Tralokinumab treatment was associated with early and sustained improvements in AD symptoms and an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with AD.

At week 12, 300 mg of tralokinumab significantly improved change from baseline in Eczema Area Severity Index score versus placebo (adjusted mean difference, −4.94; 95% CI, −8.76 to −1.13; P = .01), and a greater percentage of participants achieved an Investigator's Global Assessment response (26.7% vs 11.8%). Greater responses were found in participants with greater concentrations of biomarkers of increased IL-13 activity. Participants treated with 300 mg of tralokinumab demonstrated improvements in SCORAD, Dermatology Life Quality Index, and pruritus numeric rating scale (7-day mean) scores versus placebo. Upper respiratory tract infection was the most frequent treatment-emergent adverse event reported as related to study drug in the placebo (3.9%) and pooled tralokinumab (3.9%) groups.

In this phase 2b study ( NCT02347176 ), 204 adults were randomized 1:1:1:1 to receive 45, 150, or 300 mg of subcutaneous tralokinumab, or placebo, every 2 weeks for 12 weeks with concomitant topical glucocorticoids. Coprimary end points were change from baseline in Eczema Area Severity Index score and percentage of participants with an Investigator's Global Assessment response (0/1 score and reduction of ≥2 grades from baseline) at week 12.

We sought to evaluate the efficacy and safety of tralokinumab in adults with moderate-to-severe AD.

IL-13 has an important role in atopic dermatitis (AD) pathogenesis. Tralokinumab is a fully human mAb that potently and specifically neutralizes IL-13.

Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease arising from genetic and environmental factors that disrupt skin barrier function and immune response.Current management involves treatment combinations to suppress inflammation, restore skin barrier function, and prevent superinfection.Systemic immunosuppressants are reserved typically for treatment of moderate-to-severe AD but are associated with adverse events (AEs) and not suitable for long-term use.Therefore more effective and well-tolerated therapies are required that target the etiologic mechanisms of AD pathophysiology rather than simply providing symptom relief.

ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients.

ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients.

A key feature of AD is upregulation of IL-13 and IL-4 in lesionaland nonlesionalskin, suggesting both cytokines can contribute to AD pathogenesis.Moreover, AD severity is associated with increased IL-13 and associated chemokine mRNA and serum levels, whereas reductions in IL-13 concentrations have correlated with treatment response and improved clinical outcomes.Although treatment with dupilumab, a human mAb that inhibits both IL-4 and IL-13 signaling, has demonstrated improvements in AD symptoms,the relative contribution of each of these cytokines to AD pathogenesis is unclear.

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.

An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.

An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.

Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis.

Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.

An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.

Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis.

Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.

Tralokinumab is a fully human IgGmAb that potently and specifically binds to and neutralizes the effects of IL-13.This phase IIb study ( NCT02347176 ) investigates the efficacy, safety, and tolerability of tralokinumab in adults with moderate-to-severe AD. In exploratory analyses, serum biomarker assays were used to identify participants with increased dipeptidyl peptidase-4 (DPP-4) and periostin concentrations and to determine whether they experienced greater treatment responses.

Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma.

Results from visits after a participant had received prohibited medications were excluded from the analysis. For continuous end points, no imputation for missing data was applied. For binary end points, a last observation carried forward approach was used. Exploratory analyses of biomarker data used similar statistical methods, as described for the primary analysis.

Baseline demographics and safety data were summarized descriptively. Continuous end points were analyzed by using a mixed-model repeated-measures analysis. The model included factors of treatment, visit, and treatment-by-visit interaction and was adjusted for baseline as a covariate. The adjusted mean changes between tralokinumab and placebo, 95% CIs, and 2-sided P values were calculated. Binary end points were analyzed at each visit by logistic regression with treatment as a categorical factor and baseline as a covariate. Covariate-adjusted differences in percentages with 95% CIs were calculated for binary end points.

Covariate-adjusted difference in proportions from clinical trials using logistic regression and weighted risk differences.

The primary population for analysis was the intention-to-treat (ITT) population, which was defined as all participants treated with study drug. Safety data were reported according to the highest dose received by each participant measured in the as-treated population.

