Long-Term Safety and Efficacy of Tralokinumab in Patients with Moderate-to-Severe Atopic Dermatitis Treated for up to 6 Years: Final Results from the Open-Label Extension Trial ECZTEND

Abstract

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease often requiring continuous therapy. The objective with the ECZTEND trial was to assess the long-term safety and efficacy of tralokinumab treatment.

Methods

ECZTEND was a multicountry, open-label, 5-year extension trial conducted from September 2018 to July 2024 in patients (≥ 12 years) with moderate-to-severe AD who had received up to 1 year of tralokinumab treatment in a parent trial. Patients were eligible regardless of previous randomization (tralokinumab or placebo) or treatment response in the parent trial. The primary endpoint was the number of treatment-emergent adverse events (TEAEs) through week 268. Key secondary endpoints were Investigator’s Global Assessment (IGA) and Eczema Area and Severity Index (EASI) through week 248.

Results

In total, 1672 patients were enrolled (4466.2 patient-years of exposure; median 2.6 years). Overall, 68.4% of patients (n = 1143) completed the trial period they consented to; 7.1% (n = 117) discontinued owing to lack of efficacy; and 4.2% (n = 72) owing to adverse events. The TEAE incidence rate was 114.3/100 patient-years with a pattern consistent with that observed in the parent trials albeit at lower rates. The majority (> 97%) of TEAEs were nonserious and of mild or moderate severity. Most (> 80%) were assessed as not related to tralokinumab by the investigator and resolved by the end of the trial. Common TEAEs (≥ 5%) included nasopharyngitis, atopic dermatitis, coronavirus infection, upper respiratory tract infection, conjunctivitis, and headache. The proportions of patients with IGA 0/1 and EASI-75/EASI-90 increased during the first 16 weeks and then remained stable through week 248 at ≥ 50% for IGA 0/1 and EASI-90, and ≥ 80% for EASI-75.

Conclusions

Long-term tralokinumab treatment for up to 6 years (parent trials plus ECZTEND) in patients ≥ 12 years with moderate-to-severe AD was well tolerated and maintained long-term efficacy. A graphical abstract is available for this article.

Trial Registration

Clinicaltrials.gov listing: NCT03587805 (ECZTEND).

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-026-01656-7.

Plain Language Summary

Atopic dermatitis (AD) is a long-lasting, itchy skin disease where patients often experience periods of worsening symptoms that negatively impact their quality of life. Tralokinumab is a medication approved for treating adults and adolescents with moderate-to-severe AD. This study looks at the long-term safety and efficacy of patients (aged 12 years or older) with moderate-to-severe AD treated for up to 6 years with tralokinumab. In total, 1672 patients were treated with tralokinumab for 1 year in a clinical trial plus up to 5.1 years in the ECZTEND long-term extension trial. During long-term treatment, the safety profile for tralokinumab was consistent with that seen in clinical trials. Common side effects included symptoms of common cold, worsening of AD, conjunctivitis (pink eye), and headache. Nearly all side effects (>97%) were nonserious and of mild or moderate severity. Most (>80%) were assessed as not related to tralokinumab by the study investigator, and resolved by the end of the trial. AD severity decreased during the first 3 months of the ECZTEND trial, after which more than half of patients reported “clear” or “almost clear” skin (measured by Investigator’s Global Assessment [IGA] score of 0 or 1) and >80% reported Eczema Area and Severity Index [EASI-75] (≥ 75% reduction in EASI) throughout the trial (approximately 4.7 years [248 weeks] of treatment). In conclusion, tralokinumab treatment for up to 6 years was well tolerated and provided stable control of AD signs and symptoms in patients aged 12 years or older with moderate-to-severe AD.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-026-01656-7.

Key Summary Points

Why carry out this study?

Atopic dermatitis (AD) is a chronic and fluctuating inflammatory skin disease requiring treatment that offers stable disease control with a favorable safety profile over time.

This study assessed the safety and efficacy of tralokinumab in patients with AD aged ≥ 12 years treated up to 6 years (1 year in a parent trial plus up to 5 years in the open-label extension ECZTEND trial).

What was learned from the study?

