PowerPoint Presentation Objective Efficacy and safety of tralokinumab plus topical corticosteroids in patients with severe atopic dermatitis and prior history of dupilumab treatment: a post hoc subgroup analysis from ECZTRA 7 trial Jan Gutermuth1, Andrew Pink2, Margitta Worm3, Lise Soldbro4, Thomas Mark4, Joshua Corriveau5, Christian Bjerregård Øland4, Stephan Weidinger6 • AD is a chronic inflammatory disease,1 characterized by eczematous skin lesions and multiple symptoms, including pruritus, sleep disturbance, and depression2-4 • Tralokinumab is a high-affinity, fully human, monoclonal antibody designed to specifically neutralize interleukin-13, a key driver of the underlying inflammation in AD5-7 • The Phase 3 ECZTRA 7 trial (NCT03761537) met its primary endpoint of EASI-75 at Week 16, confirming tralokinumab plus topical corticosteroids (TCS) is superior to placebo plus TCS in treating severe atopic dermatitis (AD) in patients not adequately controlled by, or with contraindications to, oral cyclosporine A • There can be inadequate disease control with currently available treatment options and many patients with severe AD continue to experience high disease burden To describe the efficacy and safety of tralokinumab in a subgroup of ECZTRA 7 patients with prior history of dupilumab treatment 1Department of Dermatology, Universitair Ziekenhuis Brussel and Vrije Universiteit Brussel, Brussels, Belgium; 2St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3Division of Allergy and Immunology, Department of Dermatology, Venereology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, Germany; 4LEO Pharma A/S, Ballerup, Denmark; 5LEO Pharma Inc., Madison, NJ, USA; 6Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany Introduction Methods • ECZTRA 7 was a randomized, double-blinded, multicenter, placebo-controlled Phase 3 trial (Figure 1) • Key inclusion criteria for ECZTRA 7: o Adult patients with AD for ≥1 year with inadequate response to topical or documented systemic medication in the past year o Disease not adequately controlled with, or patients with contraindications to, use of oral cyclosporine A o AD involvement of ≥10% body surface area o EASI ≥20 and IGA ≥3 at screening and at baseline o Worst daily pruritus numeric rating scale (NRS) average score of ≥4 during the week prior to baseline Table 1. Baseline demographics and clinical characteristics for randomized subjects in ECZTRA 7. Patient characteristics References Disclosures Conclusions This post hoc subgroup analysis indicates that dupilumab-experienced patients can benefit from tralokinumab + TCS as needed. • Overall frequencies of adverse events in dupilumab-experienced patients treated with tralokinumab + TCS as needed were consistent with the pooled analysis of tralokinumab Phase 2 and 3 trials8 • Due to the small sample size, further data involving more patients are needed to confirm these findings 1. Weidinger S, Novak N. Lancet. 2016;387:1109–22; 2. Eckert L, et al. J Am Acad Dermatol. 2017;77:274–9.e273; 3. Silverberg JI, et al. Ann Allergy Asthma Immunol. 2018;121:340–7; 4. Dalgard FJ, et al. J Invest Dermatol. 2015;135:984–91; 5. Bieber T. Allergy. 2020;75:54–62; 6. Tsoi LC, et al. J Invest Dermatol. 