PowerPoint Presentation Objective Efficacy and safety of tralokinumab in adolescents with moderate-to-severe atopic dermatitis: results of the phase 3 ECZTRA 6 trial Amy Paller,1 Andrew Blauvelt,2 Weily Soong,3 Shinichi Imafuku,4 Chih-ho Hong,5 Marie L.A. Schuttelaar,6 Petra Amoudruz,7 Azra Kurbasic,7 Lise Soldbro,7 Katja Lophaven,7 Michael Cork,8 Anthony Bewley,9 Eric L. Simpson10 • Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that can negatively impact quality of life in adolescents1 • Negative impacts of AD include effects on school performance, social relationships, participation in sports and increased rates of anxiety, depression, and suicidal ideation2-4 • Tralokinumab is a fully human, high-affinity, monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin barrier dysfunction, inflammation and dysbiosis in AD5-9 • In adult phase 3 trials, tralokinumab demonstrated efficacy and safety for treatment of AD10 Study design (Figure 1) To evaluate the efficacy and safety of tralokinumab in adolescents with moderate-to-severe AD in the phase 3 ECZTRA 6 trial (NCT03526861) Placebo (n=94) Tralokinumab 150 mg Q2W (n=98) Tralokinumab 300 mg Q2W (n=97) Mean age, years 14.3 14.8 14.6 Age group 12-14, n (%) 49 (52.1) 37 (37.8) 45 (46.4) 15-17, n (%) 45 (47.9) 61 (62.2) 52 (53.6) Male, n (%) 51 (54.3) 51 (52.0) 47 (48.5) Race/Ethnicity, n (%) White 53 (56.4) 55 (56.1) 56 (57.7) Black or African American 11 (11.7) 7 (7.1) 14 (14.4) Asian 23 (24.5) 28 (28.6) 20 (20.6) Hispanic or Latino 6 (6.4) 10 (10.2) 9 (9.3) Mean duration of AD, years (SD) 12.7 (3.7) 12.1 (3.7) 12.1 (3.5) Mean BSA involvement with AD, % (SD) 51.4 (23.9) 52.4 (22.6) 49.6 (23.3) Severe disease (IGA=4), n (%) 43 (45.7) 44 (44.9) 48 (49.5) Mean EASI (SD) 31.2 (14.5) 32.1 (12.9) 31.8 (13.9) Mean SCORAD (SD) 67.4 (14.9) 67.7 (14.4) 68.3 (13.7) Mean CDLQI (SD) 13.3 (6.0) 12.9 (6.3) 13.4 (7.3) Mean weekly average worst daily pruritus NRS score (SD) 7.5 (1.7) 7.5 (1.6) 7.8 (1.5) 1Feinberg School of Medicine, Northwestern University, Chicago IL, USA; 2Oregon Medical Research Center, Portland, OR, USA; 3Allervie Health-Alabama Allergy & Asthma Center, Birmingham, AL, USA; 4Fukuoka University, Fukuoka, Japan; 5University of British Columbia, Vancouver, BC, Canada; 6University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; 7LEO Pharma A/S, Ballerup, Denmark; 8University of Sheffield, Sheffield, UK; 9Barts Health NHS Trust, London, UK; 10Oregon Health & Science University, Portland, OR, USA Introduction Materials and Methods • Adolescent patients were randomized 1:1:1 to subcutaneous tralokinumab 150 mg or 300 mg every 2 weeks (Q2W), or placebo for an initial treatment period of 16 weeks • Co-primary endpoints were Investigator’s Global Assessment (IGA) score 0/1 and ≥75% improvement in Eczema Area and Severity Index (EASI-75) at Week 16 • Patients achieving primary endpoints without rescue treatment were re- randomized to tralokinumab Q2W or every 4 weeks (Q4W), at their same initial dosage for 36 weeks of maintenance treatment as shown in Figure 1 • Patients not achieving primary endpoints at Week 16, those receiving rescue treatment from Week 2 to Week 16, and those meeting other specific criteria† were transferred to open-label treatment of tralokinumab 300 mg Q2W plus optional mild-to-moderate strength topical corticosteroids (TCS) • EASI-75, IGA 0/1, and secondary endpoint ≥4-point improvement in adolescent pruritus Numerical Rating Scale (NRS) were analyzed using Cochran-Mantel- Haenszel test stratified by geographic