Long-term tralokinumab treatment was well tolerated and maintained AD disease control in patients (≥ 12 years) treated for up to 6 years. The long-term safety profile was consistent with the known safety profile of tralokinumab, with no new safety signals identified.

These findings support the favorable benefit-to-risk profile of long-term tralokinumab treatment.

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.31028590.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a fluctuating course, significantly impacting quality of life [1, 2]. There is a need for treatments that offer consistent disease control with a favorable safety profile over time.

Tralokinumab is a high-affinity monoclonal antibody that specifically neutralizes interleukin-13, which plays a key role in AD pathogenesis [3]. Tralokinumab is approved for the treatment of moderate-to-severe AD in adolescents and adults in multiple countries [4]. In an interim analysis of the open-label extension trial ECZTEND, tralokinumab plus optional topical corticosteroids (TCS) demonstrated a favorable safety profile with sustained efficacy in adult patients treated with tralokinumab for up to 2 years [5]. Here we present the final end-of-study results of ECZTEND, assessing the long-term safety and efficacy of tralokinumab in patients (aged ≥ 12 years) treated for up to 6 years (up to 1 year in a parent trial plus up to 5 years in ECZTEND).

Methods

Trial Design and Patients

ECZTEND (NCT03587805) was a 5-year, open-label, single-arm, multicenter, long-term extension trial in patients (≥ 12 years) with moderate-to-severe AD who completed any of nine tralokinumab parent trials (ECZTRA 1–8 and TraSki; see electronic Supplementary Material Fig. S1a). Patients were eligible regardless of previous randomization (tralokinumab or placebo) or treatment response in the parent trial. ECZTEND was conducted between September 2018 and July 2024 at 309 sites across 11 countries.

Patients received tralokinumab 300 mg every other week, with optional TCS and/or topical calcineurin inhibitors permitted. Visits occurred at weeks 0, 2, 4, 8, 12, 16, and every 8 weeks thereafter, alternating site/phone visits every 8 weeks for years 3–5. Full eligibility criteria and study design are shown in electronic Supplementary Material Fig. S1b.

Ethics

The ECZTRA 1–8, TraSki, and ECZTEND trials were reviewed and approved by institutional review boards or ethics committees at each trial site and followed the Consolidated Standards of Reporting Trials guideline (Appendix in electronic Supplementary Material).

The ECZTRA 1–8, TraSki, and ECZTEND trials were conducted in accordance with the ethical principles derived from international guidelines, including the Declaration of Helsinki of 1964, and its later amendments, and Council for International Organizations of Medical Sciences International Ethical Guidelines, and in compliance with International Council for Harmonization guidelines for Good Clinical Practice. All participants provided written informed consent.

Endpoints and Assessments

The primary endpoint was the number of treatment-emergent adverse events (TEAEs) from baseline up to week 268. Key secondary endpoints were proportions of patients with Investigator’s Global Assessment score of 0 or 1 (IGA 0/1) or ≥ 75% improvement in Eczema Area and Severity Index (EASI-75) relative to parent trial baseline through week 248. Other endpoints included change in EASI, Worst Weekly Pruritus Numeric Rating Scale (itch NRS), Eczema-Related Weekly Sleep NRS (sleep NRS), Dermatology Life Quality Index (DLQI), Scoring Atopic Dermatitis (SCORAD), Patient-Oriented Eczema Measure (POEM), time from first dose to permanent discontinuation of tralokinumab, and presence of antidrug antibodies (ADA)/neutralizing antibodies (nAb), with persistent ADA defined as positive ADA values for at least two consecutive visits with ADA assessments. Persistence of response was assessed as proportions of patients with IGA 0/1, EASI-75, or EASI-90 at ≥ 80% of days (no to minimal fluctuations) or at 100% of the days (no fluctuations) after first response. Post hoc analyses investigated the following endpoints: proportions of patients with ≥ 90% improvement in EASI (EASI-90) from parent trial baseline, EASI ≤ 7, EASI ≤ 3, itch NRS ≤ 4, Sleep NRS ≤ 4, and DLQI ≤ 5.