2019;139:1480–9; 7. Popovic B, et al. J Mol Biol. 2017;429:208–19; 8. Simpson et al. Safety of specifically targeting interleukin 13 with tralokinumab in adult patients with moderate-to-severe atopic dermatitis: pooled analysis of five randomised, double- blind, placebo-controlled Phase 3 and Phase 2 trials. Poster presented at: 29th EADV Congress; 29-31 October 2020; Virtual. Jan Gutermuth reports honoraria as a consultant/advisory board member/ speaker and/or received grants from AbbVie, Genzyme, LEO Pharma, Lilly, Pfizer, Regeneron, and Sanofi. Andrew E. Pink has acted as an advisor/speaker for AbbVie, Almirall, Janssen, La Roche-Posay, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi, and UCB. Margitta Worm has served as a scientific advisor and/or clinical trial investigator and/or paid speaker for AbbVie, ALK, Allergopharma, Aimmune, Boehringer Ingelheim, Dermira, Eli Lilly, Galderma, Janssen, LEO Pharma, Mylan, Novartis, Pfizer, Regeneron and Sanofi-Genzyme. Lise Soldbro, Thomas Mark, Joshua Corriveau, and Christian Bjerregård Øland are employees of LEO Pharma A/S. Stephan Weidinger is co-principal investigator of the German Atopic Eczema Registry TREATgermany. He has received institutional research grants from Sanofi Deutschland GmbH, LEO Pharma, and La Roche-Posay, has performed consultancies for Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, Pfizer, Eli Lilly, Kymab and Novartis, he has also lectured at educational events sponsored by Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, Novartis and Galderma, and is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis and atopic eczema. Acknowledgements • The ECZTRA 7 clinical trial was sponsored by LEO Pharma • Editorial support was provided by Clair Geary, PhD of Alphabet Health (New York, NY), supported by LEO Pharma, according to Good Publication Practice guidelines (https://www.ismpp.org/gpp3). Results Dupilumab-Naive Dupilumab-Experienced All (N=263) All (N=14) Tralokinumab + TCS (n=6) Placebo + TCS (n=8) Variable n Median IQR n Median IQR n Median IQR n Median IQR AD duration, years 262 26.0 18.0, 34.0 14 34.0 15.0, 44.0 6 17 15.0, 43.0 8 34.0 21.0, 47.5 Age, years 263 33.0 25.0, 45.0 14 51.5 43.0, 57.0 6 50.0 43.0, 56.0 8 51.5 42.0, 62.5 BSA (%) 263 52.0 35.0, 70.0 14 56.5 34.0, 70.0 6 58.5 50.0, 72.0 8 54.5 33.5, 65.0 DLQI 257 16.0 11.0, 21.0 14 15.0 8.0, 18.0 6 11.0 7.0, 16.0 8 16.5 10.5, 21.5 EASI 261 28.7 22.4, 39.5 14 35.5 24.8, 39.6 6 37.3 29.0, 39.6 8 32.3 23.5, 38.9 SCORAD 261 68.9 61.5, 78.9 14 73.6 61.2, 77.0 6 72.6 58.0, 73.8 8 76.7 64.7, 82.2 Worst daily pruritus NRS (weekly average) 259 7.4 6.6, 8.3 14 6.7 5.4, 8.0 6 5.9 5.3, 7.6 8 7.4 6.2, 8.9 IGA 4, n (%) 263 129 (49.0) 14 8 (57.1) 6 5 (83.3) 8 3 (37.5) • Among dupilumab-experienced patients at Week 16, 100% (n/N, 6/6) of patients receiving tralokinumab + TCS achieved EASI-75 without the use of rescue therapy, compared to 50% (4/8) of those receiving placebo + TCS (difference [95% CI]: 50.0 [15.4, 84.6]; Table 2) • Numerically higher proportions of dupilumab-experienced patients receiving tralokinumab + TCS achieved IGA 0/1 (4/6, 66.7%; placebo + TCS: 3/8, 37.5%; difference: 29.2 [-21.3, 79.6]) and improvement in worst daily pruritus NRS (weekly average) ≥4 points (3/6, 50%; placebo + TCS: 3/8, 37.5%; difference: 12.5 [- 39.7, 64.7]) at Week 16 • Similarly, at Week 26, numerically higher proportions of dupilumab-experienced patients receiving tralokinumab + TCS achieved EASI-75 (6/6, 100%; placebo + TCS: 3/8, 37.5%; difference: 62.5 [29.0, 96.0]), IGA 0/1 (4/6, 66.7%; placebo + TCS: 2/8, 25%; difference: 41.7 [-6.5, 89.9]), and improvement in worst daily pruritus NRS (weekly average) ≥4 points (3/6, 50%; placebo + TCS: 3/8, 37.5%; difference: 12.5 [-39.7, 64.7]), compared to placebo + TCS Table 3. Adverse events in dupilumab-experienced subjects through 26 weeks • No serious adverse events occurred in either treatment group • From a safety