PowerPoint Presentation 3 years of tralokinumab treatment provides long-term disease control as demonstrated by clinically meaningful outcomes in moderate-to-severe atopic dermatitis Richard B Warren1, Kristian Reich2, Eric Simpson3, Richard Langley4, Antonio Costanzo5, Hidehisa Saeki6, Peter Almgren7, Emilia Vacko7, Anna Carlsson7, Melinda Gooderham8, Mette Deleuran9, Juan Francisco Silvestre10, Stefan Weidinger11, Andrew Blauvelt12 1Dermatology Centre, Salford Royal NHS Foundation Trust and NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK; 2Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 4Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, Nova Scotia, Canada; 5Dermatology Unit Department of Biomedical Sciences, Humanitas University, Milano, Italy; Skin Pathology Laboratory, Humanitas Research Hospital IRCCS, Milano, Italy; 6Department of Dermatology, Nippon Medical School, Tokyo, Japan; 7LEO Pharma A/S, Ballerup, Denmark; 8SKiN Centre for Dermatology, Peterborough, ON, Canada; Department of Dermatology, Queen's University, Kingston, ON, Canada; Probity Medical Research, Waterloo, ON, Canada; 9Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark; 10Dermatology Department, Hospital General Universitario de Alicante, Alicante, Spain; 11Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 12Oregon Medical Research Center, Portland, OR, USA ECZTEND interim efficacy analysis set n=347 Age Median years (IQR) 42.0 (30.0; 53.0) Sex n (%) Male Female 205 (59.1) 142 (40.9) Race n (%)a White Black Asian 259 (74.6) 20 (5.8) 56 (16.1) Parent trial n (%) ECZTRA 1 ECZTRA 2 224 (64.6) 123 (35.4) Age at onset of AD Median years (IQR) 3.0 (1.0; 15.0) Duration of AD Median years (IQR) 29.0 (19.0; 43.0) Parent Trial Baseline ECZTEND Baseline IGA severity n (%) Clear/minimal (score=0/1) Mild (score=2) Moderate (score=3) Severe (score=4) - - 172 (49.6) 175 (50.4) 98 (28.2) 123 (35.4) 106 (30.5) 20 (5.8) EASI Median (IQR) 26.7 (19.7; 38.4) 4.7 (2.2; 12.4) SCORAD Median (IQR) 68.1 (60.8; 78.1) 32.8 (20.6; 46.9) DLQI Median (IQR), n 17.0 (11.0; 23.0), n=343 5.0 (2.0; 10.0), n=332 Worst weekly pruritus NRSa Median (IQR), n 7.9 (6.9; 8.9), n=346 5.0 (3.0; 8.0), n=347 Table 1. Baseline demographic and disease characteristics of patients with 3 years total tralokinumab treatment (ECZTEND interim efficacy analysis set) Table 2. Summary of adverse events (AEs) in patients with 3 years total tralokinumab treatment aIn PTs, worst pruritus NRS was assessed daily; in ECZTEND, worst pruritus NRS was assessed based on recall of the previous week before the visit. Conclusions • Clinically meaningful improvements were observed in AD signs and symptoms in patients with moderate-to-severe AD treated with tralokinumab for 3 years • Nine out of ten patients achieved at least one of the clinically relevant outcomes of EASI ≤ 7, itch NRS ≤ 4, or DLQI ≤ 5, representing mild/no AD; approximately 60% achieved clinically meaningful outcomes by all three measures • The response rates were maintained over time with patients having EASI ≤ 7 for more than 80% of visits during the 3 years of treatment • These data, in combination with the favorable safety profile, suggest tralokinumab as an efficacious and well-tolerated treatment option for long-term disease control in patients with moderate-to- severe AD aIncludes 347 patients from the PTs ECZTRA 1 and 2 who had consistently received tralokinumab for a total of 3 years at data cutoff, April 30, 2021. bIncludes patients from a pooled safety analysis set from parent trials ECZTRA 1, 2, 3, 5, and Phase 2b, previously presented at RAD Virtual 20201; AEs related to study drug and AEs leading to withdrawal during initial treatment sourced from data on file; TCS rules varied across parent trials with mandatory TCS in ECZTRA 3, and TCS use not part of treatment regimen in ECZTRA 1, ECZTRA 2, and ECZTRA 5. cRate calculated by number of patients divided by PYE until first event, multiplied by 100. dRate calculated by number of events divided by PYE, multiplied by 100. eFor PTs, Cochran-Mantel-Haenszel weights were applied to calculate adjusted AE incidences and rates to account for different randomization ratios across PTs.7 fAEs related to study drug comprise AEs considered possibly or probably related by the investigator and AEs with missing causality. Objective To evaluate the