Safety and Efficacy Analyses

Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRA^©) system preferred term (PT). TEAEs were summarized by number of events, percentages of patients with at least one event, and exposure-adjusted incidence rate (IR). The IR was calculated as the number of patients with an event per 100 patient-years of exposure (PYE) at risk. PYE at risk was defined as the time until the first event or exposure end, whichever came first.

AEs of special interest (AESI), predefined to align with parent trials, included: eye disorders (conjunctivitis, keratoconjunctivitis, and keratitis); skin infections requiring systemic treatment; eczema herpeticum; and malignancy diagnosed after dosing (excluding basal cell carcinoma, localized squamous cell carcinoma of the skin, and carcinoma in situ of the cervix). As ECZTEND did not include a control arm, pooled safety results from the initial 16-week treatment period of the seven placebo-controlled parent trials (NCT03131648, NCT03160885, NCT03363854, NCT03562377, NCT03526861, NCT03761537, and NCT04587453) are provided for comparison [6–10, 14].

Primary efficacy analyses were performed using observed data without any imputation for missing values. Proportions of patients achieving binary endpoints were calculated with 95% Wilson confidence intervals (CIs). Continuous data were summarized descriptively using median and interquartile range (IQR; first quantile to third quantile). Proportions of time in response were estimated using the area under the curve between observed scheduled visits and calculated with 95% Wilson CIs.

Sensitivity analyses were conducted for the key secondary endpoints, IGA 0/1 and EASI-75, on the basis of a modified nonresponder imputation (mNRI) strategy, where patients who permanently discontinued study drug owing to AE(s) or lack of efficacy were imputed as nonresponders. Other missing data were imputed using a two-step multiple imputation (MI) strategy (described in the electronic Supplementary Material).

Results

Patients

A total of 1706 patients were screened from nine parent trials, and 1672 patients were treated with tralokinumab for up to 5.1 years in ECZTEND (Fig. 1), representing 4466.20 patient-years of exposure (PYE). The median duration of exposure in ECZTEND was 2.6 years, with maximum exposure (including the parent trial period) reaching 6.1 years (Table 1). At parent trial baseline, 46.5% of patients had IGA 4 and 53.5% had IGA 3 (Table 2). At ECZTEND baseline, disease severity had improved, reflecting that most patients enrolled had been continuously treated with tralokinumab in the parent trial for 16–52 weeks. A total of 523 patients had either received placebo in the parent trial or had a treatment gap of ≥ 16 weeks (five half-lives of tralokinumab) between the last dose in the parent trial and first dose in ECZTEND.

Fig. 1.

Patient flow in ECZTEND, the long-term, open-label extension trial of tralokinumab for moderate-to-severe atopic dermatitis. ^aPatients completed the trial if they completed the period of the trial they consented to or withdrew from the trial owing to tralokinumab becoming commercially available in their country. ^bA total of 25 patients were excluded from the efficacy analysis set. These patients were enrolled at one investigational site that was prematurely closed owing to good clinical practice (GCP) noncompliance. These patients are included in the “Discontinuation of IMP, reason unknown” category. %  percentage of patients, IMP  investigational medicinal product, n number of patients

Table 1.

Exposure time to tralokinumab in parent trials and ECZTEND

	ECZTEND baseline population N = 1672; PYE = 4467.4	Parent trial + ECZTEND N = 1664; PYE = 5487.6
PYE
Mean (SD)	2.7 (1.3)	3.3 (1.4)
Median (min;max)	2.6 (0.00;5.14)	3.3 (0.00;6.14)
Exposure time, n (%)
≥ 16 weeks	1592 (95.2)	1647 (99.0)
≥ 52 weeks (1 year)	1422 (85.0)	1551 (93.2)
≥ 104 weeks (2 years)	1184 (70.8)	1331 (80.0)
≥ 156 weeks (3 years)	701 (41.9)	978 (58.8)
≥ 208 weeks (4 years)	321 (19.2)	571 (34.3)
≥ 256 weeks (~5 years)	61 (3.6)	239 (14.4)
≥ 304 weeks (~6 years)	–	46 (2.8)

N number of patients, n number of patients with observation, PYE patient-years of exposure, SD standard deviation

Table 2.

