LEO1825B_SILVERBERG4x4-V2 Treatment with tralokinumab improves health-related quality of life in adult patients with moderate to severe atopic dermatitis: results from a Phase 2b, randomised, double-blind, placebo-controlled study Objectives • To evaluate the risk of developing ADAs with tralokinumab treatment in the Phase 2b study. • To investigate reports of anaphylaxis, or other severe hypersensitivity reactions, and compare the incidence of eye disorders, including conjunctivitis, between the placebo and tralokinumab treatment groups. Methods Study design • Patients were randomised 1:1:1:1 to receive subcutaneous tralokinumab (45 mg, 150 mg or 300 mg) or placebo every 2 weeks for 12 weeks on a TCS background (Figure 1). • Concomitant Class 3 (World Health Organisation) TCS were administered at least once daily during the 2-week run-in and as needed throughout the treatment and follow-up periods. Patients • 8) and with AD body surface area involvement of 10%, EASI score of 12, SCORAD of 25 and IGA of 3. • Key exclusion criteria included: active dermatological conditions that may confound AD diagnosis, allergic or irritant contact dermatitis and history of anaphylaxis following any biologic therapy. Measurement of anti-drug antibodies • ADAs were measured using a validated electrochemiluminescence method (Meso Scale Discovery SECTOR Imager 6000). Samples for ADA response were taken at day 1 (prior to treatment) and weeks 4, 12 and 22. Capture of anaphylaxis/serious hypersensitivity reactions • AEs associated with anaphylaxis/serious hypersensitivity were captured using the following standardised Medical Dictionary for Regulatory Activities queries: hypersensitivity, anaphylactic reaction and anaphylactic/anaphylactoid shock conditions.9 Eye disorders • Eye disorders, including but not limited to conjunctivitis, were extracted from the AEs occurring during treatment for all subjects in each treatment arm: placebo: n=51, tralokinumab 45 mg: n=50, tralokinumab 150 mg: n=51 and tralokinumab 300 mg: n=52. — All events were included regardless of seriousness, causality or any other parameter of the AEs. • Cases of eye disorders were compared between placebo and tralokinumab arms. Statistical analysis • Safety data were summarised descriptively according to the highest dosage received by each participant measured in the as-treated population. Results Patient characteristics • Overall, 204 patients were randomised in the Phase 2b study and included in the as-treated population: 153 tralokinumab-treated patients and 51 placebo-treated patients. • Baseline demographics and disease characteristics were similar between treatment groups.7 Anti-drug antibodies • Three patients in the tralokinumab 45-mg group had pre-existing ADAs at baseline. These are likely to be the result of the ‘cut point’ for the ADA assay, which is typically set expecting some positive results. • Only one tralokinumab-treated patient (300-mg group) had ADA formation, which was measured at week 22. The titre was low and had no impact on the observed pharmacokinetics of tralokinumab. — No AEs were reported for this patient. • Anaphylaxis/severe hypersensitivity reactions • Eye disorders • or all eye disorders between the placebo and pooled tralokinumab groups (Figure 2). — No dose-related trend was observed, as the greatest frequency of one or more eye disorders was reported for the tralokinumab 150-mg treatment group. • Introduction • Biologics, including human monoclonal antibodies (mAbs), are currently diseases such as psoriasis1 and atopic dermatitis (AD).2 • Potential safety concerns regarding the immunogenicity of biologics remain, including development of anti-drug antibodies (ADAs) and adverse events (AEs) such as anaphylaxis and/or severe hypersensitivity reactions.3 • conjunctivitis with treatment, as AEs of conjunctivitis were more frequently reported in patients treated with biologics targeting interleukin (IL)-13 and IL-4.4,5 • Tralokinumab is an IgG 4 6 and has been evaluated in a Phase 2b, randomised, double-blind, placebo-controlled study (NCT02347176) in adults with moderate to severe AD. — Results of the study showed improvements in the Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA) and SCORing Atopic Dermatitis (SCORAD) scores with tralokinumab on a background of topical corticosteroids (TCS), with a favourable overall safety and 7 Figure 1. Study design Weeks –6 –2 0 12 22 Follow-up period Primary endpoint Treatment period Run-in period Screening period Tralokinumab 300 mg SC Q2W + TCS (n=52) Tralokinumab 150 mg SC Q2W + TCS (n=51) Tralokinumab 45 mg SC Q2W + TCS (n=50) Patients with moderate to severe AD TCS TCS Placebo SC Q2W + TCS (n=51) AD, atopic dermatitis; Q2W, every 2 weeks; SC, subcutaneous; TCS, topical corticosteroids. 