Clinically Meaningful Improvements in Adolescents with Moderate-to-Severe Atopic Dermatitis Treated with Tralokinumab who did not Achieve Clear or Almost Clear Skin at Week 16

Abstract

Introduction

Investigator’s Global Assessment (IGA) of clear/almost clear (0/1) skin is a high standard to achieve after 16 weeks of treatment for patients with moderate-to-severe atopic dermatitis (AD) and does not capture clinically meaningful responses in other patient domains, such as improvement in itch and/or quality of life. To better evaluate the effect of tralokinumab in adolescents, we assessed the clinically meaningful impact of tralokinumab versus placebo in patients who did not meet IGA 0/1 at week 16 without rescue medication in ECZTRA 6.

Methods

These post hoc analyses included adolescents from the ECZTRA 6 (NCT03526861) phase 3 trial who did not achieve IGA 0/1 at week 16 without rescue medication (referred to as IGA >1). Clinically meaningful responses were defined as either ≥50% improvement from baseline in Eczema Area and Severity Index (EASI-50), ≥3-point improvement in Adolescent Worst Pruritus Numeric Rating Scale (itch NRS), or ≥6-point improvement in Children’s Dermatology Life Quality Index (CDLQI) at week 16.

Results

Among IGA >1 patients (n = 247), significantly greater percentages receiving tralokinumab (150 mg or 300 mg) versus placebo achieved EASI-50 (31.2% or 41.3% versus 10.0%), ≥3-point improvement in itch NRS (21.6% or 22.8% versus 8.0%), or ≥1 clinically meaningful measure (36.4% or 52.5% versus 21.1%) at week 16. The majority of IGA >1 patients who continued with open-label tralokinumab beyond week 16 achieved EASI-50 and ≥3-point improvement in itch NRS and about 40% met EASI-90 at week 52.

Conclusions

Clinically meaningful responses in both clinician-measured and patient-reported outcomes were observed in tralokinumab-treated (150 mg or 300 mg) adolescents who did not achieve IGA 0/1 at week 16 without rescue medication. Utilizing validated outcome measures of both efficacy and patient quality of life, alongside IGA scores, can enhance clinical decision-making regarding tralokinumab treatment responses in adolescents with moderate-to-severe AD.

Trial Registration

ClinicalTrials.gov identifier, NCT03526861 (ECZTRA 6); study start date: 19 June 2018; primary completion date: 15 April 2020; study completion date: 16 March 2021.

A Graphical Abstract is available for this article.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01484-1.

Plain Language Summary

Atopic dermatitis is a common and chronic skin disease where patients experience severe itch and skin lesions. Atopic dermatitis can negatively affect patient quality of life, especially for adolescents, whose self-esteem and body image can greatly influence their perception of social interactions. Tralokinumab is a medication that is approved for treating moderate-to-severe atopic dermatitis in patients aged 12 years and up. Clinical trials for atopic dermatitis therapies often define treatment success using a single clinician-measured metric of clear or almost clear skin at week 16. Patients who do not achieve this are considered a treatment failure. However, this limited definition of treatment success does not reflect the complete patient experience, especially for those with lesions across much of their skin. Here, we used data from the ECZTRA 6 phase 3 clinical trial, funded by LEO Pharma A/S, to analyze if adolescent patients treated with tralokinumab, who did not meet the trial definition for treatment success, still showed meaningful improvement in atopic dermatitis symptoms. Overall, in this group, a larger percentage of patients treated with tralokinumab, compared with those who did not receive active drug (i.e., placebo), showed improvements in the severity of skin lesions, itch, and patient quality of life at week 16. Additionally, patients continued to improve with ongoing tralokinumab treatment beyond week 16. Our results suggest using several outcomes directly reported by patients, in addition to clinician-measured metrics, can better inform tralokinumab treatment management in adolescents with moderate-to-severe atopic dermatitis

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01484-1.

Key Summary Points

Why carry out this study?

Investigator’s Global Assessment of clear/almost clear skin (IGA 0/1) is a recommended endpoint in most atopic dermatitis (AD) clinical trials; however, its exclusive utilization for defining treatment success after short-term treatment can result in underestimation of AD systemic therapy benefits.

To better evaluate the effect of tralokinumab in adolescents, we assessed the clinically meaningful impact of tralokinumab versus placebo in adolescents from ECZTRA 6 who did not meet IGA 0/1 at week 16 without rescue medication.

What was learned from this study?

Tralokinumab-treated adolescents from the ECZTRA 6 phase 3 trial who did not achieve IGA 0/1 at week 16 without rescue medication still exhibited significant clinically meaningful improvement in other patient domains, with further improvements with continued treatment to week 52.