efficacy and safety of 3 years of tralokinumab treatment, using clinically relevant outcomes indicating disease control, for adults with moderate-to-severe AD Materials and Methods Patients and treatment • In ECZTEND, patients who completed PT of tralokinumab received open-label tralokinumab 300 mg every two weeks (Q2W, home use) plus optional topical corticosteroids (TCS, US class ≥4 or Europe class ≤3) or topical calcineurin inhibitor (TCI), with visits every 8 weeks o For key inclusion and exclusion criteria, please see Blauvelt et al5 o Multiple tralokinumab PT of varying duration will contribute to the ECZTEND population (ECZTRA 1-8 and the investigator-initiated study TraSki, conducted in 11 countries) o While ECZTRA 3-5 and 7 were completed at data cutoff (April 30, 2021), participants in these trials did not receive 52 weeks of tralokinumab and therefore were not included in the 3-year efficacy analysis set • This post hoc analysis assessed tralokinumab efficacy in a homogenous group of participants with the longest tralokinumab treatment duration at data cutoff (April 30, 2021) o Data are presented from eligible adult patients with moderate-to-severe AD who completed 3 years of tralokinumab treatment irrespective of response in the PT ECZTRA 1 and 2 (1 year in PT, 2 years in ECZTEND; Figure 1; N=347 of 1442 total enrolled in ECZTEND at data cutoff) Analyses • Efficacy outcomes assessed were: o Proportion of patients with 3 years total tralokinumab treatment achieving EASI-75/90, IGA 0/1, and EASI ≤ 7 o Percentage of patients achieving mild or no disease, defined as EASI ≤ 7, itch NRS ≤ 4, or DLQI ≤ 5, after 3 years of tralokinumab treatment o Proportion of time with mild/no disease during 3 years total tralokinumab treatment • For EASI-75/90 and IGA 0/1 response rates, as observed data are presented, and intermittent missing data are presented using last observation carried forward (LOCF). Modified non-responder imputation (mNRI) sets discontinuation from ECZTEND due to adverse event(s) or lack of efficacy as non-response and uses LOCF for other missing data Results Baseline demographics and characteristics • This post hoc analysis included 347 patients from the PTs ECZTRA 1 and 2 who had entered ECZTEND and consistently received tralokinumab for a total of 3 years at data cutoff, April 30, 2021 (Fig. 1B, Table 1) • Amongst patients who completed 3 years of tralokinumab treatment (N=347), median EASI improved from 26.7 (IQR 19.7; 38.4) at PT baseline to 3.0 (IQR 1.0; 6.7) after one year of PT Sustained improvement in lesion extent and severity with continued tralokinumab • Amongst patients who completed 3 years of tralokinumab treatment at data cutoff, o EASI-75 and EASI-90 were achieved in 76% (263/347) and 54% (186/347) of patients by mNRI, respectively (Figure 2) o IGA 0/1 was achieved in 44% (151/347) by mNRI (Figure 2) o EASI ≤7 was achieved by 75% (261/347) by mNRI (Figure 2) Figure 2. Proportion of patients with 3 years total tralokinumab treatment achieving EASI-75, EASI-90, IGA 0/1, and EASI ≤7 aAs observed, includes patients from the PTs ECZTRA 1 and 2 who had consistently received tralokinumab for a total of 3 years at data cutoff, April 30, 2021. bIntermittent missing data imputed using LOCF. cDiscontinuation from ECZTEND due to adverse event(s) or lack of efficacy set as non-response, other missing imputed with LOCF. Scan to download a copy of this poster Copies of this poster and its content, obtained through this QR code, are for personal use only and may not be reproduced without written permission from the authors Introduction • Atopic dermatitis (AD) is a chronic skin disease which may impact patients throughout their lifespan, requiring efficacious long-term treatment options with a favorable safety profile1 • The European guidelines (EuroGuiDerm) define disease control or remission as satisfactory reduction of the signs and symptoms of AD whilst being on a safe long-term anti-inflammatory treatment2 o An international consensus previously defined a set of core decision points for systemic therapies at 6 months, including EASI ≤ 7, itch NRS ≤ 4 and DLQI ≤ 5 representing mild/no disease3 • Tralokinumab, a specific, high-affinity interleukin-13 inhibitor, is approved in Europe, Canada, and the United States for the treatment of adults with moderate-to-severe AD • ECZTEND (NCT03587805) is an ongoing open-label extension trial assessing the safety and efficacy of tralokinumab over 5 years after the completion of parent trials (PT) o A recently presented interim safety analysis of adult patients with up to 42 months of exposure confirmed the safety profile of tralokinumab4 Maintained improvements in clinically relevant outcomes at 3 years of tralokinumab treatment • Patients were controlled (mild/no disease) for the majority of the 3 years of tralokinumab treatment (Figure 3) • At 3 years of tralokinumab treatment, 93% (254/274, as observed) of patients achieved at least one outcome (Figure 4) • Median duration of response during PT and ECZTEND up to week 104, as observed: o >80% of visits with EASI ≤ 7 response [84.7 (Q1,Q3; 55.8, 93.8)%] o >80% of visits with DLQI ≤ 5 [84.1 (43.1, 96.9)%] o >70% of visits with Itch NRS ≤ 4 [73.8 (31.7, 91.3)%] • Using mNRI, 84% of patients achieved at least one clinically meaningful improvement, and 51% achieved clinically meaningful improvements of all three measures 93% (254/274) of patients achieved at least one outcome on tralokinumab Figure 4. Percentage of patients achieving mild or no disease by at least one outcome after 3 years of tralokinumab treatment 9% DLQI ≤5 n/N 206/270 12% 6% EASI ≤7 n/N 227/274 Itch NRS ≤4 n/N 188/273 3% 4% 3% 58% Data as observed. Denominator is the smallest number of patients with DLQI, EASI, and itch NRS measurement(s) in category, except for individuals with no response where largest number is used. No response includes non-evaluable patients, e.g., for category DLQI≤5 + EASI≤7 where DLQI is not measured for one or more patient(s). No new safety signals with continued tralokinumab treatment • The safety profile was consistent with the PTs6 and the overall ECZTEND population (n=1442),4 with no new safety signals arising with continued tralokinumab (Table 2) AEs in ECZTEND ECZTEND interim efficacy analysis seta AEs up to Week 16 in parent trials initial tralokinumab treatmentb Tralokinumab Q2W + optional TCS (n=347; PYE=707.7) Tralokinumab Q2W ± TCS (n=1605; PYE=473.2) Placebo Q2W ± TCS (n=680; PYE=193.1) n (%) Ratec [(nP/PYE)*10 0] E Rated [(nE/PYE)*10 0] n (adj. %)d E Adj. Rated,e [(nE/PYE)*10 0] n (adj. %)d E Adj. Rated,e [(nE/PYE)*10 0] All AEs 295 (85.0) 144.2 1422 200.9 1080 (65.7) 3148 639.5 449 (67.2) 1276 678.3 AEs related to study drugf 102 (29.4) 18.3 251 35.5 463 (28.0) 1025 207.6 176 (26.8) 365 195.6 Severity Mild 247 (71.2) 80.5 917 129.6 881 (53.2) 2127 429.8 326 (49.0) 738 391.0 Moderate 180 (51.9) 40.6 450 63.6 518 (31.5) 917 189.5 258 (39.0) 478 254.3 Severe 31 (8.9) 4.6 55 7.8 77 (4.6) 104 20.2 40 (6.3) 60 33.0 Serious AEs 31 (8.9) 4.6 34 4.8 37 (2.1) 38 7.4 18 (2.8) 22 11.9 Leading to withdrawal from trial 9 (2.6) 1.3 9 1.3 34 (2.0) 42 8.6 12 (1.8) 15 8.0 References 1. Weidinger S, Novak N. Lancet. 2016;387(10023):1109-1122. 2. Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2022;36(9):1409-1431. 3. de Bruin-Weller M, et al. Acta Derm Venereol 2021; 101: adv00402. 4. Blauvelt A, et al. Poster presented at: American Academy of Dermatology Annual Meeting; March 25-29, 2022, Boston, MA. 5. Blauvelt A, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02345-3. 6. Simpson E, et al. Poster presented at: Revolutionizing Atopic Dermatitis (RAD) Conference; December 13–14, 2020, Virtual. 7. Chuang-Stein C. Pharm Stat 2011; 10:3–7. Disclosures Richard B Warren has received research grants or consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, Eli Lilly, GSK, Janssen, LEO Pharma, Medac, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and UNION. He is supported by the Manchester NIHR Biomedical Research Centre. Kristian Reich has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Forward Pharma, Gilead, Galderma, Janssen-Cilag, Kyowa Kirin, Leo, Lilly, Medac, Novartis, Ocean Pharma, Pfizer, Sanofi, UCB. Kristian Reich is co-founder of Moonlake Immunotherapeutics. Eric Simpson reports grants and/or personal fees from AbbVie, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, FortéBio, Galderma, Incyte, Kyowa Kirin, LEO Pharma, MedImmune, Menlo Therapeutics, Merck, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron, Sanofi, Tioga, and Valeant. Richard Langley has served and received compensation in the form of grants and/or honoraria as principal investigator for