relat ed sleep NRS from baseline (weekly average) Weeks post - baseline % Im p ro ve m en t ov er t im e Tralokinumab Placebo *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** • A greater improvement from baseline was seen in worst daily pruritus NRS from Day 2 (p=0.001), and in eczema-related sleep interference from Day 1 (p<0.05) with tralokinumab compared to placebo (Figure 3) Timing of the effect on itch and sleep 0 1 2 3 4 5 6 0 5 10 15 % Improvement in worst daily prurit us NRS from baseline (by day) Days post - baseline % Im pr ov em en t o ve r t im e ** *** *** *** *** 1 2 3 4 5 6 - 5 0 5 10 15 % Improvement in eczema relat ed sleep NRS from baseline (by day) Days post - baseline% Im pr ov em en t o ve r t im e Tralokinumab Placebo * *** *** *** *** *** Data shown are adjusted mean percentage change ±SE from repeated measurements model. Data collected after permanent discontinuation or initiation of rescue medication (including TCS) were set to missing. *p<0.05; **p<0.01; ***p<0.001. Data shown are adjusted mean percentage change ±SE from repeated measurements model. Data collected after permanent discontinuation or initiation of rescue medication (including TCS) were set to missing. *p<0.05; **p<0.01; ***p<0.001. †Missing data or data after collected after rescue medication (including TCS) were imputed as non-response. A B A B Rapid and sustained improvements in itch and sleep with tralokinumab treatment in patients with moderate-to-severe Atopic Dermatitis, a post hoc analysis of pooled data from ECZTRA 1 and 2