Demographics, medical history, and clinical characteristics at ECZTEND baseline

Demographics	ECZTEND baseline population N = 1672; PYE = 4467.4
Age (years), median (min;max)	36.0 (13.0;87.0)
Age group (years), n (%)
12–17	103 (6.2)
≥ 18	1569 (93.9)
Sex
Female, n (%)	709 (42.4)
Male, n (%)	963 (57.6)
Race, n (%)
Asian	312 (18.7)
Black	120 (7.2)
White	1194 (71.4)
Age at onset of AD, median years (min;max)	3.0 (0.0;84.0)
Duration of AD, median years (min;max)	26.0 (0.0;78.0)
Medical history (current)
Asthma	680 (40.7)
Food allergy	625 (37.4)
Hay fever	909 (54.4)

Clinical characteristics	Parent trial baseline N = 1664a	ECZTEND baseline N = 1672
IGA score, n (%)
0/1: clear/almost clear	–	525 (31.4)
2: mild	–	608 (36.4)
3: moderate	890 (53.5)	443 (26.5)
4: severe	774 (46.5)	96 (5.7)
EASI, median (min;max)	27.0 (12.5;72.0)	4.6 (0.0;70.8)
SCORAD, median (min;max)	n = 1664 67.7 (31.6;103.0)	n = 1670 29.4 (0.0;101.4)
DLQI, median (min;max)	n = 1488 16.0 (1.0;30.0)	n = 1504 5.0 (2.0;9.0)

^aBaseline data for eight patients from the investigator-initiated trial TraSki were not transferred to LEO Pharma A/S

AD atopic dermatitis, DLQI Dermatology Life Quality Index, EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment, N number of patients, n number of patients with observation, PYE patient-years of exposure, SCORAD Scoring Atopic Dermatitis

Patients completed the trial once they completed the study period to which they consented, or when tralokinumab became commercially available in their country. In total, 68.4% completed the trial (Fig. 1). The most common reasons for study discontinuation were: “other” (7.2%; e.g., relocation, desire for pregnancy, and work/school conflict); lack of efficacy (7.1%); and withdrawal by patient (6.3%) (Fig. 1). Time from first dose to permanent discontinuation is shown in Supplementary Fig. S2.

Safety

The IR of TEAEs reported in ECZTEND was 114.3, which was lower than reported in the parent trials at week 16 (Table 3). The majority (> 97%) of TEAEs were nonserious and of mild or moderate severity. Most (> 80%) were assessed as not related to tralokinumab by the investigator and resolved by the end of the trial. Serious AEs (SAEs) and AEs leading to permanent treatment discontinuation were reported at low rates (IR = 3.54 and 1.71, respectively) and were not clustered around any system organ class. The most frequently-reported SAEs (IR ≥ 0.1) were atopic dermatitis (12 SAEs in 12 patients, IR = 0.27) and coronavirus infection (5 SAEs in 5 patients, IR = 0.11).

Table 3.

Adverse events reported during tralokinumab treatment through week 268 in open-label ECZTEND and week 16 in placebo-controlled parent trials