Using other validated clinician-measured and patient-reported outcomes, alongside IGA scores, provides a more holistic evaluation of tralokinumab treatment benefits in adolescents with moderate-to-severe atopic dermatitis.

Digital Features

This article is published with digital features, including a graphical abstract, to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.29413043.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often emerges early in life and can persist into adulthood [1], resulting in a substantial, multidimensional disease burden [2, 3]. Symptoms such as severe itch and visible lesions can negatively impact quality of life (QoL), sleep quality, social interactions, and psychological health [2, 4, 5], especially during adolescence when body image can greatly influence peer-to-peer interactions [6].

Tralokinumab is a fully human immunoglobulin G4 (IgG4) high-affinity monoclonal antibody that specifically binds to interleukin (IL)-13 [7, 8], a key driver of skin inflammation and barrier abnormalities in AD [9, 10], and blocks its interaction with the IL-13 receptor subunit alpha-1 (IL-13Rα1), preventing subsequent signaling [8]. Tralokinumab is currently approved in multiple countries for the treatment of moderate-to-severe AD in adults [11] and has more recently been approved in the EU, Canada, UK, and the US for adolescents aged 12 to 17 years with moderate-to-severe AD [12–15].

In the phase 3 ECZTRA 6 tralokinumab monotherapy trial of adolescents with moderate-to-severe AD, significantly more patients in the tralokinumab groups (150 mg, 21.4%; 300 mg, 17.5%), compared with the placebo group (4.3%), achieved an Investigator’s Global Assessment (IGA) score of clear (0) or almost clear (1) skin at week 16 without rescue medication [16]. Although IGA scales are widely utilized in AD clinical trials [17] and recommended by the US Food and Drug Administration (FDA) for primary analyses, additional measures are utilized to capture clinically meaningful responses in other patient domains, such as improvement in itch and/or QoL. As such, exclusive use of IGA 0/1 as a definition of treatment success after short-term treatment may underestimate the benefits of systemic therapies for AD, especially for patients with severe AD at baseline. Previous work in adolescents with AD have shown numerically greater placebo-adjusted IGA 0/1 response rates at week 16 for patients with moderate AD (IGA 3) versus severe AD (IGA 4) at baseline [18]. Notably, previous studies of AD biologics in adult [19, 20] and pediatric populations [21–23] have found clinically meaningful improvements even in patients who did not achieve the regulatory primary endpoints. Specifically, adults in the phase 3 ECZTRA 1 and ECZTRA 2 tralokinumab monotherapy trials, who did not achieve IGA 0/1 at week 16 without rescue medication, still exhibited clinically meaningful improvements in AD signs, symptoms, or quality of life at week 16 [20].

To better evaluate the effect of tralokinumab in adolescents, we assessed the clinically meaningful impact of tralokinumab versus placebo in adolescents with moderate-to-severe AD who did not meet IGA 0/1 at week 16 without rescue medication in ECZTRA 6.

Methods

Study Design and Patient Population

This post hoc analysis included patients from the ECZTRA 6 (NCT03526861) phase 3 trial who did not achieve one of the primary endpoints, IGA 0/1 at week 16 without rescue medication (hereinafter referred to as IGA >1).

The study design and primary results of the ECZTRA 6 trial has been previously described [16]. Briefly, ECZTRA 6 was a multinational, double-blinded, randomized, placebo-controlled, 52-week trial of tralokinumab monotherapy in adolescents (aged 12–17 years old) with moderate-to-severe AD. In the initial treatment period, patients were randomized 1:1:1 to receive either subcutaneous tralokinumab, 150 or 300 mg (after an initial loading dose on day 0, which was twice the dosage of their respective tralokinumab group), or placebo every 2 weeks (Q2W) for 16 weeks. Tralokinumab-treated patients who achieved the pre-specified primary endpoints, IGA 0/1 or ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75) at week 16 without any rescue use (including topical calcineurin inhibitors [TCI], topical corticosteroids [TCS], or systemic AD treatment), were re-randomized 1:1 to blinded maintenance treatment of either tralokinumab Q2W or every 4 weeks (Q4W) at their initially assigned dosage (150 or 300 mg) until week 52. Patients initially assigned to the placebo group who achieved the primary endpoints continued to receive placebo Q2W until week 52 to maintain blinding. Patients who did not achieve IGA 0/1 or EASI-75 at week 16 were considered “non-responders” and transferred to open-label treatment (tralokinumab 300 mg Q2W plus optional weak to moderate potency TCS or TCI) after week 16. During the 36-week maintenance treatment period, patients were transferred to open-label treatment if they exhibited a decline in response defined by predefined transfer criteria (Fig. S1) [16].