27th EADV Congress, 12−16 September 2018, Paris, France *Eye infection and iridocyclitis were reported by the same patient in the placebo group. †Three patients in the tralokinumab 150-mg group reported oedema; and 3) periorbital rash, eye swelling, increased lacrimation and allergic conjunctivitis. ‡Staphylococcal eye infection. Methods Introduction Figure 1. Study design Weeks –6 –2 0 12 22 Follow-up period Primary endpoint Treatment period Run-in period Screening period Tralokinumab 300 mg SC Q2W + TCS (n=52) Tralokinumab 150 mg SC Q2W + TCS (n=51) Tralokinumab 45 mg SC Q2W + TCS (n=50) Patients with moderate to severe AD TCS TCS Placebo SC Q2W + TCS (n=51) AD, atopic dermatitis; Q2W, every 2 weeks; SC, subcutaneous; TCS, topical corticosteroids. Fall Clinical Dermatology Conference, October 18-21, 2018, Las Vegas, NV • Atopic dermatitis (AD) is a chronic, in� ammatory skin disease associated with skin barrier disruption and immune-mediated in� ammation characterised by increased levels of type 2 cytokines, including interleukin (IL)-13.1,2 • Symptoms of AD include intense and debilitating itch, often leading to sleep disruption, anxiety or depression, and reduced health-related quality of life (HRQoL).3,4 • The burden of AD may be assessed by dermatology-specific patient-reported outcome measures, including the Dermatology Life Quality Index (DLQI). However, it is also important to assess overall aspects of health and mental well-being in patients with AD and to determine how the burden of AD compares with other non-dermatologic health disorders via the use of generic HRQoL instruments, such as the 36-Item Short Form Health Survey version 2 (SF-36v2). —The SF-36v2 is widely used in health research to assess overall HRQoL.5,6 • Tralokinumab, a fully human IgG 4 monoclonal antibody that speci�fically binds to, and neutralizes, IL-13,7 showed improvements in Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA), SCORing Atopic Dermatitis (SCORAD) and DLQI in a Phase 2b, randomised, double-blind, placebo-controlled study (NCT02347176) in adults with moderate to severe AD.8 • The tralokinumab Phase 2b study also included exploratory assessment of improvement in HRQoL in patients with moderate to severe AD. Objective • To analyse HRQoL improvement, as evaluated by the SF-36v2, in patients receiving tralokinumab as treatment for moderate to severe AD in the Phase 2b study. Methods Study design • Patients were randomised (1:1:1:1) to tralokinumab (45 mg, 150 mg or 300 mg) or placebo treatment every 2 weeks for 12 weeks on a background of topical corticosteroids (TCS) [Figure 1]. • Eligible patients were aged 18–75 years with physician-con�firmed diagnosis of AD for >1 year9 and with �10% body surface area involvement, EASI score of >12, SCORAD of >25 and IGA score of >3. • Key exclusion criteria included: active dermatological conditions that may confound AD diagnosis, allergic or irritant contact dermatitis and history of anaphylaxis following any biologic therapy. • Concomitant World Health Organisation (WHO) Class 3 TCS were administered at least once daily during the 2-week run-in and as needed throughout the treatment and follow-up periods. SF-36v2 • The SF-36v2 includes eight scale scores measuring: bodily pain, general health, mental health, role limitations related to physical health problems, role limitations related to personal or emotional problems, social functioning, vitality and physical functioning, plus Physical Component Summary (PCS) and Mental Component Summary (MCS) scores.5,6 Higher scores indicate better health.5,6 • The SF-36v2 was assessed at baseline and at weeks 6, 12 and 22. Statistical analyses • SF-36v2 results at each study visit and changes from baseline for each post-baseline visit were reported, with descriptive statistics for each domain and summary score. • All non-missing data for all patients were included in the analysis, up to the point of prohibited AD therapy being received. • Mean change from baseline for each domain and summary score was analysed with mixed model with repeated measures, with treatment, visit and treatment-by-visit interaction as categorical factors and baseline SF-36v2 as covariate. Nominal p values for each domain and summary score were derived without adjustment for multiple testing. • Minimal clinically important difference (MCID) was used to evaluate clinically relevant improvements (adjusted mean difference versus placebo: MCS, 3; PCS, 2; bodily pain, 3; general health, 2; mental health, 3; role-physical, 3; role-emotional, 4; social functioning, 3; vitality, 2; physical functioning, 3). • Results are presented for the tralokinumab 300-mg treatment and placebo treatment groups at week 12, as the tralokinumab 300-mg dose was chosen for further evaluation in Phase 3 trials. Results Patient characteristics • Overall, 204 patients were randomised in the Phase 2b study; of these, 52 patients received tralokinumab 300 mg and 51 patients received placebo. • Mean (standard deviation [SD]) age at baseline was 39.4 (14.5) years for placebo and 35.7 (14.6) years for tralokinumab 300 mg; 43.1% (n=22) and 