	ECZTEND (up to week 268)			Placebo-controlled parent trials (up to week 16)a
	Tralokinumab N = 1672; PYE = 4466.2			Tralokinumab N = 1939; PYE = 587.2			Placebo N = 913; PYE = 271.3
	E	n (%)	IR	E	N (adj %)	Adj IR	E	N (adj %)	Adj IR
Overall treatment-emergent AEs
All AEs	8119	1421(85.0)	114.33	3894	1325 (67.5)	424.8	1746	616 (68.1)	475.3
Severity
Mild	5436	1248 (74.4)	72.70	2669	1087 (55.4)	295.2	1067	471 (51.6)	278.5
Moderate	2455	868 (51.9)	31.15	1101	617 (30.5)	125.5	604	326 (37.0)	174.7
Severe	228	145 (8.7)	3.40	124	90 (4.3)	14.7	75	55 (6.4)	22.6
SAEs	189	151 (9.0)	3.54	44	43 (2.0)	6.7	36	29 (3.3)	11.1
AEs leading to permanent discontinuation of trial drug	79	76 (4.5)	1.71	51	42 (2.0)	6.8	24	18 (2.0)	7.0
Outcome
Fatal	1b	1 (0.1)	0.02	1c	1 (0.1)	0.3	0	0 (0.0)	–
Treatment-emergent AEs (reported in ≥ 5% of patients in ECZTEND) by preferred term
Atopic dermatitis	632	357 (21.4)	9.28	394	299 (13.5)	50.9	292	194 (23.0)	99.5
Nasopharyngitis	599	372 (22.2)	10.09	378	313 (15.9)	58.6	141	114 (12.6)	46.5
Coronavirus infection	322	299 (17.9)	7.22	0	0 (0)	-	0	0 (0)	-
Upper respiratory tract infection	233	147 (8.8)	3.57	134	122 (6.2)	21.3	46	42 (4.6)	16.3
Headache	143	114 (6.8)	2.66	128	95 (5.1)	17.7	52	40 (40.4)	15.0
Conjunctivitis	131	103 (6.2)	2.41	115	100 (4.9)	16.9	15	14 (1.6)	5.4
AEs of special interest
Eye disordersf	260	189 (11.3)	4.59	184	158 (8.0)	27.8	35	30 (3.4)	11.4
Skin infections requiring systemic treatment	82	61 (3.6)	1.39	55	48 (2.3)	7.7	54	45 (5.1)	18.1
Eczema herpeticume	30	23 (1.4)	0.52	9	9 (0.5)	1.6	12	12 (1.4)	4.8
Malignancyg	17	17 (1.0)	0.38	1	1 (< 0.1)	0.1	1	1 (0.1)	0.4

^aStudy size-adjusted % and IR. ^bA patient in their 50s was treated with study drug for 1 year in the parent trial and 3.5 years (1271 days) in ECZTEND and had previously received cyclosporine and azathioprine. The patient was diagnosed with COVID-19 infection and subsequently hospitalized for 31 days in the ICU for respiratory distress and extensive pneumopathy, during which the patient was diagnosed with cutaneous T cell lymphoma (CTCL) and rehospitalized 25 days later with febrile dyspnea, worsening of interstitial lung disease, and major biological inflammatory syndrome with hypereosinophilia. The patient died 5 days later owing to multiple organ failure and refractory hypoxemia, later classified as worsening of an interstitial lung disease related to CTCL and possible sequelae of COVID-19. ^cThe details of the reported death in the initial period of the vaccine study (ECZTRA 5) have been previously published [1]. ^dThe difference between ECZTEND and the parent trials for coronavirus infection was consistent with the timing of trials relative to the COVID-19 pandemic. ^eEczema herpeticum category includes PTs such as eczema herpeticum and Kaposi’s varicelliform eruption. ^fEye disorders category includes several PTs, such as conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial, conjunctivitis viral, keratitis, keratitis viral, ulcerative keratitis, and atopic keratoconjunctivitis. ^gMalignancies diagnosed after dosing (excluding basal cell carcinoma, localized squamous cell carcinoma of the skin, and carcinoma in situ of the cervix)

AE adverse event, COVID-19 coronavirus disease 2019, CTCL T cell lymphoma, E number of AEs, ICU intensive care unit, IR incidence rate (n/100 PYE) (for IR calculations, patient exposure was censored at the time of first event), n number of patients with ≥ 1 event (unless otherwise specified), N number of patients in indicated treatment set, PT preferred term, PYE patient-years of exposure, SAE serious AE

One death was reported during treatment in ECZTEND: A patient in their 50s who was treated for 1 year in the parent trial and 3.5 years (1271 days) in ECZTEND. This patient had previously received cyclosporine and azathioprine. The patient was diagnosed with coronavirus disease 2019 (COVID-19) infection and was subsequently admitted to the intensive care unit for 31 days for respiratory distress and extensive pneumopathy, during which the patient was diagnosed with cutaneous T cell lymphoma (CTCL) and rehospitalized 25 days later with febrile dyspnea, worsening of interstitial lung disease, and major biological inflammatory syndrome with hypereosinophilia. The patient died 5 days later owing to multiple organ failure and refractory hypoxemia, later classified as worsening of an interstitial lung disease related to CTCL and a possible sequelae of COVID-19.