The study was powered at 80% to detect the minimal clinically important7-point difference in EASI score change from baseline between tralokinumab and placebo, assuming an SD of 10 points. Furthermore, combining data from the 2 highest tralokinumab dose groups would provide 80% power to detect a difference in IGA response compared with placebo of 35% versus 10%. A hierarchical testing strategy was used to preserve type I error rates for the coprimary efficacy end points (see the Methods section in this article's Online Repository).

The percentage of participants achieving a reduction of 75% or more in EASI score by visit up to week 22 was measured. Primary end points were also evaluated in subgroups defined by serum periostin and DPP-4 (biomarkers for IL-13 activity), CCL17/thymus- and activation-regulated chemokine (TARC), and IgE concentrations equal to or greater than or less than the total population median baseline concentration. Adjusted mean change from baseline in serum DPP-4 concentration and adjusted mean ratio to baseline for serum periostin, CCL17/TARC, and IgE were reported over time.

Coprimary efficacy end points were change in EASI score from baseline to week 12 and percentage of participants achieving an IGA response of 0 (clear) or 1 (almost clear) with a reduction of 2 grades or more from baseline to week 12. Secondary end points included change from baseline in EASI and SCORAD scores by visit up to week 22, percentage of participants with a reduction of 50% or more in EASI score and reduction of 50% or more in SCORAD score at week 12, and percentage of participants achieving an IGA response by visit up to week 22. Change in pruritus numeric rating scale and Dermatology Life Quality Index from baseline to week 12 were also measured. Safety end points measured through week 22 included treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). The immunogenicity potential of tralokinumab (measured by percentage of participants with an anti-drug antibody [ADA] response) was determined. Samples for ADA response were taken at day 1 and weeks 4, 12, and 22.

The protocol and amendments (see Table E1 in this article's Online Repository at www.jacionline.org ) were approved by the independent ethics committee or institutional review board at each study center. Informed written consent was obtained from all participants. The study was conducted according to the ethical principles of the Declaration of Helsinki.

This phase IIb randomized, double-blind, placebo-controlled, dose-ranging study in participants with moderate-to-severe AD took place across 55 sites in Australia, Canada, Germany, Japan, Poland, and the United States. Eligible participants were aged 18 to 75 years, with a physician-confirmed diagnosis of AD (according to Hanifin and Rajka), AD body surface area involvement of 10% or more, Eczema Area Severity Index (EASI) score of 12 or more, SCORAD score of 25 or more, and Investigator's Global Assessment (IGA) score of 3 or more (6-point scale: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe). During the 2-week run-in period and treatment period, participants were treated at least once daily with concomitant class 3topical glucocorticoids to reflect the expected clinical use of biologics for moderate-to-severe AD. A run-in period of 2 weeks was considered adequate in length to identify and exclude any participants with a treatment response to topical glucocorticoids and to eliminate any potential issues associated with a variable response to study treatment. Participants were randomized 1:1:1:1 to receive placebo or tralokinumab (45, 150, or 300 mg) subcutaneously every 2 weeks for 12 weeks before a 10-week follow-up period. Detailed inclusion and exclusion criteria are provided in the Methods section in this article's Online Repository at www.jacionline.org

Few TESAEs were reported, and all were considered unrelated to study drug ( Table II ). Ten participants discontinued treatment because of TEAEs, with the highest frequency in the placebo group ( Table II and see Table E6 in this article's Online Repository at www.jacionline.org ).

All participants included in the safety analysis received at least 1 dose of study drug. Most TEAEs were considered mild or moderate. Those considered study drug related were experienced by 17.6% of participants, with the most frequent being upper respiratory tract infection and headache ( Table II ). Injection-site reactions were reported by 3.9% of participants in the placebo group and 5.2% in the pooled tralokinumab group (see Table E4 in this article's Online Repository at www.jacionline.org ). Conjunctivitis was experienced by 3.9% of participants in the placebo group, 2.0% of participants in the 45-mg tralokinumab group, and 5.9% of participants in the 150-mg tralokinumab group (see Table E5 in this article's Online Repository at www.jacionline.org ). Other incidences of viral infection were also low (see Table E5 ); 3 incidents of nasopharyngitis (1 each in the placebo, 45-mg tralokinumab, and 300-mg tralokinumab groups) and 1 incident of oral herpes (45-mg tralokinumab group) were considered study drug related.