Ethical Approval

The trial protocol was approved by all relevant ethics committees and institutional review boards (see Supplementary Table S4). The trial was conducted according to the principles of the Declaration of Helsinki and the International Council on Harmonization Guidelines for Good Clinical Practice and conformed with all relevant country-specific laws and regulations. All patients, or their legal representatives, provided written informed consent.

Outcomes

Week 16

Clinician-measured outcomes included the percentages of patients who achieved IGA 0/1, ≥50% improvement from baseline in EASI (EASI-50), EASI-75, EASI-90, EASI-100, as well as the mean change from baseline to week 16 in SCORing Atopic Dermatitis (SCORAD). Patient-reported outcomes (PROs) included the percentages of patients who achieved ≥3-point or ≥4-point improvement in Adolescent Worst Pruritus Numeric Rating Scale (itch NRS), ≥3-point improvement in Eczema-related Sleep interference NRS (sleep NRS), ≥6-point improvement in Children’s Dermatology Life Quality Index (CDLQI) or Patient-Oriented Eczema Measure (POEM), and CDLQI ≤6.

Specifically, clinically meaningful responses were defined as either EASI-50, ≥3-point improvement in itch NRS, or ≥6-point improvement in CDLQI at week 16 based on previous data describing minimal clinically important differences exhibited by adult [24–26] or adolescent [27, 28] patients with AD. Additionally, the percentages of patients who used ≥1 rescue medication as well as the time to rescue use were reported.

Week 52

Clinician-measured outcomes included the percentages of patients who achieved IGA 0/1, EASI-50, EASI-75, EASI-90, and EASI-100. PROs included the percentages of patients who achieved ≥3-point or ≥4-point improvement in itch NRS and a ≥6-point improvement in CDLQI or POEM.

Statistical Analysis

Binary outcomes at week 16 were assessed using a composite estimand. Nonresponder imputation (NRI) was implemented for patients who utilized rescue medication or had missing data. Comparisons between the tralokinumab and placebo groups were analyzed using the Cochran–Mantel–Haenszel test, stratified by region and baseline IGA.

Continuous outcomes at week 16 were assessed using a composite estimand. The worst observation was carried forward for all patients who utilized rescue medication after week 2, whereas patients with missing data were imputed using multiple imputation (MI). Comparisons between the tralokinumab and placebo groups were analyzed using an analysis of covariance model (Change = Treatment + Baseline + Region + Baseline IGA).

Results at week 16 for IGA >1 patients were also assessed using a treatment policy estimand. Use of rescue medication was ignored. Missing data was imputed via MI. The rationale was that rescue mediation (e.g., TCS or TCI) is commonly used alongside biologic treatments for AD in the clinical setting (Figs. S2 and S3).

Binary outcomes at week 52 were assessed using a treatment policy estimand. Use of rescue medication was ignored. Missing data was imputed via MI.

Individual patient-level data for percentage improvement from baseline in EASI are visualized in waterfall plots. Use of rescue medication was ignored. For missing data, worst observation carried forward (WOCF) was used for the week 16 analysis, and last observation carried forward (LOCF) was used for the week 52 analysis.

Results

Patient Disposition and Baseline Characteristics

At Week 16, significantly greater percentages of tralokinumab-treated patients (150 mg, 21.4% [21/98]; 300 mg, 17.5% [17/97]) achieved IGA 0/1 without rescue medication compared with those in the placebo group (4.3%, 4/94) [16]. Among IGA >1 patients (i.e., those who did not achieve IGA 0/1 at week 16 without rescue medication), baseline demographic and clinical characteristics were similar between tralokinumab and placebo groups. In the tralokinumab-treated (150 mg, 300 mg) IGA >1 groups, 51.9% and 53.8% of patients exhibited severe disease at baseline (IGA 4), while the mean EASI was 33.1 and 33.5, respectively (Table 1). In the tralokinumab-treated patients who achieved IGA 0/1 at week 16 without rescue medication, 19.0% and 29.4% of patients had IGA 4, and the mean EASI was 25.7 and 26.7, respectively (Table S1).

Table 1.