region and baseline disease severity • Patients receiving rescue therapy between Week 2 and 16 or with missing data at Week 16 were considered non-responders • Secondary endpoints, change from baseline in SCORing AD (SCORAD) and Children’s Dermatology Life Quality Index (CDLQI) were analyzed using a linear mixed model for repeated measurements • Data after use of rescue or discontinuation were disregarded • A closed testing procedure with hierarchical tests, alpha splitting, and alpha recycling were applied for above efficacy endpoints • The safety population was defined as all randomized patients who received ≥1 injection of study drug Statistical analyses and endpoints Figure 1. ECZTRA 6 study design Table 1. Baseline characteristics Patient characteristics • Baseline demographic and clinical characteristics were comparable across treatment groups (Table 1) BSA: Body surface area. AD: Atopic Dermatitis. n: Number of subjects in analysis set. Q2W: Every 2 weeks. IGA: Investigator's Global Assessment. EASI: Eczema Area and Severity Index. SCORAD: Scoring Atopic Dermatitis. CDLQI: Children's Dermatology Life Quality Index. NRS: Numeric rating scale. References Disclosures Safety through Week 16 • Through Week 16, percentages of adverse events (AEs), serious AEs, AEs leading to discontinuation, and conjunctivitis events were similar between the tralokinumab (150 mg/300 mg) and placebo treatment groups (Table 2) • The majority of AEs in all treatment groups were mild or moderate in severity and subjects recovered from most of the AEs Conclusions • At Week 16, tralokinumab 150 mg and 300 mg Q2W demonstrated significant efficacy vs placebo across primary and secondary endpoints in adolescents with moderate-to- severe AD • Tralokinumab was well tolerated; efficacy and safety profiles were comparable to those in phase 3 adult tralokinumab trials 1. Marciniak J. Acta Derm Venereol. 2017;97(6):711–714. doi: 10.2340/00015555-2633. 2. Ricci G. Dermatol Reports. 2011;4(1):e1. doi: 10.4081/dr.2012.e1. 3. Slattery M. J Allergy Clin Immunol. 2011; 128(3):668–671.e3. doi: 10.1016/j.jaci.2011.05.003. 4. Halvorsen J. J Invest Dermatol. 2014;134(7):1847–1854. doi: 10.1038/jid.2014.70. 5. Bieber T. Allergy. 2020;75(1):54-62. doi: 10.1111/all.13954. 6. Furue K et al. Immunology. 2019; 158(4): 281-286. doi: 10.1111/imm.13120. 7. Szegedi K et al. JEADV. 2015;29(11):2136–2144. doi: 10.1111/jdv.13160. 8. Tsoi LC et al. J Invest Dermatol. 2019;139(7):1480-1489. doi: 10.1016/j.jid.2018.12.018. 9. Popovic B et al. J Mol Biol. 2017; 429(2): 208–219. doi: 10.1016/j.jmb.2016.12.005. 10. Wollenberg A. Br J Dermatol. 2021; 184(3):437–449. doi: 10.1111/bjd.19574. Amy Paller has served as an investigator for AbbVie, Anaptysbio, Incyte, Janssen, KrystalBio, LEO Pharma, Regeneron, and UCB, received honorarium for consultancy from AbbVie, Abeona, Almirall, Anaptysbio, Arena, Azitra, BiomX, Boehringer Ingelheim, Castle Biosciences, Catawba, Dermira, Exicure, Forté, Kamari, LEO Pharma, Lilly, LifeMax, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Seanergy, and UCB, and served on a Data Safety Monitory Board for AbbVie, Bausch, Galderma, and Novan. Andrew Blauvelt is a scientific adviser and clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly, Evommune, Forte, Galderma, Incyte, Janssen, Landos, LEO Pharma, Novartis, Pfizer, Rapt, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, Sun Pharma, UCB Pharma. Weily Soong has served on the advisory board and received research grants from Abbvie, Leo, Genentech, Inc., Teva, Novartis, and