Preferred terms presented are from the Medical Dictionary for Regulatory Activities, Version 18.1.

Tralokinumab demonstrated low potential to cause immunogenicity; only 1 participant (treated with 300 mg of tralokinumab) had positive test results for a low-titer ADA response after dosing, indicating a transient response. The participant was not symptomatic.

No clinically meaningful differential effects on treatment response were observed for the CCL17/TARC and IgE subgroups (see Table E3 in this article's Online Repository at www.jacionline.org ). At week 12, tralokinumab-treated participants demonstrated greater decreases from baseline in serum periostin, CCL17/TARC, and IgE concentrations compared with those receiving placebo; conversely, DPP-4 concentrations increased compared with those in placebo-treated participants at the same time point (see Fig E2 in this article's Online Repository at www.jacionline.org ).

Exploratory analyses of adjusted mean change from baseline over time for EASI scores and adjusted percentage of participants with an IGA response are shown in Fig 1 for the DPP-4-high ( Fig 1 , B and C) and periostin-high ( Fig 1 , E and F) subgroups. Tralokinumab-treated participants in these subgroups demonstrated greater improvements in EASI scores versus placebo than in the ITT population (adjusted mean difference for 300 mg of tralokinumab versus placebo, −4.94 [ITT population], −9.78 [DPP-4-high subgroup], and −6.76 [periostin-high subgroup]). Differences in IGA responses for tralokinumab-treated participants versus placebo-treated participants were mostly improved for these subgroups than in the ITT population (difference in response rates for 300 mg of tralokinumab vs placebo, 14.8% [ITT population], 26.1% [DPP-4-high subgroup], and 21.4% [periostin-high subgroup]; Table I ).

Median baseline serum DPP-4, periostin, CCL17/TARC, and IgE concentrations were 265.8 ng/mL, 29.8 ng/mL, 1478.2 ng/mL, and 3045.6 kU/L, respectively.

Participants demonstrated improvements from baseline at week 12 in pruritus numeric rating scale (7-day mean) scores versus those receiving placebo when receiving 45 or 300 mg of tralokinumab (adjusted mean difference, −0.77 [95% CI, −1.52 to −0.02; P = .04] and −1.14 [95% CI, −1.88 to −0.41; P = .002], respectively). These improvements were observed from week 1 onward for all tralokinumab doses and maintained beyond week 12 ( Fig 3 , B). Furthermore, improvements in Dermatology Life Quality Index score were reported at week 12 for those receiving 300 mg of tralokinumab versus placebo (adjusted mean difference, −3.51 [95% CI, −6.00 to −1.02; P = .006]). However, these improvements were not maintained beyond the 12-week treatment period ( Fig 3 , C).

Improvements in SCORAD score versus placebo were achieved for participants treated with 150 and 300 mg of tralokinumab (adjusted mean difference, −9.42 [95% CI, −15.56 to −3.29; P = .003] and −9.84 [95% CI, −15.91 to −3.77; P = .002], respectively). Improvements in SCORAD score were observed from week 2 onward for all doses of tralokinumab and maintained beyond week 12, with the greatest effect observed in participants treated with 300 mg of tralokinumab ( Fig 3 , A). The percentage of participants with a reduction of 50% or more in SCORAD score at week 12 was greater in the 150-mg tralokinumab group (44.2%, P = .008) and the 300-mg tralokinumab group (44.1%, P = .009) versus placebo (19.5%; Fig 2 , B).

Adjusted mean change from baseline in SCORAD score (A) , pruritus numeric rating scale (NRS) score (B) , and Dermatology Life Quality Index (DLQI) score (C) for the ITT population.

Fig 3 Adjusted mean change from baseline in SCORAD score (A) , pruritus numeric rating scale (NRS) score (B) , and Dermatology Life Quality Index (DLQI) score (C) for the ITT population.

