PowerPoint Presentation Tralokinumab demonstrated a consistent safety profile with up to 42 months of treatment in moderate-to- severe atopic dermatitis: including adverse events of special interest Kristian Reich1, Eric Simpson2, Richard Langley3, Richard B Warren4, Antonio Costanzo5, Hidehisa Saeki6, Peter Almgren7, Le Gjerum7, Anna Carlsson7, Melinda Gooderham8, Andreas Pinter9, Marjolein De Bruin Weller10, and Andrew Blauvelt11 1Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, DE; 2Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 3Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, Nova Scotia, CA; 4Dermatology Centre, Salford Royal NHS Foundation Trust and NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK; 5Dermatology Unit Department of Biomedical Sciences, Humanitas University, Milano, IT; Skin Pathology Laboratory, Humanitas Research Hospital IRCCS, Milano, IT; 6Department of Dermatology, Nippon Medical School, Tokyo, JP; 7LEO Pharma A/S, Ballerup, DK; 8SKiN Centre for Dermatology, Peterborough, ON, CA; Department of Dermatology, Queen's University, Kingston, ON, CA; Probity Medical Research, Waterloo, ON, CA; 9Department of Dermatology, Venereology, and Allergology, Goethe-Universität Frankfurt am Main, Frankfurt am Main, DE; 10Department of Dermatology and Allergology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, NL; 11Oregon Medical Research Center, Portland, OR, USA Table 1. ECZTEND interim analysis baseline demographic and disease characteristics Table 2. AESIs in ECZTEND at April 30, 2021 data cut-off Conclusions • This analysis of 1442 patients with up to 42 months of treatment supports the long-term benefit-risk profile of targeted IL-13 inhibition with tralokinumab for patients with moderate- to-severe AD, with no new safety signals identified • Exposure-adjusted incidence rates of AEs of special interest were generally similar to or lower than rates reported during the short-term, placebo-controlled period up to Week 16 and declined over time • Overall, tralokinumab demonstrated sustained long-term improvement in extent and severity of atopic dermatitis over 104 weeks of treatment in ECZTEND Figure 1. ECZTEND study design (A) and patient cohorts in interim analyses (B) Objective To report an interim safety analysis of patients treated with tralokinumab for up to 42 months, including adverse events of special interest (AESI) Materials and Methods Study design and patient cohorts • ECZTEND is an open-label, 5-year extension trial including adult and adolescent patients with AD in 11 countries who previously participated in the tralokinumab PTs ECZTRA 1-8 or the TraSki investigator- initiated study • In ECZTEND, patients received open-label tralokinumab 300 mg Q2W (home use) plus optional topical corticosteroids (TCS), with visits every 8 weeks (Figure 1A) • Interim safety analyses presented here include all patients transferred from ECZTRA 1-5 and 7; with patients having received up to 42 months maximum tralokinumab exposure (≤1 year in PTs and ≤2.5 years in ECZTEND; safety analysis set, n=1442) (Figure 1B) • ECZTRA 1/2: double-blinded, randomized, placebo-controlled, 52-week monotherapy trials • ECZTRA 3: double-blinded, randomized, placebo-controlled, 32-week TCS combination trial • ECZTRA 4: open-label, 14-week, drug-drug interaction (DDI) trial • ECZTRA 5: double-blinded, randomized, placebo-controlled, 16-week, vaccine antibody-response trial • ECZTRA 7: randomized, double-blinded, placebo-controlled, 26-week TCS combination trial in Cyclosporin A (CsA) refractory patients • Interim efficacy analyses are also presented from the ECZTEND Week 104 cohort (n=616), which includes all patients who reached the 2-year time point or would have reached that time point had they not discontinued earlier (Figure 1B) Endpoints and analyses • Primary endpoint: Number of AEs during the treatment period from baseline of ECZTEND up to Week 268 • Secondary endpoints: Proportions of patients achieving an Investigator’s Global Assessment (IGA) score of 0/1 (clear/almost clear) and >75% improvement in Eczema Area and Severity Index (EASI-75) from Week 16 to Week 248 • A summary of the number of AEs, the rate of AEs, the number (percentage) of patients with any treatment-emergent adverse events (TEAEs), deaths, SAEs, and withdrawals from the trial due to AEs are presented • AESIs were predefined in the trial based on areas of safety interest for monoclonal antibodies in AD: skin infections requiring systemic treatment, eczema herpeticum, malignancies, and eye disorders. Other safety areas of interest were captured retrospectively using MedDRA searches of all AEs Results Patients, Demographics, and Clinical Characteristics • Patients had up to 42 months of tralokinumab exposure (including PTs plus ECZTEND) with a median time on tralokinumab total of 131.5 weeks (approximately 31 months; IQR 83.4-161.8 weeks), at the time of data cut-off • Long-term use of tralokinumab 300 mg Q2W was well-tolerated, and no new safety signals were identified with up to 42 months of treatment relative to initial treatment in parent trials (Figure 2) • The pattern of frequently reported AEs in ECZTEND (≥5.0% of patients) was similar to that observed with tralokinumab in the PTs, including viral upper respiratory tract infection, atopic dermatitis, upper respiratory tract infection, headache, and conjunctivitis (reported by preferred term) • No events of conjunctivitis AEs were SAEs; only 4 patients discontinued due to conjunctivitis AEs (0.3 %) Figure 2. Long-term use of tralokinumab 300 mg Q2W was well-tolerated in ECZTEND References 1. Nutten S. Ann Nutr Metab. 2015;66(Suppl 1):8-16; 2. Weidinger S, Novak N. Lancet. 2016;387:1109-22; 3. Popovic B, et al. J Mol Biol. 2017;429:208-19; 4. Wollenberg A, et al. Br J Dermatol. 2021;184(3):437-449; 5. Silverberg JI, et al. Br J Dermatol. 2021;184(3):450-463; 6. Blauvelt A, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02345-3.Disclosures 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; Professor 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. 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. 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, Le Gjerum, 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. Andreas Pinter has served as an investigator and/or speaker and/or advisor for AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Biontec, Boehringer-Ingelheim, Celgene, Celltrion, GSK, Eli-Lilly, Galderma, Hexal, Janssen, LEO Pharma, MC2, Medac, Merck Serono, Mitsubishi, MSD, Novartis, Pascoe, Pfizer, Tigercat Pharma, Regeneron, Roche, Sandoz Biopharmaceuticals, Sanofi-Genzyme, Schering-Plough and UCB Pharma. Marjolein S. de Bruin-Weller is a consultant/advisor for AbbVie, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and UCB and has received grant/research support from Regeneron and Sanofi Genzyme. Andrew Blauvelt has served as a speaker, scientific adviser, and / or clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Anaptysbio, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, EcoR1, Eli Lilly, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, Janssen, Landos, LEO Pharma, Merck, 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 according and editorial support from Alphabet Health by Meredith Whitaker, PhD was funded LEO Pharma A/S, Ballerup, Denmark, 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. 