The following TEAEs were reported in ≥ 5% of patients over 5 years: nasopharyngitis (22.2%; IR = 10.09), atopic dermatitis (21.4%; IR = 9.28), coronavirus infection (17.9%; IR = 7.22), upper respiratory tract infection (8.8%; IR = 3.57), conjunctivitis (6.2%; IR = 2.41), and headache (6.8%; IR = 2.66) (Table 3). The pattern of frequently reported AEs in ECZTEND was consistent with that observed in the parent trials, except for coronavirus infection reflecting the emergence of COVID-19 during the study period.

IRs for AESIs in ECZTEND were generally consistent with, or lower than, those observed in the parent trials (Table 3). Eye disorder AESI were mainly driven by PT conjunctivitis with the IR decreasing over time (Fig. 2). Most eye disorder AESI were nonserious, mild, or moderate in severity, and resolved during the trial. Seven (0.4%) patients discontinued treatment owing to AESI eye disorders (Supplementary Table S1). Eye disorder AESI by PT are presented in Supplementary Table S2.

Fig. 2.

Adverse events of special interest during tralokinumab treatment of moderate-to-severe atopic dermatitis for up to 5 years (268 weeks) in ECZTEND. Incidence rate = n/100 patient years exposure; AESI eye disorders consisted of the clusters: conjunctivitis, keratoconjunctivitis, and keratitis. n number of patients with the indicated metric, AESI adverse events of special interest

For AESI malignancies, there were five breast cancer-related events (PTs: breast cancer [two events]; invasive ductal breast carcinoma [two events]; and invasive breast carcinoma [one event]). Most patients with these events had pre-existing risk factors for breast cancer, and the observed cases did not indicate an increased risk for breast cancer in patients treated with tralokinumab when compared to sex-adjusted background rates in the community [11].

The overall percentage of patients who were ADA-positive in the combined study period (parent trial plus ECZTEND) was 4.2%. Persistent ADA was reported in 1.0% and nAb in 0.9% of patients.

The number of patients developing ADA was generally higher during the parent trials and early in ECZTEND (up to week 16), after which the number was low. ADA titers were generally low, and there was no indication that the presence of ADA in the parent trial and/or ECZTEND had any impact on the systemic exposure, efficacy, or safety of tralokinumab.

Efficacy

The proportions of patients with IGA 0/1 and EASI-75/EASI-90 increased during the first 16 weeks and then remained stable throughout the trial at ≥ 50% for IGA 0/1 and EASI-90, and ≥ 80% for EASI-75 (Fig. 3). At week 248, IGA 0/1 was observed in 66.7% (95% confidence interval [CI]; 56.1–75.8), EASI-90 in 81.0% (71.3–87.9), EASI-75 in 92.9% (85.3–96.7) (Fig. 3), and absolute EASI ≤ 7 and ≤ 3 in 95.2% (88.4–98.1) and 83.3% (73.9–89.8), respectively (Supplementary Fig. S3). Response rates of IGA 0/1 and EASI-75, using modified NRI sensitivity analyses to account for missing data, were consistent with analyses of observed values (Fig. 4).

Fig. 3.

Proportions of patients achieving IGA 0/1 (a) and EASI 75/90 (b) over 248 weeks of tralokinumab treatment for moderate-to-severe atopic dermatitis in ECZTEND. Error bars represent 95% CI; ^aoverall, 25 patients were excluded from the efficacy analysis set. These patients were enrolled at one investigational site that was prematurely closed owing to GCP noncompliance. ^bStudy duration varied on the basis of patients’ consent to the amendment to prolong the study from 3 to 5 years and the country of enrollment. ^cBaseline data for the eight patients included from the investigator-initiated study TraSki were not transferred to LEO Pharma A/S. % percentage of patients with observation (as-observed), CI confidence interval, EASI Eczema Area and Severity Index, EASI-75/90 at least 75/90% reduction in EASI score, GCP good clinical practice, IGA Investigator’s Global Assessment, n number of patients with the indicated metric

Fig. 4.