Improvements in adjusted mean change from baseline in EASI score were evident at week 4 and maintained beyond week 12 for participants treated with 300 mg of tralokinumab ( Fig 1 , A). A greater adjusted percentage of tralokinumab-treated participants achieved a reduction of 50% or more in EASI score versus placebo at week 12, and differences were most substantial in the 300-mg tralokinumab group (73.4% vs 51.9%, P = .03; Fig 2 , A). A similar trend was observed when analyzing the percentage of participants with a reduction of 75% or more in EASI score (42.5% in the 300-mg tralokinumab group vs 15.5% in the placebo group, P = .003; Fig 2 , A).

Adjusted percentage of participants achieving a reduction of 50% or more (EASI50) and 75% or more (EASI75) in EASI score (A) and 50% or more in SCORAD score (SCORAD50; B ) at week 12. Analyses were last observation carried forward, excluding data from participants who took prohibited medications.

Fig 2 Adjusted percentage of participants achieving a reduction of 50% or more (EASI50) and 75% or more (EASI75) in EASI score (A) and 50% or more in SCORAD score (SCORAD50; B ) at week 12. Analyses were last observation carried forward, excluding data from participants who took prohibited medications.

At week 12, the adjusted mean difference from baseline in EASI score was significantly different than the value in the placebo group: −4.36 (95% CI, −8.22 to −0.51; P = .03) for the 150-mg tralokinumab group and −4.94 (95% CI, −8.76 to −1.13; P = .01) for the 300-mg tralokinumab group ( Table I ). Testing the 150- and 300-mg tralokinumab pooled doses compared with placebo did not demonstrate a significant difference in the percentage of participants with an IGA response at week 12 (23.0% vs 11.8%, P = .10); therefore the hierarchical testing procedure was discontinued. However, numeric improvements in IGA response rates were observed with increasing doses of tralokinumab ( Fig 1 , D). The greatest absolute percentage difference from placebo was observed in participants treated with 300 mg of tralokinumab (26.7% vs 11.8% [+14.8%]; 95% CI, 0.0 to 29.7; P = .06; Table I ).

A-C, Adjusted mean change in EASI score from baseline over time for the ITT population (Fig 1, A∗), DPP-4-high subgroup (Fig 1, B†), and periostin-high subgroup (Fig 1, C‡). D-F, Adjusted percentage of participants with an IGA response at week 12 for the ITT population (Fig 1, D∗), DPP-4-high subgroup (Fig 1, E†), and periostin-high subgroup (Fig 1, F‡). Participants were considered IGA responders if they had an IGA response of 0 or 1 and a reduction of 2 grades or more from baseline to week 12. IGA severity categories are as follows: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe. ∗Participants randomized to treatment: placebo, n = 51; tralokinumab 45 mg, n = 50; tralokinumab 150 mg, n = 51; tralokinumab 300 mg, n = 52. †Participants randomized to treatment: placebo, n = 24; tralokinumab 45 mg, n = 25; tralokinumab 150 mg, n = 23; tralokinumab 300 mg, n = 30. ‡Participants randomized to treatment: placebo, n = 25; tralokinumab 45 mg, n = 24; tralokinumab 150 mg, n = 25; tralokinumab 300 mg, n = 28.

Fig 1 A-C, Adjusted mean change in EASI score from baseline over time for the ITT population (Fig 1, A∗), DPP-4-high subgroup (Fig 1, B†), and periostin-high subgroup (Fig 1, C‡). D-F, Adjusted percentage of participants with an IGA response at week 12 for the ITT population (Fig 1, D∗), DPP-4-high subgroup (Fig 1, E†), and periostin-high subgroup (Fig 1, F‡). Participants were considered IGA responders if they had an IGA response of 0 or 1 and a reduction of 2 grades or more from baseline to week 12. IGA severity categories are as follows: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe. ∗Participants randomized to treatment: placebo, n = 51; tralokinumab 45 mg, n = 50; tralokinumab 150 mg, n = 51; tralokinumab 300 mg, n = 52. †Participants randomized to treatment: placebo, n = 24; tralokinumab 45 mg, n = 25; tralokinumab 150 mg, n = 23; tralokinumab 300 mg, n = 30. ‡Participants randomized to treatment: placebo, n = 25; tralokinumab 45 mg, n = 24; tralokinumab 150 mg, n = 25; tralokinumab 300 mg, n = 28.

