ECZTRA 1 (n=603) and ECZTRA 2 (n=593) ECZTRA 1 (n=199) and ECZTRA 2 (n=201) Tralokinumab 300 mg q2w Placebo q2w 3:1 randomization 16 weeks0 Patients with clinical response IGA-0/1 or EASI-75 –6 weeks Initial treatmentScreening Maintenance treatmenta Key inclusion criteria • Diagnosis of atopic dermatitis 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 weekly average score �4 prior to baseline Primary endpoints • IGA-0/1 at week 16 • EASI-75 at week 16 Sleep measures assessed up to week 16 • NRS for eczema-related sleep interference • SCORAD sleep score • POEM sleep score Figure 1. ECZTRA 1 and 2 trial design Introduction Methods Objective ● To assess the effect of tralokinumab monotherapy on sleep loss in patients with moderate-to-severe atopic dermatitis from the ECZTRA 1 and ECZTRA 2 trials during the initial 16-week treatment period Specifically targeting interleukin-13 with tralokinumab improved sleep in two Phase 3, randomized, double-blind, placebo-controlled trials in patients with atopic dermatitis Jonathan I. Silverberg,1 Sébastien Barbarot,2 Melinda Gooderham,3 Jan C. Simon,4 Eric Simpson,5 Azra Kurbasic,6 Christina Kurre Olsen,6 Michael J. Cork7 1Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; 2Department of Dermatology, CHU, Nantes, France; 3SKiN Centre for Dermatology, Peterborough, Ontario, Canada; 4Department of Dermatology, Venereology and Allergology, University Medical Center, Leipzig, Germany; 5Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 6LEO Pharma A/S, Ballerup, Denmark; 7Sheffield Dermatology Research, Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, UK 0.0 Tralokinumab q2w (n=601) Placebo (n=197) –0.5 –1.0 C h a n g e in s le e p N R S (9 5% C I) –1.5 –2.0 –2.5 –3.0 0.0 –0.5 –1.0 –1.5 –2.0 –2.5 –3.0 0 1 2 3 4 5 6 7 8 Week 9 10 11 12 13 14 1615 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16150 Week 16 Tralokinumab q2w (n=591) Placebo (n=201) A B C h a n g e in s le e p N R S (9 5% C I) –2.6 –1.5 –2.9 –1.9 *** ** *** *** *** *** *** *** *** *** ** ** ** ** ** ** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** ECZTRA 1 ECZTRA 2 Figure 2. Change in eczema-related sleep NRS in (A) ECZTRA 1 and (B) ECZTRA 2 by week during the initial treatment period 100 80 P a ti e n ts , % 60 40 20 0 ECZTRA 1Baseline Week 16 A Placebo (n=197) Tralokinumab 300 mg q2w (n=601) Placebo (n=197) Tralokinumab 300 mg q2w (n=601) Every day 5–6 days 3–4 days 1–2 days No days Sleep disturbance 100 80 P a ti e n ts , % 60 40 20 0 ECZTRA 2Baseline Week 16 B Placebo (n=201) Tralokinumab 300 mg q2w (n=591) Placebo (n=201) Tralokinumab 300 mg q2w (n=591) Every day 5–6 days 3–4 days 1–2 days No days Sleep disturbance 33.3% 10.9% 16.7% 19.1% 20% 51.5% 17% 10% 10.5% 11% 65.4% 14% 10.4% 8% 68% 11% 8.5% 10.5% 36.8% 11.4% 16% 19.4% 16.5% 51.6% 13.9% 15.5% 11.9% 7.2% 63.7% 12.6% 12.7% 7.8% 62.9% 15.5% 14.4% 5.7% Figure 4. POEM sleep scores at baseline and week 16 in (A) ECZTRA 1 and (B) ECZTRA 2 Sleep measure Scale Collected NRS for eczema-related sleep interference (24-hour recall) 11-point numeric scale of the extent to which eczema interfered with sleep the last night 0 = “did not interfere” to 10 = “completely interfered” Daily via eDiary by patients SCORAD sleep score (3-day recall) Visual analog scale of average sleeplessness over the last 3 days/nights 0 = “no sleeplessness” to 10 = “worst imaginable sleeplessness” At biweekly visits POEM sleep score (7-day recall) 5-point categorical scale of the frequency of sleep disturbance in