and is on the scientific advisory board or has served as a speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, Novartis, Pfizer, and UCB. Antonio Costanzo has received research grants or consulting fees from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, UCB. Hidehisa Saeki has received lecture fees from Kyorin, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Maruho, Sanofi, Tokiwa, and Taiho; and scholarship donations from Esai, Mitsubishi Tanabe, Maruho, and Torii. Peter Almgren, Emilia Vacko, and Anna Carlsson are employees of LEO Pharma. Melinda Gooderham has been an investigator, speaker and/or advisor for: AbbVie, Amgen, Akros, AnaptysBio, Aslan, Arcutis, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Mette Deleuran has received research support, honoraria for lecturing, and/or is on consulting/advisory board agreements with AbbVie, Arena Pharmaceuticals, ASLAN Pharmaceuticals, Incyte, La Roche Posay, LEO Pharma, Lilly, Pfizer, Pierre Fabre, Regeneron, and Sanofi Genzyme. Juan Francisco Silvestre has served as a consultant and received speaking fees at educational events for Sanofi-Genzyme, Regeneron, AbbVie, Leo Pharma, and Novartis and has served as the principal investigator in clinical trials sponsored by AbbVie, Amgen, AstraZeneca, BMS, Galderma, Incyte, LEO Pharma, Lilly, Novartis, and Pfizer. Stephan Weidinger 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 Almirall, he has also lectured at educational events sponsored by Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, and Eli Lilly, and is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis and atopic dermatitis. Andrew Blauvelt has served as a speaker, scientific adviser, and / or clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, EcoR1, Eli Lilly, Evommune, Forte, Galderma, Incyte, Janssen, Landos, LEO Pharma, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, Vibliome, and Xencor Acknowledgements This analysis was sponsored by LEO Pharma A/S. Medical writing and editorial support from Alphabet Health by Meredith Whitaker, PhD and Juliel Espinosa, PhD was funded LEO Pharma A/S, Ballerup, Denmark, according to Good Publication Practice guidelines (https://www.ismpp.org/gpp3). Richard B Warren is supported by the Manchester NIHR Biomedical Research Centre. This work was previously presented at EADV 2022. Abbreviations %, percentage of patients with ≥1 event; adj., adjusted (for PTs, Cochran-Mantel-Haenszel weights were applied to calculate adjusted AE incidences and rates to account for different randomization ratios across PTs)7; AE, adverse event; AD, atopic dermatitis; BP, parent trial baseline; DLQI, dermatology life quality index; E, number of adverse events; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; IQR, interquartile range; Itch NRS, peak worst weekly itch NRS; LOCF, last observation carried forward; mNRI, modified non-responder imputation; n, number of patients achieving the indicated metric, or with ≥1 event; nE, number of events; nP, number of patients; N, number of patients with recorded observation; NRS, numerical rating scale; PYE, patient-years of exposure; PT, parent trial; Q2W, every 2 weeks; SCORAD, scoring atopic dermatitis; SD, standard deviation; TCI, or topical calcineurin inhibitor; TCS, topical corticosteroids. Limitations • The analysis presented here represents a subgroup of patients who were eligible, chose to enter from two of the PTs and were treated for two years in ECZTEND by the time of data cutoff, and as such, the data may not be generalizable to the full tralokinumab population (see Figure 1B). Analyses on the full two-year cohort were previously presented4) In ECZTEND, worst itch NRS was assessed based on recall of the previous week before the visit Figure 3. Percent response from parent trial baseline in disease severity, itch, and life quality over 3 years Figure 1. Schematic of (A) ECZTEND interim analysis of patients previously treated with tralokinumab monotherapy for 52 weeks in ECZTRA 1 and 2, followed by 104 weeks of treatment in ECZTEND and (B) patient disposition at parent trial completion, ECZTEND baseline, and at April 30, 2021 data cutoff https://www.ismpp.org/gpp3 Slide 1: 3 years of tralokinumab treatment provides long-term disease control as demonstrated by clinically meaningful outcomes in moderate-to-severe atopic dermatitis