Baseline characteristics for ECZTRA 6 patients with IGA >1 at Week 16

	IGA >1a at week 16
	Placebo (N = 90)	Tralo 150 mg (N = 77)	Tralo 300 mg (N = 80)
Age (years), mean (SD)	14.3 (1.6)	14.8 (1.7)	14.6 (1.7)
Male, n (%)	50 (55.6)	38 (49.4)	42 (52.5)
Race, n (%)
White	50 (55.6)	44 (57.1)	44 (55.0)
Black or African American	10 (11.1)	7 (9.1)	11 (13.8)
Asian	23 (25.6)	21 (27.3)	18 (22.5)
American Indian or Alaska Native	1 (1.1)	2 (2.6)	0 (0.0)
Native Hawaiian or Other Pacific Islander	2 (2.2)	0 (0.0)	2 (2.5)
Other	4 (4.4)	3 (3.9)	5 (6.3)
Body mass index (kg/m2), mean (SD)	23.3 (6.2)	22.3 (5.0)	23.3 (5.1)
Duration of AD (years), mean (SD)	12.0 (3.4)	13.0 (3.4)	12.1 (3.8)
BSA involvement with AD (%), mean (SD)	51.3 (24.3)	54.5 (22.8)	52.1 (24.3)
IGA, n (%)
IGA 3 (moderate)	48 (53.3)	37 (48.1)	37 (46.3)
IGA 4 (severe)	42 (46.7)	40 (51.9)	43 (53.8)
EASI, mean (SD)	31.4 (14.7)	33.5 (13.3)	33.1 (14.8)
Itch NRS, mean (SD)	7.5 (1.7), N = 88	7.5 (1.6), N = 75	7.8 (1.5), N = 79
CDLQI, mean (SD)	13.6 (5.9), N = 85	13.4 (6.1), N = 76	13.8 (7.0), N = 78
Sleep NRS, mean (SD)	6.8 (2.1), N = 88	6.4 (2.3), N = 75	7.0 (2.1), N = 79
POEM, mean (SD)	21.0 (5.5), N = 83	20.9 (5.3), N = 76	20.9 (5.3), N = 78
SCORAD, mean (SD)	67.6 (15.0)	68.5 (14.6)	68.8 (14.1)

^aPatients who did not achieve IGA 0/1 at Week 16 and/or used rescue medication. Individual row N values are shown when different from respective total number of patients in group

AD atopic dermatitis, BSA body surface area, CDLQI Children’s Dermatology Life Quality Index, EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment, IGA 0/1 clear/almost clear skin, N total number of patients per group, n number of patients meeting indicated metric, NRS numeric rating scale, POEM Patient Oriented Eczema Measure, SCORAD SCORing Atopic Dermatitis, SD standard deviation, Tralo tralokinumab

Improvements in Week 16 Outcomes in Tralokinumab-Treated IGA >1 Patients

Clinically meaningful responses were defined as either EASI-50, ≥3-point improvement in itch NRS, or ≥6-point improvement in CDLQI at week 16. Significantly greater percentages of IGA >1 patients in the tralokinumab 150 mg versus placebo group achieved EASI-50 (31.2% versus 10.0%, P = 0.018), ≥3-point improvement in itch NRS (21.6% versus 8.0%, P = 0.018), or at least one clinically meaningful measure (36.4% versus 21.1%, P = 0.030) (Fig. 1). In IGA >1 patients treated with tralokinumab 300 mg, compared with placebo, significantly greater percentages achieved EASI-50 (41.3% versus 10.0%, P < 0.001), ≥3-point improvement in itch NRS (22.8% versus 8.0%, P = 0.011), ≥6-point improvement in CDLQI (35.2% versus 15.0%, P = 0.002), or at least one measure (52.5% versus 21.1%, P < 0.001) (Fig. 1).

Fig. 1.

Percentages of IGA >1 patients who achieved clinically meaningful responses (EASI-50, ≥3-point improvement in itch NRS, ≥6-point improvement in CDLQI) at week 16. Asterisks denote tralokinumab dose (150 or 300 mg) versus placebo in the IGA >1 population: *P < 0.05, **P < 0.01, ***P < 0.001. To provide greater context of the IGA >1 data, stacked (no fill) bars denote percentages for the corresponding total ECZTRA 6 total population (IGA 0/1 without rescue use + IGA >1 patients). Percentages of responders, rounded to nearest whole number, are listed within bars. Composite estimand used NRI for patients who utilized rescue medication or had missing data. CDLQI Children’s Dermatology Life Quality Index, EASI Eczema Area and Severity Index, EASI-50 at least 50% improvement in EASI, IGA Investigator’s Global Assessment, n number of patients with available data, NRI non-responder imputation, NRS numeric rating scale