Proportions of patients achieving EASI-75 and IGA 0/1 as-observed and with modified NRI sensitivity analysis over 248 weeks of tralokinumab treatment for moderate-to-severe atopic dermatitis in ECZTEND. Error bars represent 95% CI; ^astudy duration varied on the basis of patients’ consent to the amendment to prolong the study from 3 to 5 years and the country of enrollment. AO as-observed, CI confidence interval, EASI Eczema Area and Severity Index, EASI-75 at least 75% reduction in EASI score, IGA Investigator’s Global Assessment, mNRI modified nonresponder imputation, n number of patients with the indicated metric, NRI nonresponder imputation

A large proportion of patients (44.5% with IGA 0/1, 75.1% with EASI-75, and 54.7% with EASI-90) maintained a stable response, with no-to-minimal disease fluctuations on ≥ 80% of days after first endpoint achievement up to end of treatment (Fig. 5).

Fig. 5.

Persistence of response over time. Proportion of patients that maintained stable response on ≥ 80% or 100% of days after first occurrence. EASI Eczema Area and Severity Index, EASI-75 at least 75% reduction in EASI score, EASI-90 at least 90% reduction in EASI score, IGA Investigator’s Global Assessment

The remaining efficacy endpoints (SCORAD, POEM, itch NRS, sleep NRS, and DLQI) supported the response observed for IGA 0/1 and EASI-75 (Supplementary Figs. S4–S8). Symptomatic measures (itch and sleep NRS, and POEM) were sustained at levels equivalent to no-to-mild severity. The proportions of patients with itch NRS ≤ 4 points and sleep NRS ≤ 4 points increased to ≥ 65% and ≥ 80% at week 16, respectively, and were sustained at those levels throughout the trial (Supplementary Fig. S9). The impact on quality of life improved from a very large effect to a small effect on life quality, and the proportion of patients with DLQI ≤ 5 points reached approximately 70% at week 16 and was sustained at ≥ 70% throughout the trial (Supplementary Fig. S10).

Discussion

AD remains an unpredictable disease for many patients, with frequent periods of worsening signs and symptoms. Achieving long-term disease control without compromising safety is an important ongoing need [12, 13]. In this final analysis of the 5-year, open-label extension trial, ECZTEND, long-term tralokinumab treatment was well tolerated with no new safety signals and with maintained improvements in AD signs, symptoms, and quality of life equivalent to no-to-mild disease.

The overall safety profile in ECZTEND was consistent with both the parent trials and earlier interim analysis of this open-label extension trial [5]. Most TEAEs reported were nonserious, mild or moderate in severity, and did not lead to permanent discontinuation. Eye disorders are of special interest for biologics targeting the IL-13/IL-4 pathway. Overall, the IRs of eye disorders (mainly reported as PT conjunctivitis) were low, and treatment discontinuation owing to eye disorders was rare (0.4%). Patients with AD have an increased risk of bacterial and viral infections owing to skin barrier impairment and immune dysregulation. In an integrated safety analysis of the initial placebo-controlled treatment period of the parent trials, the rate of skin infections requiring systemic treatment was 57% lower in patients treated with tralokinumab compared with patients in the placebo group, and 68% lower for eczema herpeticum [14]. Interestingly, as shown here in ECZTEND, these IRs decrease further over time. This may be attributable to the restoration of skin barrier function seen with long-term tralokinumab treatment [15].

In ECZTEND, improvements in both physician- and patient-reported efficacy outcomes were observed in the first 16 weeks of treatment, followed by sustained efficacy up to week 248. The initial improvement can be ascribed to the fact that some patients were treated with placebo in a parent trial and others had a treatment gap of ≥ 16 weeks (five half-lives of tralokinumab) between the last dose in the parent trial and the first dose in ECZTEND. The heterogeneity of the patient population entering ECZTEND, and the impact on the initial efficacy seen in the first 16 weeks of ECZTEND, has been discussed in detail previously [5].

As AD is a fluctuating disease, stable responses achieved on a group-level may not fully reflect disease trajectories for individual patients. This was addressed by assessing proportion of time in response after first occurrence of IGA 0/1, EASI-75, or EASI-90. These analyses showed that high levels of the response achieved were maintained up to the end of treatment. These data support the concept that patients with moderate-to-severe AD transition from flare-driven treatment with topical therapies to stable disease control over time with tralokinumab treatment.