the previous week 0 = “no days” to 4 = “every day” Electronically at biweekly visits up to week 8, then weeks 12 and 16 Table 1. Patient-reported sleep measures assessed during the initial 16-week treatment period E C Z T R A 1 ( n = 8 0 2 ) E C Z T R A 2 ( n =7 9 4 ) P l a c e b o ( n = 1 9 9 ) Tr a l o k i n u m a b q 2 w ( n = 6 0 3 ) P l a c e b o ( n = 2 0 1 ) Tr a l o k i n u m a b q 2 w ( n = 593 ) Mean age, years 39 39 35 37 Male, n (%) 123 (62) 351 (58) 114 (57) 359 (61) Mean duration of atopic dermatitis, years 29.6 27.9 27.5 28.3 Mean BSA involvement with atopic dermatitis, % 54.2 52.7 53.0 52.6 Severe disease (IGA-4), % 51.3 50.6 50.2 48.2 Mean EASI 32.9 32.2 32.6 32.1 Mean weekly average eczema-related sleep NRS 6.8 6.9 7.3 7.2 Mean SCORAD sleep score 6.4 6.5 7.2 7.0 Mean POEM sleep score 3.3 3.3 3.3 3.3 Table 2. Patient demographics and baseline characteristics at baseline 0.0 Tralokinumab q2w (n=601) Placebo (n=197) –1.0 C h a n g e in S C O R A D s le e p s co re (9 5% C I) –2.0 –3.0 –4.0 –1.0 –2.0 –3.0 –4.0 –5.0 0.0 –5.0 0 2 4 6 8 Week 10 12 14 2 4 6 8 10 12 14 16 0 Week ECZTRA 1 ECZTRA 2 16 Tralokinumab q2w (n=591) Placebo (n=201) A B C h a n g e in S C O R A D s le e p s co re (9 5% C I) –2.6 –1.8 –3.0 –1.8 *** *** *** *** *** *** *** *** *** *** *** *** * ** ** ** Figure 3. Change in SCORAD sleep score in (A) ECZTRA 1 and (B) ECZTRA 2 by week during the initial treatment period *P<0.05 versus placebo; **P<0.01 versus placebo; ***P<0.001 versus placebo. Data collected after permanent discontinuation of the IMP or initiation of rescue medication not included. In case of no post-baseline assessment before initiation of rescue medication, the week 2 change was imputed as 0. Repeated measurements model: change = treatment*week + baseline*week + region + baseline IGA. **P<0.01 versus placebo; ***P<0.001 versus placebo. Data collected after permanent discontinuation of the IMP or initiation of rescue medication not included. In case of no post-baseline assessment before initiation of rescue medication, the week 2 change was imputed as 0. Repeated measurements model: change = treatment*week + baseline*week + region + baseline IGA. Data collected after permanent discontinuation of IMP or initiation of rescue medication not included. Missing data at week 16 imputed using the LOCF, i.e. last observation of POEM sleep score prior to permanent discontinuation of the IMP or initiation of rescue medication was carried forward. Results Disclosures 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. Sébastien Barbarot has received research grants, personal fees, and non-financial support from AbbVie, Bioderma, Pierre Fabre Laboratory, Fondation pour la dermatite atopique, Janssens, Laboratoire La Roche Posay, LEO Pharma, Novartis, and Sanofi-Genzyme. Melinda Gooderham has been an investigator, consultant, and/or speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Dermira, Galderma, GSK, Janssen, LEO Pharma, Lilly Medimmune, Merck Serono, Novartis, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Pfizer, and Valeant. Jan C. Simon has received speaker’s honoraria and is member of advisory boards of AbbVie Pharma, Janssen Pharma, Novartis Pharma, and UCB Pharma, and received travel grants from these companies and from LEO Pharma. Eric Simpson reports grants and personal fees from AbbVie, Lilly, LEO Pharma, MedImmune, Pfizer, and Regeneron; grants from Celgene, Galderma, Kyowa Hakko Kirin, Merck, Novartis, and Tioga; and personal fees from Boehringer Ingelheim, Dermavant, Dermira, FortéBio, Incyte, Menlo Therapeutics, Ortho Dermatologics, Pierre Fabre, Sanofi, and Valeant. Azra Kurbasic and Christina Kurre Olsen are employees of LEO Pharma. Michael J. 