Additional clinician-measured and PROs of interest were also assessed. Significantly greater percentages of IGA >1 patients in the tralokinumab 150 mg versus placebo group achieved EASI-75 (9.1% versus 2.2%, P = 0.047), ≥4-point improvement in itch NRS (12.2% versus 3.5%, P = 0.043), ≥6-point improvement in POEM (25.0% versus 9.8%, P = 0.015), or CDLQI ≤6 (31.6% versus 17.4%, P = 0.035) (Fig. 2). In IGA >1 patients treated with tralokinumab 300 mg, compared with placebo, significantly greater percentages achieved EASI-75 (15.0% versus 2.2%, P = 0.002), ≥3-point improvement in sleep NRS (29.7% versus 10.5%, P = 0.003), ≥4-point improvement in itch NRS (19.0% versus 3.5%, P = 0.002), ≥6-point improvement in POEM (42.3% versus 9.8%, P < 0.001), or CDLQI ≤6 (37.5% versus 17.4%, P = 0.001) (Fig. 2). Compared with IGA >1 patients in the placebo group, significantly greater mean change from baseline to Week 16 in SCORAD was observed for patients in the tralokinumab 150 mg (−9.4 versus −0.9, P = 0.001) and 300 mg (−15.5 versus −0.9, P < 0.001) groups (Fig. S4).

Fig. 2.

Percentages of IGA >1 patients who achieved additional outcomes of interest at Week 16. Asterisks denote tralokinumab dose (150 or 300 mg) versus placebo in the IGA >1 population: *P < 0.05, **P < 0.01, ***P < 0.001. To provide greater context of the IGA >1 data, stacked (no fill) bars denote percentages for the corresponding total ECZTRA 6 total population (IGA 0/1 without rescue use + IGA >1 patients). Percentages of responders, rounded to nearest whole number, are listed within bars. Note that percentage of responders for 4-improvement in Itch NRS in the placebo group is as follows: IGA >1 population = 3.5%, total population = 3.3%. Composite estimand used NRI for patients who utilized rescue medication or had missing data. CDLQI, Children’s Dermatology Life Quality Index; EASI Eczema Area and Severity Index, EASI-75 at least 75% improvement in EASI, IGA Investigator’s Global Assessment, n number of patients with available data, NRI non-responder imputation, NRS numeric rating scale, POEM Patient Oriented Eczema Measure

Overall, the vast majority of tralokinumab-treated patients (pooled 150 mg and 300 mg doses) showed improvement from baseline in EASI at week 16 (Fig. S5). When analyzed by week 16 IGA score, 54.7% (29/53) of tralokinumab-treated patients with IGA 2 achieved EASI-75 at week 16 (Fig. S5A). Moreover, 51.4% (36/70) of tralokinumab-treated patients with IGA 3 at week 16 achieved EASI-50 (Fig. S5A).

A numerically greater percentage of patients in the placebo group utilized any rescue medication (58.9%, 53/90) during the initial 16-week treatment period compared with patients in either the tralokinumab 150 mg (42.9%, 33/77) or 300 mg (36.3%, 29/80) groups (Table S2) and this difference was evident by week 2 (placebo, 21.1% [19/90]; tralokinumab 150 mg, 11.7% [9/77]; tralokinumab 300 mg, 11.3% [9/80]; Fig. 3).

Fig. 3.

Percentage of IGA >1 patients who initiated any rescue medication use before or at week 16. n number of patients with available data

Week 52 Endpoints in Tralokinumab-Treated IGA >1 Patients Transferred to Open-Label Treatment at Week 16

Among IGA >1 patients who were initially treated with tralokinumab 150 mg or 300 mg Q2W and continued with open-label treatment (tralokinumab 300 mg + optional TCS or TCI), response rates at week 52 were 35.4% and 31.4% for IGA 0/1 and 63.1% and 52.9% for EASI-75, respectively [16]. When analyzed by week 16 IGA score, almost half of patients with IGA 2 at week 16 achieved IGA 0/1 at week 52 with open-label treatment (in patients transferred from initial 150 mg [49.5%] or 300 mg [40.0%] treatment) (Fig. 4a, b). Similarly, when analyzed by week 16 EASI improvement, approximately two-thirds of patients with EASI-50 to < EASI-75 at week 16 achieved EASI-75 at week 52 with open-label treatment (initial 150 mg, 66.5%; initial 300 mg, 69.0%) (Fig. 4c, d).

Fig. 4.