Pfizer; served on the advisory board, received research grants, and was a speaker for Amgen, AstraZeneca, Regeneron, Sanofi, and GlaxoSmithKline; received research grants and was a speaker for Optinose; received research grants from Aimmune, Avillion, Galderma, Gossamer Bio, 3M, and LEO Pharma. Shinichi Imafuku is a researcher, consultant, or speaker for Abbvie, Amgen, Celgene, DaiichiSankyo, Eisai, KyowaKirin, Lilly, Taihoyakuhinkogyo, TanabeMitsubishi, Tsumura, Torii, Maruho, Novartis, Leo Pharma and Janssen. Chih-ho Hong is a researcher, consultant, and/or advisor for AbbVie, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, Celgene, Dermavant, Dermira, DS Biopharma, Galderma, GlaxoSmithKline, Incyte, Janssen, LEO Pharma, Lilly, MedImmune, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Marie L.A. Schuttelaar has served on advisory boards for Sanofi Genzyme, Pfizer, LEO Pharma, Eli Lilly, Galderma, and Abbvie; as an investigator for AbbVie, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, and Galderma; as a consultant for Regeneron Pharmaceuticals, Inc.; has received research grants from Sanofi Genzyme and Novartis. Petra Amoudruz, Azra Kurbasic, Lise Soldbro, and Katja Lophaven are employees of LEO Pharma A/S. Michael Cork has served as a clinical trial investigator for Astellas, Galapagos, Johnson & Johnson, LEO Pharma, La Roche-Posay, MSD, Novartis, Perrigo, Regeneron, Sanofi Genzyme, and Stiefel; has served as an advisory board member, consultant, and/or invited lecturer for Pfizer Inc., Amgen, Astellas, Bayer, Johnson & Johnson, LEO Pharma, L’Oréal, MSD, Novartis, Regeneron, Sanofi Genzyme, Stiefel, and Unilever; has received honoraria from Astellas, Johnson & Johnson, LEO Pharma, Novartis, Regeneron, Sanofi Genzyme, and Stiefel; and has received research funding from Bayer. Anthony Bewley has been a consultant for and received consultancy fees or travel bursaries from AbbVie, Almiral, Eli Lilly, Galderma, Janssen, LEO Pharma, Novartis, Sanofi and UCB Pharma. Eric Simpson is a consultant and investigator for Regeneron/Sanofi, Dermira, Menlo Pharmaceuticals, Lilly, Abbvie, Genentech, Medimmune, GSK, LEO Pharma, Celgene, and Pfizer. Acknowledgements • The ECZTRA 6 clinical trial was sponsored by LEO Pharma A/S, Ballerup, Denmark • Medical writing and editorial support from Alphabet Health by Clair Geary, PhD, was funded by LEO Pharma A/S, Ballerup, Denmark • This work was previously presented at Fall Clinical Dermatology Conference, Oct 21-24, 2021 Table 2. Summary of AEs from Week 0 to 16 Figure 2. Tralokinumab treatment demonstrated efficacy vs placebo across endpoints at Week 16. A. IGA 0/1 B. EASI-75 C. ≥4-point improvement in adolescent pruritus NRS D. Change in SCORAD E. Change in CDLQI A B C D • Age 12 – 17 • History of AD for ≥1 year • BSA involvement ≥10% at screening and baseline • EASI score ≥12 at screening and ≥16 at baseline • IGA score ≥3 at screening and baseline • History of TCS and/or topical calcineurin inhibitor treatment failure, or subjects for whom these treatments are medically inadvisable • Stable dose of emollient ≥2 times daily for ≥14 days before randomization Key inclusion criteria Results • At Week 16, significantly greater proportions of patients receiving tralokinumab achieved the primary endpoints of IGA 0/1 and EASI-75 without use of rescue compared to those receiving placebo (Figure 2A, B) • Significantly greater proportions of patients receiving tralokinumab vs placebo achieved ≥4-point improvement in adolescent