Participants were considered IGA responders if they had an IGA response of 0 or 1 and a reduction of 2 grades or more from baseline to week 12. IGA severity categories are as follows: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe.

∗ Participants were considered IGA responders if they had an IGA response of 0 or 1 and a reduction of 2 grades or more from baseline to week 12. IGA severity categories are as follows: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe.

Participants were considered IGA responders if they had an IGA response of 0 or 1 and a reduction of 2 grades or more from baseline to week 12. IGA severity categories are as follows: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe.

∗ Participants were considered IGA responders if they had an IGA response of 0 or 1 and a reduction of 2 grades or more from baseline to week 12. IGA severity categories are as follows: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; and 5, very severe.

Biomarker-high subgroups include participants with baseline concentrations of 265.8 ng/mL or greater for DPP-4 and 29.8 ng/mL or greater for periostin.

† Biomarker-high subgroups include participants with baseline concentrations of 265.8 ng/mL or greater for DPP-4 and 29.8 ng/mL or greater for periostin.

Biomarker-high subgroups include participants with baseline concentrations of 265.8 ng/mL or greater for DPP-4 and 29.8 ng/mL or greater for periostin.

† Biomarker-high subgroups include participants with baseline concentrations of 265.8 ng/mL or greater for DPP-4 and 29.8 ng/mL or greater for periostin.

Summary of coprimary end points for the ITT population and subgroups defined by baseline serum DPP-4 and periostin concentrations (exploratory analysis)

Table I Summary of coprimary end points for the ITT population and subgroups defined by baseline serum DPP-4 and periostin concentrations (exploratory analysis)

The first participant was enrolled on January 23, 2015, and the first participant was dosed on February 13, 2015. Of the 299 participants who were screened, 204 were randomized (placebo, n = 51; 45 mg of tralokinumab, n = 50; 150 mg of tralokinumab, n = 51; and 300 mg of tralokinumab, n = 52) and included in the ITT and as-treated populations (see Fig E1 in this article's Online Repository at www.jacionline.org ). Baseline demographics and disease characteristics were similar between treatment groups (see Table E2 in this article's Online Repository at www.jacionline.org ).

Discussion

16 Poole A.

Urbanek C.

Eng C.

Schageman J.

Jacobson S.

O'Connor B.P.

et al. Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease. , 17 Ranade K.

Pham T.-H.

Damera G.

Brohawn P.

Pilataxi F.

Kuziora M.

et al. Dipeptidyl Peptidase-4 (DPP-4) is a novel predictive biomarker for the investigational anti-Il-13 targeted therapy tralokinumab. , 18 Izuhara K.

Arima K.

Ohta S.

Suzuki S.

Inamitsu M.

Yamamoto K. Periostin in allergic inflammation. , 19 Parulekar A.D.

Atik M.A.

Hanania N.A. Periostin, a novel biomarker of Th2-driven asthma. 6 Ungar B.

Garcet S.

Gonzalez J.

Dhingra N.

da Rosa J.C.

Shemer A.

et al. An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease. , 7 Khattri S.

Shemer A.

Rozenblit M.

Dhingra N.

Czarnowicki T.

Finney R.

et al. Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. , 20 Hamilton J.D.

Suarez-Farinas M.

Dhingra N.

Cardinale I.

Li X.

Kostic A.

et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. , 21 Khattri S.

Brunner P.M.

Garcet S.

Finney R.

Cohen S.R.

Oliva M.

et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. , 22 Brunner P.M.

Khattri S.

Garcet S.

Finney R.

Oliva M.

Dutt R.

et al. A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis. , 23 Tintle S.

Shemer A.

Suarez-Farinas M.

Fujita H.

Gilleaudeau P.

Sullivan-Whalen M.

et al. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. , 24 Rozenblit M.