63.5% (n=33) of participants were male in the placebo and tralokinumab 300-mg groups, respectively. • At baseline, mean (SD) EASI scores were 26.4 (12.6) and 27.3 (10.9) for the placebo and tralokinumab 300-mg groups, respectively. HRQoL • SF-36v2 data were available at baseline for 49 patients in the placebo group and 52 patients in the tralokinumab 300-mg group. • At baseline, mean (SD) MCS was 43.72 (13.23) for the placebo group and 43.02 (12.36) for the tralokinumab 300-mg group; mean (SD) PCS was 47.07 (7.94) and 47.20 (8.17), respectively (Table 1). • At week 12, significantly improved SF-36v2 summary scores were seen in patients treated with tralokinumab 300 mg compared to placebo for both MCS (adjusted mean di� erence: 4.23; p=0.011) and PCS (adjusted mean difference: 4.26; p�0.001) [Table 1 and Figure 2]. • Significant improvements were also seen in all other domains for the tralokinumab 300-mg group compared to placebo (i.e. bodily pain, general health, role-physical, role-emotional, social functioning, vitality, physical functioning), except for mental health, which showed a numerical increase but did not reach statistical significance. • MCS and PCS summary scores and all other domains, except for physical functioning, surpassed MCID for the tralokinumab 300-mg group compared to placebo (Figure 2) Conclusions • Treatment with tralokinumab 300 mg on a background of TCS provided significant and clinically relevant improvements over a broad range of HRQoL domains in adult patients with moderate to severe AD compared to placebo in this exploratory analysis of a Phase 2b study. • Moderate to severe AD was associated with a profoundly negative impact on both mental and physical aspects of patients’ lives at baseline. • Phase 3 trials using the tralokinumab 300-mg dose are underway to further evaluate and confirm the impact that tralokinumab monotherapy (NCT03131648; NCT03160885) or tralokinumab in combination with TCS (NCT03363854) may have on reducing the disease burden of moderate to severe AD. compared to placebo at week 12 for SF-36v2 domains, with MCID indicated for each score 0 1 2 3 4 5 6 7 8 9 sc o re c o m p ar ed t o p la ce b o MCS PCS Bodily pain General health Mental health Role- physical Role- emotional Social functioning Vitality Physical functioning p=0.011 p 0.001 p=0.001 p=0.014 p=0.079 p=0.002 p=0.007 p=0.003 p=0.013 p=0.031 MCID Summary; SE, standard error; SF-36v2, 36-Item Short Form Health Survey version 2. References 1. Silverberg JI, Kantor R. Dermatol Clin 2017; 35: 327–334. 2. Nutten S. Ann Nutr Metab 2015; 66 (Suppl 1): 8–16. 3. Eckert L et al. J Am Acad Dermatol 2017; 77: 274–279. 4. Drucker AM et al. J Invest Dermatol 2017; 137: 26–30. 5. Ware JE, Jr, Sherbourne CD. Med Care 1992; 30: 473–483. 6. Ware JE, Jr et al. User’s Manual for the SF-36v2 Health Survey. 2nd ed. QualityMetric Incorporated; Lincoln, RI: 2007. 7. Popovic B et al. J Mol Biol 2017; 429: 208–219. 8. Wollenberg A et al. J Allergy Clin Immunol 2018; pii: S0091-6749(18)30850-9. doi: 10.1016/j. jaci.2018.05.029. [Epub ahead of print]. 9. Acknowledgements The tralokinumab Phase 2b study was sponsored by MedImmune. This poster was sponsored by LEO Pharma. Medical writing and editorial support was provided by Natalie Prior and Jane Beck from Complete HealthVizion, funded by LEO Pharma. Table 1. Summary of SF-36v2 scores at baseline and adjusted mean change in SF-36v2 from baseline at week 12 MCS PCS Bodily pain General health Mental health Role- physical Role- emotional Social functioning Vitality Physical functioning Placebo SF-36v2 score at baseline, mean (SD) n=49 Mean (SD) 43.72 (13.23) 47.07 (7.94) 45.10 (10.41) 42.24 (9.31) 45.11 (11.65) 45.32 (11.79) 43.71 (13.36) 45.30 (11.58) 45.37 (11.06) 50.01 (8.36) Adjusted mean change from baseline in SF-36v2 at week 12,* mean (SE) n=36 Mean (SE) 1.18 (1.222) –0.21 (0.907) –0.43 (1.369) 0.00 (1.022) 1.03 (1.297) –0.02 (1.109) 0.20 (1.278) 1.57 (1.271) 1.39 (1.208) 0.66 (0.883) Tralokinumab 300 mg SF-36v2 score at baseline, mean (SD) n=52 Mean (SD) 43.02 (12.36) 47.20 (8.17) 44.64 (11.55) 42.47 (10.16) 43.98 (11.18) 45.70 (10.81) 44.83 (13.30) 43.99 (11.64) 44.37 (10.71) 50.22 (8.08) Adjusted mean change from baseline in SF-36v2 at week 12,* mean (SE) n=46 Mean (SE) 5.41 (1.095) 4.05 (0.828) 5.63 (1.242) 3.43 (0.934) 4.12 (1.164) 4.80 (1.008) 4.95 (1.160) 6.81 (1.138) 5.47 (1.087) 3.26 (0.799) *Analysis of SF-36v2 change from baseline with repeated measures, excluding data after prohibited medications. MCS, Mental Component Summary; PCS, Physical Component Summary; SD, standard deviation; SE, standard error; SF-36v2, 36-Item Short Form Health Survey version 2. Jonathan I Silverberg,1 Nana Kragh,2 Emma Guttman-Yassky,3 Andreas Wollenberg4 1Departments of Dermatology, Preventive Medicine, and Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; LEO Pharma A /S, Ballerup, Denmark; Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany