Tralokinumab 300 mg q2w Placebo q2w Placebo q2w Tralokinumab 300 mg q4w Alternating with placebo Open-label treatment Tralokinumab 300 mg q2w � optional TCS 3:1 randomization Washout of TCS and other AD medication 300 mg q2w after initial loading dose (600 mg) Patients with clinical response of IGA-0/1 or EASI-75 2:2:1 randomization Screening Initial treatment Maintenance treatment Safety follow-up 66 weeks52 weeks16 weeks0-6 weeks Tralokinumab 300 mg q2w Placebo q2w ECZTRA 1 (n=603) ECZTRA 2 (n=593) ECZTRA 1 (n=199) ECZTRA 2 (n=201) Figure 1. ECZTRA 1 and 2 trial design IG A -0 /1 , % n/N 14/197 95/601 16/197 115/601 22/201 131/591 25/201 142/591 Sensitivity analysisb (rescue allowed) Primary analysisa (NRI) Primary analysisa (NRI) Sensitivity analysisb (rescue allowed) ECZTRA 1 ECZTRA 240 35 30 25 20 15 10 5 0 Placebo Tralokinumab 300 mg q2w EA S I- 75 , % n/N 25/197 150/601 34/197 201/601 23/201 196/591 3/201 224/591 Sensitivity analysisb (rescue allowed) Primary analysisa (NRI) Primary analysisa (NRI) Sensitivity analysisb (rescue allowed) A B 7.1% 8.1% 10.9% 12.4% 15.8%* 19.1%** 22.2%** 24.0%** 12.7% 17.3% 11.4% 16.4% 25.0%*** 33.4%** 33.2%** 37.9%**ECZTRA 1 ECZTRA 240 35 30 25 20 15 10 5 0 Placebo Tralokinumab 300 mg q2w Figure 2. IGA-0/1 and EASI-75 at week 16 ECZTRA 1a30 25 20 15 10 5 0 A B ECZTRA 2a Week 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1615 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1615 Week W o rs t d a ily p ru ri tu s N R S re d u ct io n �� 4 , % 30 25 20 15 10 5 0 W o rs t d a ily p ru ri tu s N R S re d u ct io n �� 4 , % Placebo (n=194) Tralokinumab q2w (n=594) Placebo (n=200) Tralokinumab q2w (n=575) 20.0% 10.3% 25.0% 9.5% * ** ** *** ** ** *** *** *** *** *** *** ****** ** ** *** *** *** *** *** *** ** *** *** *** ***** Figure 3. Worst daily pruritus NRS (weekly average) reduction 4Introduction Results Methods Objectives ● The objectives of ECZTRA 1 (NCT03131648) and 2 (NCT03160885) were to evaluate the efficacy and safety of tralokinumab monotherapy compared with placebo in patients with moderate-to- severe AD for up to 1 year, as assessed by severity and extent of AD, itch, and health-related quality of life ECZTRA 1 (n=802) ECZTRA 2 (n=794) Placebo (n=199) Tralokinumab q2w (n=603) Placebo (n=201) Tralokinumab q2w (n=593) Table 1. Demographic and clinical characteristics of randomized patients at baseline Conclusions ● Tralokinumab demonstrated superiority over placebo in all primary and secondary endpoints at week 16 ● The majority of patients maintained responses at week 52 with tralokinumab q2w (without the use of TCS) ● After having achieved response, q4w dosing could be appropriate for some patients ● Continued treatment beyond 16 weeks resulted in additional patients achieving treatment success ● The overall frequency of AEs among tralokinumab-treated patients was comparable with that in the placebo group over 52 weeks ● Specifically targeting IL-13 with tralokinumab represents a novel and efficacious approach for the long-term treatment of AD ● Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itch and eczematous lesions1 ● The underlying pathophysiology of AD is a complex and multifaceted combination of skin barrier dysfunction and immune dysregulation, leading to chronic type 2 inflammation2,3 ● Tralokinumab is a fully human monoclonal antibody designed to specifically neutralize interleukin (IL)-13, a key driver of the underlying inflammation in AD4-8 ● The ECZTRA 1 and ECZTRA 2 studies were identically designed, multinational, double-blind, randomized, placebo- controlled, 52-week trials of tralokinumab monotherapy in more than 1500 patients with moderate-to-severe AD Patients ● Eligible patients were 18 years of age, with a confirmed diagnosis of AD for 1 year, and candidates for systemic therapy due to a recent (within 1 year) history of inadequate response to treatment with topical treatments or for whom topical treatments were medically inadvisable ● Rescue treatment for AD could be provided if medically necessary. However, patients who received rescue treatment were considered non-responders in the primary analyses Study design ● Patients were randomly assigned 