Suarez-Farinas M.

Shemer A.

Khattri S.

Gilleaudeau P.

Sullivan-Whalen M.

et al. Residual genomic profile after cyclosporine treatment may offer insights into atopic dermatitis reoccurrence. Our study provides evidence for targeting IL-13 in patients with AD. Treatment with 150 or 300 mg of tralokinumab subcutaneously every 2 weeks for 12 weeks achieved clinically significant improvements in EASI scores from week 4 in participants with moderate-to-severe AD who received concomitant topical glucocorticoids. IL-13 upregulates DPP-4 and periostin expression, and both are considered biomarkers of IL-13 signaling.In exploratory analyses additional treatment benefits were observed in DPP-4- and periostin-high subgroups, driven in part by a smaller reduction in EASI scores in the placebo group for DPP-4-high participants than in the ITT population. Previous AD studies have largely focused on reversing clinical symptoms, with few documenting biomarker changes.In our study we observed greater changes in serum biomarker concentrations versus placebo after tralokinumab treatment. Biomarkers are playing an increasingly important role in predicting treatment response, and our results are likely to assist in progressing AD treatment toward a more personalized approach.

25 Eichenfield L.F.

Tom W.L.

Berger T.G.

Krol A.

Paller A.S.

Schwarzenberger K.

et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. Participants entering the study had not achieved an adequate response to stable topical glucocorticoids during the 2-week run-in period and therefore represent a population with moderate-to-severe AD and major unmet treatment needs. The clinically meaningful benefits observed by combining tralokinumab treatment with topical glucocorticoids suggest that tralokinumab could demonstrate improvements in participants whose symptoms cannot be effectively controlled by topical glucocorticoids alone. These agents are widely used in AD treatment; however, they are associated with multiple systemic and topical side effects, precluding long-term use on a large body surface area.Therefore agents that reduce the need for high-dose topical glucocorticoids are greatly needed.

H 2 inflammation in AD pathogenesis. 4 Gittler J.K.

Shemer A.

Suarez-Farinas M.

Fuentes-Duculan J.

Gulewicz K.J.

Wang C.Q.

et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. , 20 Hamilton J.D.

Suarez-Farinas M.

Dhingra N.

Cardinale I.

Li X.

Kostic A.

et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. , 26 Moreno A.S.

McPhee R.

Arruda L.K.

Howell M.D. Targeting the T helper 2 inflammatory axis in atopic dermatitis. , 27 Hamilton J.D.

Ungar B.

Guttman-Yassky E. Drug evaluation review: dupilumab in atopic dermatitis. 8 Simpson E.L.

Bieber T.

Guttman-Yassky E.

Beck L.A.

Blauvelt A.

Cork M.J.

et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. , 9 Beck L.A.

Thaci D.

Hamilton J.D.

Graham N.M.

Bieber T.

Rocklin R.

et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. , 10 Thaçi D.

Simpson E.L.

Beck L.A.

Bieber T.

Blauvelt A.

Papp K.

et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. , 20 Hamilton J.D.

Suarez-Farinas M.

Dhingra N.

Cardinale I.

Li X.

Kostic A.

et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. , 28 Blauvelt A.

de Bruin-Weller M.

Gooderham M.

Cather J.C.

Weisman J.

Pariser D.

et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. 29 Simpson E.L.

Flohr C.

Eichenfield L.F.

Bieber T.

Sofen H.

Taieb A.

et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE). The positive results of our study add to the growing body of evidence supporting a central role for T2 inflammation in AD pathogenesis.These include studies of dupilumab, an inhibitor of both IL-13 and IL-4 signaling, which have shown improved clinical responses in adults with moderate-to-severe AD in a dose-dependent mannerand data from a phase IIb study showing benefits with lebrikizumab, which inhibits IL-13 signaling.In our study participants received treatment with topical glucocorticoids during the 2-week run-in period before randomization. Participants who demonstrated improvements in AD symptoms on this treatment regimen such that they no longer met the study's inclusion criteria (EASI score ≥12, SCORAD score ≥25, or IGA score ≥3) were then excluded. Therefore, given the differences in study design, outcomes assessed, and participant selection criteria, it is difficult to compare the efficacy of tralokinumab with other agents targeting IL-13 in AD treatment. Future phase III studies of tralokinumab both as monotherapy and in conjunction with topical glucocorticoids are needed to provide further understanding of the relevant contribution of IL-13 alone to AD compared with IL-4 and IL-13 in combination. It might also be of benefit for future studies to analyze clinical response in participants classified by AD form (classical, nummular, or prurigo) to determine whether response is dependent on these factors.