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 and debilitating inflammatory skin disease requiring long-term treatment options with a favorable safety profile1,2 • Tralokinumab, a first-in-class, fully human monoclonal antibody, specifically neutralizes IL-13 with high affinity3 • Phase 3 studies with tralokinumab have demonstrated favorable safety and sustained efficacy in adult patients with AD for up to 1 year4,5 • An ongoing extension trial, ECZTEND (NCT03587805), is assessing the safety and efficacy of treatment with subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) following participation in a parent trial (PT) • With one additional year added to the previously published data6 this analysis further describes the safety profile of tralokinumab during long-term treatment Figure 3. AESIs in ECZTEND at April 30, 2021 data cut-off Summary of AESIs in ECZTEND • AESIs were observed at rates similar to or lower than reported in PTs (Figure 3, Table 2) • The most frequent eye disorder was conjunctivitis, including bacterial, allergic and viral types • There was no clustering in type of malignancy and none reported in more than 2 patients • There was no specific clustering in any type of skin infection requiring systemic treatment • Other areas of interest, based on common concerns for those with AD, were: • Injection site reaction: reported for 35 patients [2.4%, 2.5 vs 22.9 and 4.0 (nE/PYE)*100 in ECZTEND vs PT tralokinumab and placebo] • Rates for herpes simplex, oral herpes and herpes zoster: similar or lower than placebo up to week 16 and rates decreased over time [2.0/1.6/1.3 vs 5.2/3.1/1.4 and 3.7/8.1/2.0 (nE/PYE)*100 in ECZTEND vs PT tralokinumab and placebo] Abbreviations %, percentage of patients with ≥1 event; AD, atopic dermatitis; adj., adjusted; AE, adverse event; AESI, adverse event of special interest; DLQI, Dermatology Life Quality Index; E, number of adverse events; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; LOCF, last observation carried forward; n, number of patients with ≥1 event; nE, number of events; nP, number of patients; NRI, non-responder imputation; NRS, Numeric Rating Scale; PYE, patient-years of exposure; PT, parent trial; Q2W, every 2 weeks; TCS, topical corticosteroids. Figure 4. Proportion of patients achieving EASI-75, IGA 0/1, Worst Weekly Pruritus NRS ≤3, and DLQI ≤5 with tralokinumab at Week 104 Site visit. IGA, EASI, SCORAD, worst weekly pruritus NRS, eczema-related sleep NRS, patient use of topical treatment Screening and follow-up visits Home use training POEM, DLQI/CDLQI, EQ-5D-5L ADA/pharmacokinetic measurement Weeks from first treatment in ECZTEND 5640322416 484 8–2 0 Screening period TCS use allowed Visit schedule until end of May 2021b SFU 16 weeks after last IMP 24864 72 80 88 96 1042 12 Patient cohorts in ECZTEND interim analysis April 30, 2021 data cut-off All patients who reached the 2-year time point (Week 104) or would have reached that time point had they not discontinued earlier Week 104 efficacy cohort (n=616) All patients transferred from ECZTRA 1, 2, 3, 4, 5, and 7; Up to 42 months maximum tralokinumab exposure (≤1 year in PTs and ≤2.5 years in ECZTEND) Safety analysis set (n=1442) ECZTEND interim safety analysis set n=1442 Age Median years (IQR) 38.0 (27.0; 50.0) Sex n (%) Male Female 831 (57.6) 611 (42.4) Race n (%)a White Black Asian 1093 (75.9) 108 (7.5) 203 (14.1) Parent trial n (%) ECZTRA 1 ECZTRA 2 ECZTRA 3 ECZTRA 4 ECZTRA 5 ECZTRA 7 450 (31.2) 293 (20.3) 282 (19.6) 31 (2.1) 149 (10.3) 237 (16.4) Age at onset of AD Median years (IQR) 3.0 (1.0; 15.0) Duration of AD Median years (IQR) 27.0 (18.0; 39.0) Patients who permanently discontinued ECZTEND n (%) 330 (22.9) Parent Trial Baseline ECZTEND Baseline IGA severity n (%) Clear/minimal (score=0/1) Mild (score=2) Moderate (score=3) Severe (score=4) - - 765 (53.1) 677 (46.9) 442 (30.6) 524 (36.3) 391 (27.1) 85 (5.9) EASI Median (IQR) 26.8 (20.5; 37.6) 4.8 (1.7; 12.0) SCORAD Median (IQR) 67.7 (60.0; 77.9) 30.2 (18.7; 45.0) DLQIb Median (IQR), n 16.0 (11.0; 22.0), 1391 5.0 (2.0; 10.0), 1400 Worst weekly pruritus NRSc Median (IQR), n 7.9 (6.8; 8.8), 1257 5.0 (3.0; 7.0), 1440 aAvailable in 1440 patients. bSubjects from the ECZTRA 4 parent trial did not have DLQI assessments in the parent trial, and thus are missing parent trial baseline for DLQI assessments. cIn PTs, worst pruritus NRS is assessed daily; in ECZTEND, worst pruritus NRS is assessed based on recall of