3:1 to receive either subcutaneous tralokinumab 300 mg or placebo every 2 weeks (q2w) for an initial treatment period of 16 weeks (Figure 1) Eric Simpson,1 Andrew Blauvelt,2 Emma Guttman-Yassky,3 Margitta Worm,4 Charles Lynde,5 Hidehisa Saeki,6 Yves Poulin,7 Andreas Wollenberg8 1Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 2Oregon Medical Research Center, Portland, OR, USA; 3Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Division of Allergy and Immunology, Department of Dermatology, Venereology, and Allergy, Charité – Universitätsmedizin Berlin, Berlin, Germany; 5Lynde Dermatology, Probity Medical Research, Markham, ON, Canada and Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Department of Dermatology, Nippon Medical School, Tokyo, Japan; 7Laval University and Centre Dermatologique du Québec Métropolitain and Centre de Recherche Dermatologique du Québec Métropolitain, Québec, QC, Canada; 8Klinikum der Universität München, Klinik und Poliklinik für Dermatologie und Allergologie, Munich, Germany Endpoints ● Primary efficacy endpoints were an IGA score of 0 (clear) or 1 (almost clear) [IGA-0/1] and a 75% improvement in EASI (EASI-75), both at week 16 ● Key secondary endpoints were change from baseline to week 16 in SCORing AD (SCORAD) score, reduction of worst daily pruritus Numeric Rating Scale (NRS) [weekly average] 4 from baseline to week 16, and change from baseline to week 16 in Dermatology Life Quality Index (DLQI) score ● Maintenance endpoints were IGA-0/1 at week 52 among patients with IGA-0/1 at week 16, achieved without rescue medication, and EASI-75 at week 52 among patients with EASI-75 at week 16, achieved without rescue medication, both after initial randomization to tralokinumab ● Adverse events (AEs) were assessed at baseline and each subsequent visit Statistical analysis ● To control for the overall type 1 error rate at a 5% significance level, a prespecified testing hierarchy was used for assessment of the primary, key secondary, and maintenance endpoints ● The primary analysis of the binary endpoints considered patients who received rescue medication (including TCS) and patients with missing data to be non-responders. An alternative analysis was also applied where all observed data was used, irrespective of rescue medication use, with missing data imputed as non-responders — The difference between response rates among treatment groups was analyzed using the Cochran-Mantel- Haenszel test, stratified by baseline IGA score and region ● For the primary analysis of the continuous endpoints, a repeated measurements model was used, where data collected after permanent discontinuation or initiation of rescue medication were excluded from the analysis ● The primary analysis of the maintenance endpoints considered patients who, prior to week 52, received rescue medication and/or were transferred to open-label treatment as non-responders. The differences in response rates were analyzed using the Cochran-Mantel-Haenszel test, stratified by region Patient characteristics ● Patients were randomly assigned to recieve either tralokinumab 300 mg every other week or placebo; 603:199 in ECZTRA 1 and 593:201 in ECZTRA 2 ● Baseline demographics and disease characteristics were well balanced between randomized groups. Patients had a long duration of AD and over 50% had severe AD (IGA-4) at baseline (Table 1) Maintenance/open-label phase ● After the initial 16-week treatment period, eligible patients were transferred to either the maintenance phase or open-label tralokinumab as appropriate (Figure 1) ● IGA-0/1 response at week 16, achieved without rescue medication, was maintained at week 52 in 51.3% and 59.3% of patients who continued tralokinumab q2w (Figure 5A) and EASI-75 response at week 16, achieved without rescue medication, was maintained at week 52 in 59.6% and 55.8% of patients who continued with tralokinumab q2w (Figure 5B) aUSA only in ECZTRA 1; USA and Canada in ECZTRA 2; bFrance, Germany, and Spain in ECZTRA 1; Italy, Poland, Russia, Denmark, and UK in ECZTRA 2; cJapan in ECZTRA 1 and Korea in ECZTRA 2. Primary endpoints ● At week 16, significantly greater IGA-0/1 and EASI-75 response rates were observed