Percentages of IGA >1 patients initially treated with tralokinumab 150 mg or 300 mg, who achieved IGA 0/1 (a-b) or EASI-75 (c-d) over 36 weeks with open-label tralokinumab Q2W + optional TCS or TCI. Patients in open-label treatment (initially treated with tralokinumab 150 mg or 300 mg) who achieved IGA 0/1 at week 52 are grouped by their respective week 16 IGA score (i.e., IGA 2, 3, or 4) in panels a and b. Patients in the open-label arm who achieved EASI-75 at week 52 are grouped by their respective week 16 EASI improvement (i.e., EASI 50% to <75%, EASI 25% to <50%, or EASI <25%) in panels c and d. Treatment policy estimand used data as observed, regardless of rescue medication and other intercurrent events, and multiple imputation for missing data. EASI Eczema Area and Severity Index, EASI-75 at least 75% improvement in EASI, IGA Investigator’s Global Assessment, IGA 0/1/2/3/4 clear/almost clear/mild/moderate/severe, n number of patients with available data, Q2W every 2 weeks, TCI topical calcineurin inhibitors, TCS topical corticosteroids

Overall, 40.6% (54/133) of IGA >1 patients initially treated with tralokinumab (pooled 150 mg and 300 mg doses) achieved EASI-90 by week 52 with open-label treatment (Fig. 5). When analyzed by week 16 IGA score, 45.0% (9/20) with IGA 4 at week 16 achieved EASI-75 at week 52 with open-label treatment (Fig. 5). Moreover, 37.7% (26/69) with IGA 3 at week 16 achieved EASI-90 at week 52 with open-label treatment (Fig. 5). Additionally, 6.8% (9/133) of IGA >1 patients initially treated with tralokinumab achieved EASI-100 by week 52 with open-label treatment, including six patients who had IGA 3 at week 16 (Fig. 5).

Fig. 5.

Improvement in EASI from baseline to week 52 in IGA >1 patients initially treated with tralokinumab at 150 mg or 300 mg who continued with open-label tralokinumab Q2W + optional TCS or TCI. ^aLOCF used for missing data. ^bUse of rescue mediation between week 2 and week 16. EASI Eczema Area and Severity Index, EASI-50/75/90/100 at least 50%/75%/90%/100% improvement in EASI, IGA Investigator’s Global Assessment, IGA 0/1/2/3/4 clear/almost clear/mild/moderate/severe, n number of patients with available data, Q2W every 2 weeks, TCI topical calcineurin inhibitors, TCS topical corticosteroids, LOCF last observation carried forward

Additionally, at week 52 with open-label treatment, the majority of IGA >1 patients achieved EASI-50 (initial treatment: 150 mg, 85.0%; 300 mg, 83.0%), ≥3-point improvement in itch NRS (initial treatment: 150 mg, 58.6%; 300 mg, 52.3%), ≥6-point improvement in CDLQI (initial treatment: 150 mg, 66.5%; 300 mg, 62.8%), or ≥6-point improvement in POEM (initial treatment: 150 mg, 73.4%; 300 mg, 63.5%) (Fig. 6). Moreover, about one-half of IGA >1 patients achieved both EASI-50 and ≥3-point improvement in itch NRS (initial treatment: 150 mg, 54.7%; 300 mg, 46.9%) and almost one-third achieved both EASI-90 and ≥3-point improvement in itch NRS (initial treatment: 150 mg, 33.3%; 300 mg, 21.9%) at week 52 with open-label treatment.

Fig. 6.

Percentages of IGA >1 patients initially treated with tralokinumab 150 mg or 300 mg who achieved EASI-50, ≥3- or ≥4-point improvement in itch NRS, or ≥6-point improvement in CDLQI or POEM at Week 52 with open-label tralokinumab Q2W + optional TCS or TCI. Percentages of responders, rounded to nearest whole number, are listed above bars. Number of patients in the analysis set listed below respective bar. Treatment policy estimand used data as observed, regardless of rescue medication and other intercurrent events, and multiple imputation for missing data. CDLQI Children’s Dermatology Life Quality Index, EASI Eczema Area and Severity Index, EASI-50 at least 50% improvement in EASI, IGA Investigator’s Global Assessment, n number of patients with available data, NRS numeric rating scale, POEM Patient Oriented Eczema Measure, Q2W every 2 weeks, TCI topical calcineurin inhibitors, TCS topical corticosteroids

Discussion

Overall, among adolescents who did not achieve IGA 0/1 at week 16 without rescue medication (IGA >1), significantly greater percentages achieved clinically meaningful responses with tralokinumab (150 mg or 300 mg) compared with placebo. About one-third and one-half of IGA >1 patients in the tralokinumab 150 mg and 300 mg groups, respectively, achieved a clinically meaningful response in at least one outcome representing different disease domains (EASI-50, ≥3-point improvement in itch NRS, or ≥6-point improvement in CDLQI). These results extend previous tralokinumab findings in adults [20] to the adolescent population, demonstrating that many adolescents who did not meet this primary endpoint still exhibited clinically meaningful improvement with 16 weeks of tralokinumab treatment.