the previous week before the visit. A B Placebo, N=680 Tralokinumab, N=1605 Tralokinumab, N=1442 Up to Week 16 parent trialsa ECZTEND data cutoff aPooled safety analysis set includes patients from parent trials ECZTRA 1, 2, 3, 5, and Phase 2b. bRate calculated by number of events divided by PYE, multiplied by 100. cFor PTs, Cochran-Mantel-Haenszel weights were applied to calculate adjusted AE incidences and rates to account for different randomization ratios across PTs. dConjunctivitis reported by preferred term. n (%) 449 (67.2) 1080 (65.7) 1127 (78.2) 18 (2.8) 37 (2.1) 101 (7.0) 20 (2.8) 38 (2.3) 34 (2.4) Eczema herpeticum Malignancies Skin infections requiring systemic treatment Eye disorders [Conjunctivitisd] Placebo, N=680 Tralokinumab, N=1605 Tralokinumab, N=1442 Up to Week 16 parent trialsa ECZTEND data cutoff aPooled safety analysis set includes patients from parent trials ECZTRA 1, 2, 3, 5, and Phase 2b. bRate calculated by number of events divided by PYE, multiplied by 100. cFor PTs, Cochran-Mantel-Haenszel weights were applied to calculate adjusted AE incidences and rates to account for different randomization ratios across PTs. dConjunctivitis category includes several preferred terms, such as conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial and conjunctivitis viral. AEs in ECZTEND interim safety analysis set AEs up to Week 16 in parent trials initial tralokinumab treatmenta Tralokinumab Q2W + optional TCS (n=1442; PYE=2446.2; 131.5 weeks median exposure) Tralokinumab Q2W ± TCS (n=1605; PYE=473.2) Placebo Q2W ± TCS (n=680; PYE=193.1) n (%) Rateb [(nP/PYE)*100] E Rate [(nE/PYE)*100] n (adj. %)c E Adj. Rateb,c [(nE/PYE)*100] n (adj. %)c E Adj. Rateb,c [(nE/PYE)*100] Eczema herpeticum 17 (1.2) 0.7 18 0.7 6 (0.3) 6 1.2 10 (1.5) 10 5.2 Malignancies 8 (0.6) 0.3 8 0.3 1 (0.1) 1 0.2 0 (0) 0 0 Skin infections requiring systemic treatment 36 (2.5) 1.5 51 2.1 42 (2.6) 46 9.7 35 (5.5) 42 22.8 Eye disorders 132 (9.2) 5.8 174 7.1 132 (7.9) 155 31.1 22 (3.4) 24 12.9 Conjunctivitisd 125 (8.7) 5.4 160 6.5 126 (7.5) 145 29.0 21 (3.2) 23 12.3 Keratoconjunctivitis 8 (0.6) 0.3 8 0.3 5 (0.3) 5 1.2 0 0 0 Keratitis 6 (0.4) 0.2 6 0.2 4 (0.2) 5 0.9 1 (0.2) 1 0.6 • Tralokinumab demonstrated sustained long-term improvement in AD signs and symptoms in patients who reached the 2-year time point (Week 104), or would have reached that time point had they not discontinued earlier, prior to data cutoff April 30, 2021 (Figure 4) Summary of safety in ECZTEND • Long-term use of tralokinumab 300 mg Q2W was well-tolerated, and no new safety signals were identified with up to 42 months of treatment relative to initial treatment in parent trials (Figure 2) 5.2 0 22.8 12.9 1.2 0.2 9.7 31.1 0.7 0.3 2.1 7.1 0 5 10 15 20 25 30 35 R a te [( n E / P Y E )* 10 0 ]b ,c 6.5 29 12.3 n (%) 10 (1.5) 6 (0.3) 17 (1.2) 0 (0.0) 1 (0.1) 8 (0.6) 35 (5.5) 42 (2.6) 36 (2.5) 22 (3.4) 132 (7.9) 132 (9.2) PT ECZTEND aPooled safety analysis set includes patients from parent trials ECZTRA 1, 2, 3, 5, and Phase 2b. bRate calculated by number of events divided by PYE, multiplied by 100. cFor PTs, Cochran-Mantel-Haenszel weights were applied to calculate adjusted AE incidences and rates to account for different randomization ratios across PTs. dConjunctivitis category includes several preferred terms, such as conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial and conjunctivitis viral. Sustained improvement in AD signs and symptoms Data is relative to baseline in parent trial, n=616. NRS refers to worst weekly pruritis NRS ≤3. The observed analysis includes data for all participants with a valid measurement at the indicated timepoint. The LOCF method imputes the value recorded at the participant’s last visit for subsequent missed timepoints. The modified NRI method considers participants who discontinue from trial due to adverse event(s) or lack of efficacy as non-responders, and other missing are imputed with LOCF. https://www.ismpp.org/gpp3