with tralokinumab compared with placebo, using both the primary and alternative analysis approaches (Figure 2) ● In the primary analysis, IGA-0/1 was achieved by 15.8% versus 7.1% (P0.01) and 22.2% versus 10.9% (P0.001) with tralokinumab versus placebo in ECZTRA 1 and 2 and EASI-75 was achieved by 25.0% versus 12.7% and 33.2% versus 11.4% with tralokinumab versus placebo in ECZTRA 1 and 2 (Figure 2) — Rescue medication was used by 35.8% and 22.8% of patients receiving tralokinumab and by 46.2% and 44.3% of patients receiving placebo in ECZTRA 1 and 2, respectively *P<0.01 versus placebo; **P<0.001 versus placebo. aUse of rescue medication considered as non-response and missing data imputed as non-response; bAll data used as observed at week 16, regardless of rescue medication use, and missing data imputed as non-response. NRI, non-responder imputation. Primary analysis approach: use of rescue medication considered non-response and missing data imputed as non-response. *P<0.05 versus placebo; **P<0.01 versus placebo; ***P<0.001 versus placebo. aBased on full analysis set with baseline worst daily pruritus NRS (weekly average) ≥4. IG A -0 /1 , % n/N n/N ECZTRA 1 ECZTRA 270 60 50 40 30 20 10 0 70 60 50 40 30 20 10 0 Re-randomization q2w to q2w q2w to q4w q2w to placebo Re-randomization q2w to q2w q2w to q4w q2w to placebo EA S I- 75 , % A B 51.3% 38.9% 47.4% 59.6% 49.1% 33.3% 25.0% 44.9% 21.4% 51.4%* 59.3%** 55.8%** ECZTRA 1 ECZTRA 2 28/47 28/57 10/30 43/77 38/74 9/42 20/39 14/36 9/19 32/54 22/49 7/28 Figure 5. Maintenance of clinical response at week 52a *P<0.01 versus placebo; **P<0.001 versus placebo. aAssessed in patients achieving given primary endpoint (IGA-0/1, EASI-75) at week 16 without use of rescue medication after initial randomization to tralokinumab. Patients who, after week 16, received rescue medication or were transferred to open-label treatment are considered non-responders at week 52. Missing values imputed as non-response. 7.6% 29.3% 40.7% 53.2% 17.1% 36.5% IG A -0 /1 , % IGA-0/160 50 40 30 20 10 0 60 50 40 30 20 10 0 EA S I- 75 , % A B EASI-75 16 20 24 28 32 36 40 44 48 52 Week 16 20 24 28 32 36 40 44 48 52 Week IGA-2 (n=167) IGA-3 (n=386) IGA-4 (n=132) Week 16 IGA score 50-�75% (n=269) 25-�50% (n=177) �25% (n=215) Week 16 EASI reduction Figure 6. IGA-0/1 and EASI-75 with open-label tralokinumab 1 optional TCS by AD disease activity at week 16 Data are pooled from ECZTRA 1 and 2; all patients were initially randomized to tralokinumab up to week 16 n (%) in the initial 16-week period ECZTRA 1 ECZTRA 2 Placebo (n=196) Tralokinumab q2w (n=602) Placebo (n=200) Tralokinumab q2w (n=592) Frequent AEs (≥5% in any treatment group)a Table 2. Summary of AEs in the 16 week initial treatment period aAEs reported by system organ class and preferred term according to Medical Dictionary for Regulatory Activities, version 20.0 in the initial treatment period. References 1. Weidinger S, Novak N. Lancet 2016; 387: 1109–1122. 2. Boguniewicz M, Leung DY. Immunol Rev 2011; 242: 233–246. 3. Guttman-Yassky E et al. Semin Cutan Med Surg 2017; 36: 100–103. 4. Szegedi K et al. J Eur Acad Dermatol Venereol 2015; 29: 2136–2144. 5. Popovic B et al. J Mol Biol 2017; 429: 208–219. 6. Furue K et al. Immunology 2019; 158: 281–286. 7. Tsoi LC et al. J Invest Dermatol 2019; 139: 1480–1489. 8. Bieber T. Allergy 2020; 75: 54–62. Disclosures Eric Simpson reports grants and/or personal fees from AbbVie, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Forte Bio Galderma, Incyte, Kyowa Hakko Kirin, LEO Pharma, Lilly, MedImmune, Menlo Therapeutics, Merck, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron, Sanofi, Tioga, and Valeant. Andrew Blauvelt has served as a scientific adviser and/or clinical study investigator for AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Dermira, Lilly, FLX Bio, Forte, Galderma, Janssen, LEO Pharma, Novartis, Ortho, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun Pharma, and UCB Pharma, and as a paid speaker for AbbVie. Emma Guttman-Yassky has received honoraria for consultant services from AbbVie, Almirall, Amgen, Asana Biosciences, Boerhinger Ingelhiem, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Lilly, EMD