pruritus NRS at Week 16 without use of rescue (Figure 2C) • Tralokinumab treatment was associated with greater improvement than placebo in SCORAD and CDLQI from baseline to Week 16 (Figure 2D, E) Week 16 Efficacy Analyses E Placebo (n=94) Tralokinumab 150 mg Q2W (n=98) Tralokinumab 300 mg Q2W (n=97) Patient-Years of Exposure 27.93 29.33 29.48 AEs, n (%) 58 (61.7) 66 (67.3) 63 (64.9) SAEs 5 (5.3) 3 (3.1) 1 (1.0) AEs leading to discontinuation 0 1 (1.0) 0 Severity, n (%) Mild 40 (42.6) 48 (49.0) 47 (48.5) Moderate 31 (33.0) 33 (33.7) 32 (33.0) Severe 7 (7.4) 5 (5.1) 3 (3.1) AEs of special interest Eye disorders 2 (2.1) 4 (4.1) 4 (4.1) Conjunctivitis 2 (2.1) 4 (4.1) 3 (3.1) Eczema herpeticum 1 (1.1) 1 (1.0) 0 Skin infections requiring systemic treatment 2 (2.1) 5 (5.1) 2 (2.1) Injection site reactions 1 (1.1) 9 (9.2) 7 (7.2) *loading dose of 600 mg for patients receiving 300 mg Q2W or 300 mg for those receiving 150 mg Q2W †Patients not achieving EASI-75 over ≥4 weeks with IGA ≥2 after IGA=0 at Week 16, or with IGA ≥3 after IGA=1 at Week 16, or who had IGA >1 at Week 16; patients who receive rescue treatment after Week 16 AD, atopic dermatitis; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; Q2W, every 2 weeks; Q4W, every 4 weeks; TCS, topical corticosteroids. Tralokinumab 150 mg Q2W Placebo Q2W Tralokinumab 150 mg Q2W Tralokinumab 150 mg Q4W Alternating with placebo Placebo Q2W Tralokinumab 300 mg Q2W plus optional TCS Initial treatmentScreening Maintenance treatment Patients with clinical response IGA-0/1 or EASI-75 without rescue Safety follow-up Open-label treatment 1:1:1 randomization • Patients not achieving IGA=0/1 or EASI-75 Week 16 • Patients receiving rescue treatment from Week 2 to Week 16 • Patients meeting specific criteria† Washout of previous AD treatment (2 weeks for TCS) After initial loading dose* 1:1 16 weeks0–6 weeks 52 weeks 66 weeks Tralokinumab 300 mg Q2W Tralokinumab 300 mg Q2W Tralokinumab 300 mg Q4W Alternating with placebo 1:1 Error bars show 95% confidence intervals. P-values compare respective tralokinumab dose to placebo. Tables show the number of patients who had a valid measurement value at the specified week. Q2W: Every 2 weeks. IGA: Investigator's Global Assessment. EASI: Eczema Area and Severity Index. NRS: Numeric rating scale. SCORAD: Scoring Atopic Dermatitis. CDLQI: Children's Dermatology Life Quality Index. 0 2 4 6 8 10 12 14 16 0 10 20 30 Week IG A 0 / 1 R e s p o n d e rs ( % ) Tralokinumab 300 mg (n=97) Placebo (n=94) Tralokinumab 150 mg (n=98) 4.3 21.4 17.5 0 2 4 6 8 10 12 14 16 0 10 20 30 40 50 Week E A S I- 7 5 R e s p o n d e rs ( % ) Tralokinumab 300 mg (n=97) Placebo (n=94) Tralokinumab 150 mg (n=98) 6.4 28.6 27.8 0 2 4 6 8 10 12 14 16 0 10 20 30 40 Week A d o le sc e n t P ru ri tu s N R S ≥ 4 R e s p o n d e rs ( % ) Tralokinumab 300 mg (n=96) Placebo (n=90) Tralokinumab 150 mg (n=95) 3.3 23.2 25.0 0 2 4 6 8 10 12 14 16 -40 -30 -20 -10 0 Week C h a n g e i n S C O R A D f ro m B a s e lin e Tralokinumab 300 mg Placebo Tralokinumab 150 mg -9.5 -27.5 -29.1 0 2 4 6 8 10 12 14 16 -10 -8 -6 -4 -2 0 Week C h a n g e i n C D L Q I fr o m B a se lin e Tralokinumab 300 mg Placebo Tralokinumab 150 mg -4.1 -6.1 -6.7 94 94 69 66 53 47 44 24 35 98 98 85 76 72 69 65 62 61 97 97 87 81 77 71 71 67 66 Placebo Tralokinumab 150 mg Tralokinumab 330 mg 89 88 63 60 49 41 33 95 93 80 70 69 63 58 94 93 83 79 76 67 65 Placebo Tralokinumab 150 mg Tralokinumab 330 mg ; P=0.04 ; P=0.007 ; P<0.001 ; P<0.001 ; P<0.001 ; P<0.001 ; P<0.001 ; P=0.002 ; P<0.001 ; P=0.001