These findings are important when considering the utility of the IGA 0/1 metric in clinical practice and in shared decision-making with patients regarding tralokinumab treatment expectations. Additionally, these data highlight a fundamental inability of the IGA scale to capture the holistic patient experience and effectiveness of AD biologics in the highly heterogeneous moderate-to-severe patient population. Although previous work has shown a correlation between clinician-measured and patient-reported disease severity [29], exclusively highlighting achievement of a single clinician-measured metric, such as IGA 0/1, after short-term treatment could result in underestimation of the benefits of treatment with AD biologics. As such, an international consensus-building study has recommended using a combination of clinician-measured endpoints and PROs (eg, EASI-50, ≥3-point improvement in itch NRS, and ≥4-point improvement in DLQI at 3 months, and EASI-75 and DLQI ≤5 at 6 months) as treatment targets to enhance clinical decision-making [30, 31]. These recommendations align with our data showing that many adolescents who did not meet the trial’s primary endpoint still exhibited clinically meaningful improvement with 16 weeks of tralokinumab treatment, as well as similar previous analyses of phase 3 AD clinical trials in dupilumab-treated pediatric populations [22, 23].

While we primarily focused on the treatment response at week 16, we also observed that IGA >1 patients continue to improve with tralokinumab treatment beyond week 16, as the majority achieved EASI-50, ≥3-point improvement in itch NRS, and/or ≥6-point improvement in CDLQI or POEM at week 52 with open-label treatment. While greater numerical response rates for ≥6-point improvement in CDLQI at week 16 were observed with tralokinumab 300 mg, relative to tralokinumab 150 mg, patients who continued tralokinumab treatment after week 16 achieved similar improvements in treatment responses by Week 52 regardless of initial tralokinumab dosage. Moreover, about 40% of tralokinumab-treated patients with IGA >1 at week 16 who continued with open-label treatment achieved EASI-90 by Week 52, which is considered an optimal 1-year treatment target [32]. These adolescent data align with previous data in adults, which show that patients who did not meet the strict primary endpoint at week 16 with monotherapy or plus optional TCS, often exhibit improvements in AD signs and symptoms with continued tralokinumab treatment [33, 34]. These insights are especially relevant for patients with greater disease severity at baseline, as continued improvement in signs and symptoms is an important aspect of comprehensively evaluating treatment efficacy.

Limitations of this analyses include its post hoc nature. The use of the prespecified primary composite estimand, where NRI is utilized for patients who used rescue medication (or had missing data), reflects monotherapy trial settings, but not necessarily real-world scenarios, since rescue medication is commonly permitted alongside biologic treatment in clinical practice. However, we also reported binary endpoint results using the tertiary treatment policy estimand, in which rescue medication use was ignored, and found that IGA >1 patients showed improvements in assessed outcomes with tralokinumab versus placebo (Figs. S2 and S3). An additional limitation was that patients were selected on the basis of their week 16 outcome (i.e., patients who received either tralokinumab 150 mg or 300 mg or placebo who did not achieve IGA 0/1 without rescue medication). As such, the three groups being examined were not randomized and thus may not be balanced in terms of baseline characteristics.

Conclusions

Overall, adolescents who did not achieve IGA 0/1 at week 16 without rescue medication exhibited significant clinically meaningful responses with tralokinumab (150 mg or 300 mg) treatment compared with placebo. Additionally, patients continued to show improvements with ongoing tralokinumab treatment beyond week 16. The utilization of multiple validated clinician-measured and PROs, alongside IGA scores, can enhance clinical decision-making regarding tralokinumab treatment responses in adolescents with moderate-to-severe AD.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Amy S Paller, Andrew Blauvelt, Weily Soong, H. Chih-ho Hong, Marie LA Schuttelaar, Shannon KR Schneider, and Eric L Simpson contributed to the conceptualization, investigation, writing, and reviewing/editing of the manuscript. Shannon KR Schneider contributed to the data curation, formal analysis, and methodology. All authors read and approved the final version of the manuscript.

Funding

The ECZTRA 6 clinical trial was sponsored by LEO Pharma A/S (Ballerup, Denmark), which contributed to study design, data collection, data analysis, data interpretation, manuscript preparation, and publication decisions (including Rapid Service Fees). The authors received no honoraria related to the development of this publication.

Data Availability

The data that support the findings of this study will be made available, upon request to the study sponsor, following review by the external Patient and Scientific Review Board.