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. The ECZTRA 1 and 2 studies were sponsored by LEO Pharma A/S, Ballerup, Denmark. References 1. Weidinger S, Novak N. Lancet 2016; 387: 1109–1122. 2. Silverberg JI et al. Ann Allergy Asthma Immunol 2018; 121: 340–347. 3. Dalgard FJ et al. J Invest Dermatol 2015; 135: 984–991. 4. Chang Y, Chiang B. J Allergy Clin Immunol 2018; 142: 1033−1040. 5. Silverberg JI et al. J Invest Dermatol 2015; 135: 56−66. 6. Jeon C et al. Dermatol Ther (Heidelb) 2017; 7: 249−264. 7. Bieber T. Allergy 2020; 75: 54−62. 8. Tsoi LC et al. J Invest Dermatol 2019; 139: 1480−1489. 9. Popovic B et al. J Mol Biol 2017; 429: 208−219. 10. Simpson E et al. Presented at the American Academy of Dermatology Annual Meeting, March 20–24, 2020, Denver, CO, USA. 11. Lei D et al. Ann Allergy Asthma Immunol 2020; 124: 261−266. ● Atopic dermatitis is a chronic inflammatory skin disease that is associated with sleep loss and impaired quality of life1-3 ● Several factors may contribute to sleep loss in atopic dermatitis, including pruritus, scratching, and dysregulated cytokine levels4-6 ● Tralokinumab is a fully human, immunoglobulin G4 monoclonal antibody that specifically binds to the IL-13 cytokine with high affinity, preventing interaction with the IL-13 receptor and subsequent downstream IL-13 signaling, thus preventing its pro-inflammatory activity7-9 ● In Phase 3 trials, ECZTRA 1 (NCT03131648) and ECZTRA 2 (NCT03160885), investigating tralokinumab monotherapy in adults with moderate-to-severe atopic dermatitis, significantly more patients receiving tralokinumab monotherapy achieved the primary endpoints of Investigator Global Assessment of 0 or 1 (IGA-0/1) [clear or almost clear skin] and 75% improvement in Eczema Area and Severity Index (EASI-75) compared with placebo at week 16 of the initial treatment period10 Study design and patients ● ECZTRA 1 and 2 were identically designed, randomized, double-blind, placebo-controlled, multinational, 52-week trials of tralokinumab monotherapy in patients with moderate-to-severe atopic dermatitis ● Eligible patients were ≥18 years of age with a confirmed diagnosis of atopic dermatitis for ≥1 year and were candidates for systemic therapy due to a recent (within 1 year) history of inadequate response or intolerance to topical treatment. Additional eligibility criteria included an EASI score of ≥16, IGA ≥3, and worst daily pruritus Numeric Rating Scale (NRS) ≥4 ● Patients were randomized 3:1 to receive either subcutaneous tralokinumab 300mg or placebo every 2 weeks for an initial treatment period of 16 weeks (Figure 1) aFull design of treatment regime after week 16 not shown. BSA, body surface area; q2w, every 2 weeks. Measures of sleep ● SCORing Atopic Dermatitis (SCORAD) and Patient-Oriented Eczema Measure (POEM) sleep scores were recently validated for use as single-item, patient-reported assessments of sleep loss in adults with atopic dermatitis11 ● Several measures of sleep were assessed in ECZTRA 1 and 2 during the initial 16-week treatment period (Table 1): — NRS for eczema-related sleep interference — SCORAD sleep score — POEM sleep score Statistical analysis ● Changes in eczema-related sleep interference NRS and SCORAD sleep score were assessed by a repeated measurements model, including baseline