30 Brightling C.E.

Chanez P.

Leigh R.

O'Byrne P.M.

Korn S.

She D.

et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. , 31 Piper E.

Brightling C.

Niven R.

Oh C.

Faggioni R.

Poon K.

et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. 8 Simpson E.L.

Bieber T.

Guttman-Yassky E.

Beck L.A.

Blauvelt A.

Cork M.J.

et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. , 9 Beck L.A.

Thaci D.

Hamilton J.D.

Graham N.M.

Bieber T.

Rocklin R.

et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. , 10 Thaçi D.

Simpson E.L.

Beck L.A.

Bieber T.

Blauvelt A.

Papp K.

et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. , 32 Wenzel S.

Ford L.

Pearlman D.

Spector S.

Sher L.

Skobieranda F.

et al. Dupilumab in persistent asthma with elevated eosinophil levels. , 33 Wenzel S.

Castro M.

Corren J.

Maspero J.

Wang L.

Zhang B.

et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. 29 Simpson E.L.

Flohr C.

Eichenfield L.F.

Bieber T.

Sofen H.

Taieb A.

et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE). , 34 Hanania N.A.

Noonan M.

Corren J.

Korenblat P.

Zheng Y.

Fischer S.K.

et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. 8 Simpson E.L.

Bieber T.

Guttman-Yassky E.

Beck L.A.

Blauvelt A.

Cork M.J.

et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. , 10 Thaçi D.

Simpson E.L.

Beck L.A.

Bieber T.

Blauvelt A.

Papp K.

et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. The safety profile of tralokinumab in patients with AD was similar to results from previous trials of tralokinumab in patients with asthma. The most common events were upper respiratory tract infections and headache, the majority of TEAEs were mild or moderate, and none of the 5 TESAEs reported across the tralokinumab groups were considered study drug related.These findings are broadly in line with those reported in studies of dupilumaband lebrikizumabin patients with AD and asthma. Conjunctivitis has been reported at a higher rate in participants receiving dupilumab relative to placebo.Although not predefined as an AE of special interest in our study, conjunctivitis was reported infrequently, with no incidents considered study drug related.

31 Piper E.

Brightling C.

Niven R.

Oh C.

Faggioni R.

Poon K.

et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. , 35 Oh C.K.

Faggioni R.

Jin F.

Roskos L.K.

Wang B.

Birrell C.

et al. An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males. , 36 Baverel P.G.

Jain M.

Stelmach I.

She D.

Agoram B.

Sandbach S.

et al. Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing. , 37 Singh D.

Kane B.

Molfino N.A.

Faggioni R.

Roskos L.

Woodcock A. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma. 30 Brightling C.E.

Chanez P.

Leigh R.

O'Byrne P.M.

Korn S.

She D.

et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Only 1 participant had a positive test result for an ADA response to tralokinumab, and they were asymptomatic. This is comparable with immunogenicity results from asthma trials, which reported noor few participants (2/151 participants receiving 300 mg of tralokinumab every 4 weeks)with positive test results for an ADA response.

The observed improvements in placebo-treated participants indicate that topical glucocorticoids provided partial benefit, despite all participants having inadequate disease control with such therapy at enrollment. Although a study of tralokinumab monotherapy would provide a more definitive measurement of efficacy than in combination with topical glucocorticoids, in clinical practice it is expected that biologics will be prescribed concomitantly to topical therapies. Therefore our study reflects a real-world setting, demonstrating tralokinumab efficacy with concomitant topical glucocorticoids and providing further support for the role of IL-13 in AD pathogenesis.