perspective, there were 2 patients who had previously discontinued dupilumab due to conjunctivitis; adverse events of conjunctivitis were not reported for either patient during 26 weeks of tralokinumab + TCS treatment Table 2. Binary efficacy endpoints in dupilumab-experienced subjects. Figure 1. ECZTRA 7 trial design. • Dupilumab-experienced (n=14) and dupilumab-naïve (n=263) cohorts had comparable baseline characteristics, except that median (interquartile range, IQR) age was 51.5 (43.0, 57.0) years for dupilumab-experienced patients and 33.0 (25.0, 45.0) years for dupilumab-naïve patients (Table 1) • Median (IQR) EASI and percentage of patients with an IGA of 4 were 35.5 (24.8, 39.6) and 57.1% among dupilumab-experienced patients and 28.7 (22.4, 39.5) and 49.0% among dupilumab-naïve patients, respectively • Among dupilumab-experienced patients, baseline and clinical characteristics were similar between the tralokinumab + TCS as needed (n=6) and placebo + TCS as needed (n=8) groups (Table 1) o 50% of patients in each of these two groups discontinued dupilumab due to either lack of efficacy or safety concerns Visit Endpoint Tralokinumab + TCS (n=6) Placebo + TCS (n=8) Difference (95% CI)† Week 16 EASI75 6 /6 (100.0%) 4 /8 (50.0%) 50.0 (15.4,84.6) IGA 0/1 4 /6 (66.7%) 3 /8 (37.5%) 29.2 (-21.3,79.6) Itch NRS≥4* 3 /6 (50.0%) 3 /8 (37.5%) 12.5 (-39.7,64.7) Week 26 EASI75 6 /6 (100.0%) 3 /8 (37.5%) 62.5 (29.0,96.0) IGA 0/1 4 /6 (66.7%) 2 /8 (25.0%) 41.7 (-6.5,89.9) Itch NRS≥4* 3 /6 (50.0%) 3 /8 (37.5%) 12.5 (-39.7,64.7) †Estimated treatment difference and 95% CI from Mantel-Haenszel analysis with treatment as only strata *Improvement in worst daily pruritus NRS (weekly average) ≥4 points from baseline Tralokinumab + TCS (n=6) Placebo + TCS (n=8) Any adverse event 4 /6 (66.7%) 7 /8 (87.5%) Any serious adverse event 0 /6 (0.0%) 0 /8 (0.0%) Conjunctivitis* 1 /6 (16.7%) 1/8 (12.5%) *Search was done for adverse event of special interest: conjunctivitis • Eligible patients were randomized 1:1 to subcutaneous tralokinumab 300 mg every 2 weeks with TCS as needed or placebo with TCS as needed for a treatment period of 26 weeks, following a 600 mg loading dose on Day 0 • For this analysis, prior history of dupilumab treatment was confirmed and further details were collected via queries before trial unblinding • Dupilumab-experienced patients are defined as those with a confirmed history of dupilumab use prior to the trial • Cochran-Mantel-Haenszel with treatment as only strata was used for analysis AD, atopic dermatitis; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; Q2W, every 2 weeks; TCS, topical corticosteroid. Tralokinumab 300 mg + TCS Placebo + TCS TreatmentScreening Safety follow-up ECZTRA 7 (n=140) ECZTRA 7 (n=137) 1:1 randomization Up to 6 weeks washout of AD medication except TCS/TCI 300 mg Q2W after initial loading dose (600 mg) 16 weeks0–6 40 weeks8 26 weeksWeeks from treatment start Visit number –2 1 2 3 11 16 177 Primary endpoint Tralokinumab response in dupilumab-experienced patients Safety • Through the 26 weeks, 66.7% (4/6) of dupilumab-experienced patients receiving tralokinumab + TCS reported any adverse event, compared to 87.5% (7/8) of those receiving placebo + TCS (Table 3) • One placebo patient reported 2 events of conjunctivitis, 1 mild and 1 of moderate severity; 1 tralokinumab patient reported 1 mild event of conjunctivitis Efficacy and safety of tralokinumab plus topical corticosteroids in patients with severe atopic dermatitis and prior history of dupilumab treatment: a post hoc subgroup analysis from ECZTRA 7 trial