IGA, region, and treatment-by-week interactions as factors and interaction between week and baseline value as covariates — Change = Treatment*Week + baseline*Week + Region + Baseline IGA ● The percentage of patients in each of the five POEM sleep score categories was assessed at baseline and week 16 — Missing data at week 16 was imputed using last observation carried forward (LOCF), whereby the last observation of POEM sleep score prior to permanent discontinuation of the investigational medicinal product (IMP) or initiation of rescue medication was carried forward ● Data collected after permanent discontinuation of the IMP or initiation of rescue medication were excluded from the analyses Patient characteristics ● In total, 802 and 794 patients were randomized in ECZTRA 1 and 2, respectively (Table 2) ● Overall, baseline characteristics were similar across both trials Eczema-related sleep interference NRS ● There was a greater improvement in weekly average eczema-related sleep interference NRS with tralokinumab compared with placebo in both ECZTRA 1 and ECZTRA 2 (Figure 2) — Change from baseline in eczema-related sleep interference NRS was larger with tralokinumab compared with placebo at each week, with separation observed between the treatment groups (P0.001) from week 1 ● The least-square mean (LSM) change from baseline at week 16 was greater with tralokinumab compared with placebo in both trials (ECZTRA 1, –2.6 [95% confidence interval (CI) –2.9, –2.4] vs –1.9 [95% CI –2.4, –1.5]; P=0.007, and ECZTRA 2, –2.9 [95% CI –3.1, –2.7] vs –1.5 [95% CI –1.9, –1.1]; P0.001) SCORAD sleep score ● There was a greater improvement in SCORAD sleep score with tralokinumab compared with placebo in both ECZTRA 1 and ECZTRA 2 (Figure 3) — Change from baseline in SCORAD sleep score was greater with tralokinumab compared with placebo, with separation observed between the treatment groups from week 2 (P0.001) and at each week onwards (P0.05) ● The LSM change from baseline at week 16 was greater with tralokinumab compared with placebo (ECZTRA 1, −2.6 [95% CI –2.9, –2.3] vs –1.8 [95% CI –2.3, –1.3]; P=0.004, and ECZTRA 2, –3.0 [95% CI –3.2, –2.7] vs –1.8 [95% CI –2.3, –1.2]; P0.001) POEM sleep score ● There was a greater shift towards lower POEM sleep scores with tralokinumab compared with placebo in both ECZTRA 1 and ECZTRA 2 (Figure 4) — The majority of patients (87.5−92.8%) across treatment groups reported ≥3 nights of sleep disturbance at baseline in both trials — At week 16, 64.2% and 60.9% of tralokinumab-treated patients reported ≥3 nights of sleep disturbance compared to 81% and 78.5% of patients with placebo ● A greater proportion of tralokinumab-treated patients (35.9−39.1%) reported “No days” or “1−2 days” of sleep disturbance at week 16 versus placebo (19.1−21.5%) Winter Clinical Dermatology Conference, January 16-24, 2021 Conclusions ● Tralokinumab monotherapy 300 mg every 2 weeks demonstrated improvements compared with placebo in three sleep measures (NRS for eczema-related sleep interference, SCORAD sleep score, and POEM sleep score) during the initial 16-week treatment period ● Improvement in sleep measures was consistent across two large Phase 3 trials, ECZTRA 1 and ECZTRA 2 ● A greater proportion of tralokinumab-treated patients reported either “no days” or “1–2 days” of sleep disturbance ● Early improvement in sleep measures as early as week 1 with tralokinumab is consistent with its effects on the signs and troublesome symptoms of atopic dermatitis, including pruritus