Declarations

Conflict of Interest

Amy S Paller has served as an investigator for AbbVie, Applied Pharma Research, Biomendics, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, Timber, and UCB; a consultant for Abeona, Apogee, Arcutis, Aslan, BioCryst, Boehringer-Ingelheim, Castle Creek, Bristol-Myers-Squibb, Dermavant, Incyte, Krystal, LEO, L’Oreal, Mitsubishi Tanabe, MoonLake Immunotherapeutics, Procter and Gamble, Regeneron, Sanofi, Seanergy, and UCB; and on the data safety monitoring board for AbbVie, Abeona, Biocryst, Daiichi Sankyo, and Galderma. Andrew Blauvelt has served as a speaker (received honoraria) for Eli Lilly and Company and UCB, has served as a scientific adviser (received honoraria) for AbbVie, Abcentra, Aclaris, Affibody, Aligos, Almirall, Alumis, Amgen, Anaptysbio, Apogee, Arcutis, Arena, Aslan, Athenex, Bluefin Biomedicine, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Celldex, CTI BioPharma, Dermavant, EcoR1, Eli Lilly and Company, Escient, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, InnoventBio, Janssen, Landos, LEO Pharma, Lipidio, Microbion, Merck, Monte Rosa Therapeutics, Nektar, Novartis, Overtone Therapeutics, Paragon, Pfizer, Q32 Bio, Rani, Rapt, Regeneron, Sanofi Genzyme, Spherix Global Insights, Sun Pharma, Takeda, TLL Pharmaceutical, TrialSpark, UCB Pharma, Union, Ventyx, Vibliome, and Xencor; has acted as a clinical study investigator (institution has received clinical study funds) for AbbVie, Acelyrin, Allakos, Almirall, Alumis, Amgen, Arcutis, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Concert, Dermavant, DermBiont, Eli Lilly and Company, Evelo, Evommune, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Takeda, UCB Pharma, and Ventyx; and owns stock in Lipidio and Oruka. Weily Soong reports grants from LEO Pharma during the conduct of the study; personal fees from LEO Pharma, Regeneron, Sanofi, Genentech, Lilly, AbbVie, Pfizer, Amgen, and AstraZeneca; grants from Regeneron, Genentech, Lilly, Glenmark, Allakos, AbbVie, Pfizer, Incyte, Aslan, and Amgen; serving on the advisory boards of and receiving research grants from Incyte, Lilly, Genentech, Novartis, and UCB; serving on the advisory boards, receiving research grants, and serving as a speaker for AbbVie, LEO Pharma, Amgen, AstraZeneca, Pfizer, Regeneron, and Sanofi; and receiving research grants from Allakos, Dermavant. Galderma. H. Chih-ho Hong has received honoraria as a speaker/consultant for Abbvie, Amgen, Arcutis, ASLAN pharmaceutics, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Dermavant, Eli-Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi-Genzyme, Sun Pharma, and UCB; and has received grants as an investigator from Abbvie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli Lilly, Evelo Biosciences, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Sanofi-Genzyme, Roche, and UCB. Marie LA Schuttelaar reports support from LEO Pharma as an investigator during the conduct of the study; has received honoraria as an adviser/consultant/speaker for LEO Pharma, Sanofi/Genzyme, Eli Lilly, AbbVie, Galderma; received research grants from Sanofi/Genzyme, Pfizer, and Novartis. Shannon KR Schneider is an employee of LEO Pharma Inc. Eric L Simpson reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Aslan Pharma, Benevolent AI Bio Limited “BAI”, BiomX Ltd, Bluefin Biomedicine Inc, Boehringer-Ingelheim, Boston Consulting Group, Collective Acumen, LLC (CA), Coronado, Dermira, Eli Lilly, Evidera, ExcerptaMedica, Galderma, GlaxoSmithKline, Forte Bio RX, Incyte Dermatologics, Janssen, Kyowa Kirin Pharmaceutical Development, LEO Pharma, Medscape LLC, Merck, Novartis, Ortho Galderma, Pfizer, Physicians World LLC, Pierre Fabre Dermo Cosmetique, Regeneron, Roivant, Sanofi- Genzyme, SPARC India, Trevi therapeutics, WebMD and Valeant; reports grants (or served as Principal Investigator role) from AbbVie, Amgen, Arcutis, Aslan, Castle Biosciences, Inc Celegene, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, Kymab, Kyowa Hakko Kirin, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, and TARGET-DERM.

Ethical Approval

The trial protocol was approved by all relevant ethics committees and institutional review boards (see Supplementary Table S4). The trial was conducted according to the principles of the Declaration of Helsinki and the International Council on Harmonization Guidelines for Good Clinical Practice and conformed with all relevant country-specific laws and regulations. All patients, or their legal representatives, provided written informed consent.