Serono, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Sienna Biopharma, and Union Therapeutics, and received research grants for investigator services from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boerhinger Ingelhiem, Celgene, Concert, Dermavant, Dermira, DS Biopharma, Lilly, Glenmark, Galderma, Innovaderm, Janssen, Kiniska, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, Regeneron, Sienna Biopharma, UCB, and Union Therapeutics. Margitta Worm declares that she has receipt honoraria or consultation fees by ALK-Abelló Arzneimittel GmbH, Mylan Germany GmbH, LEO Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Regeneron Pharmaceuticals, Inc., DBV Technologies S.A, Stallergenes GmbH, HAL Allergie GmbH, Allergopharma GmbH & Co. KG, Bencard Allergie GmbH, Aimmune Therapeutics UK Limited, Actelion Pharmaceuticals Deutschland GmbH, Novartis AG and Biotest AG. Charles Lynde has received honoraria or consultant fees from AbbVie, Amgen, Bausch Health, Boerhinger Ingelheim, Celgene, Lilly, Galderma, Glenmark, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and Valeant. Hidehisa Saeki is an advisor to LEO Pharma. Yves Poulin has received grant funding and honoraria for services as an investigator, speaker, and member of advisory boards from AbbVie, Amgen, Bausch, Centocor Ortho/Janssen, UCB Biopharma, and has received grant funding as an investigator from Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galderma, Genentech, GlaxoSmithKline, Lilly, Incyte, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Serono, and Takeda. Andreas Wollenberg has received grants, personal fees, or nonfinancial support from AbbVie, Almirall, Beiersdorf, Bioderma, Chugai, Galapagos, Galderma, Hans Karrer, Leo Pharma, Lilly, L’Oreal, Maruho, MedImmune, Novartis, Pfizer, Pierre Fabre, Regeneron, Santen, and Sanofi-Aventis. The ECZTRA 1 and 2 studies were sponsored by LEO Pharma. Patient images provided with consent to use; courtesy of Prof. Ketty Peris. Figure 4. Example patient case of improvement in EASI from baseline to week 16 Week 0 EASI: 32 NRS: 8 Week 8 EASI: 4 NRS: 3 Week 16 EASI: 4 NRS: 3 Efficacy and safety of tralokinumab monotherapy in adult patients with moderate-to-severe atopic dermatitis: results from two 52-week, Phase 3 trials (ECZTRA 1 and ECZTRA 2) 2020 Fall Clinical Dermatology Conference, October 29-November 1, 2020, Live Virtual Meeting Secondary endpoints ● A reduction in worst daily pruritus NRS (weekly average) 4 was achieved by more patients treated with tralokinumab than with placebo in ECZTRA 1 (20% vs. 10.3%; P=0.002) and in ECZTRA 2 (25% vs. 9.5%; P0.001) at week 16 (Figure 3) ● Mean change from baseline in SCORAD at week 16 was greater with tralokinumab compared with placebo in ECZTRA 1 (–25.2 vs. –14.7; P0.001) and ECZTRA 2 (–28.1 vs. –14.0; P0.001) ● Mean change from baseline in DLQI at week 16 was greater with tralokinumab than with placebo in ECZTRA 1 (–7.1 vs. –5.0; P=0.02) and ECZTRA 2 (–8.8 vs. –4.9; P0.001) ● Greater improvements in SCORAD and DLQI with tralokinumab compared with placebo were observed from the first assessment (week 2) and at each assessment throughout the initial treatment period ● At 16 weeks, tralokinumab responders (Investigator’s Global Assessment [IGA]-0/1 and/or Eczema Area and Severity Index [EASI]-75 were re-randomized 2:2:1 to receive tralokinumab 300mg q2w or every 4 weeks (q4w), or placebo, for an additional 36 weeks of maintenance treatment ● Non-responders at week 16 were transferred to open-label tralokinumab 300 mg q2w with optional use of topical corticosteroids (TCS) for an additional 36 weeks ● Some patients − transferred to open-label tralokinumab q2w plus optional TCS − not achieving IGA-0/1 or EASI-75 at week 16 improved with continued treatment (Figure 6) Safety ● The overall frequency and severity of AEs over 16 weeks was comparable between tralokinumab and placebo (Table 2) ● In total, 97% of conjunctivitis cases were mild to moderate, and only one led to treatmentdiscontinuation ● The safety profile at week 52 was comparable with that in the initial treatment period ● There was visible improvement in AD lesions within 16 weeks (Figure 4)