For patients who achieve clear or almost clear skin with tralokinumab therapy, many countries have approved a dosing regimen to switch dosing from every 2 weeks (Q2W) to every 4 weeks (Q4W), which has shown to be effective for most patients who achieved stable disease control as shown by clear/almost clear skin and no-to-mild itch [16]. A limitation of the ECZTEND study is that it did not include the option of switching well-controlled stable patients to the Q4W regimen.

Strengths of this study include the prolonged duration of treatment and the inclusion of a large patient number regardless of response achieved in parent trials. Limitations include the open-label and single-arm design of ECZTEND. Furthermore, the long duration of ECZTEND could result in attrition bias that might have skewed the trial population over time toward patients benefiting from treatment.

Attrition bias resulting from patient withdrawals owing to treatment failure (either from lack of efficacy or occurrence of AEs) may influence the observed response rates over time, particularly at later timepoints. However, discontinuation rates owing to treatment failure were low, with permanent discontinuation of tralokinumab occurring in 7.1% of patients owing to lack of efficacy (IR: 2.66) and 4.3% of patients owing to AEs (IR: 1.61). To address potential attrition bias, sensitivity analyses were conducted using mNRI to account for missing data for the key secondary endpoints. These analyses support that patient withdrawals owing to treatment failure during ECZTEND have no substantial impact on the results.

Lastly, the lower visit frequency where patients reported AEs in ECZTEND compared with the parent trials may have resulted in less accurate patient recall. Any bias here is likely smaller for predefined AESIs, severe AEs, and SAEs, owing to the special focus on collecting information on these events compared with, for example, headache and symptoms of common cold.

Conclusions

The long-term use of tralokinumab for up to 6 years (up to 1 year in parent trials plus up to 5 years in ECZTEND), was well tolerated with no new safety signals identified in patients aged 12 years and over with moderate-to-severe AD. Tralokinumab treatment demonstrated long-term efficacy with maintained improvements in AD signs, symptoms, and quality of life. These findings support the favorable benefit-to-risk profile of long-term tralokinumab treatment.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Formal data analysis was conducted by Farzaneh Safavimanesh. Andrew Blauvelt, H. Chih-ho Hong, Norito Katoh, Richard G. Langley, Vivian Laquer, Aleksandra Lesiak, Ketty Peris, Julien Seneschal, Juan-Francisco Silvestre, Richard B. Warren, Andreas Wollenberg, Matthew Zirwas, Niels Højsager Bennike, Farzaneh Safavimanesh, Ann-Marie Tindberg, and Kristian Reich contributed to data interpretation, provided critical revision of the manuscript for intellectual content, and approved the final version for publication.

Funding

The study was sponsored by LEO Pharma A/S (Ballerup, Denmark), and supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) (NIHR203308). Funding for the Dermatology and Therapy rapid service fee was provided by LEO Pharma A/S as is written in the manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

Andrew Blauvelt has served as a speaker (received honoraria) for Eli Lilly and Company, UCB, and Almirall; has served as a scientific adviser (received honoraria) for AbbVie, Almirall, Alumis, Amgen, Anaptysbio, Apogee, Arcutis, Astria, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Corvus, Dermavant, Eli Lilly and Company, Galderma, GlaxoSmithKline, Immunovant, Incyte, IQVIA, Janssen, LEO Pharma, Lipidio, Merck, Novartis, Oruka, Paragon, Pfizer, Regeneron, Sanofi, Spherix Global Insights, Sun Pharma, Syncona, Takeda, UCB, Union, and Zai Lab; has acted as a clinical study investigator (institution has received clinical study funds) for AbbVie, Acelyrin, Almirall, Alumis, Amgen, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly and Company, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Takeda, and UCB; and owns stock in Lipidio and Oruka. H. Chih-ho Hong is a researcher, consultant, and/or advisor for AbbVie, Amgen, Arcutis, Aslan, Bausch Health, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Dermavant, Dermira, DS Biopharma, Eli Litty, Evelo, Galderma, GlaxoSmithKline, Incyte, Janssen, LEO Pharma, MedImmune, Novartis, Organon, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Norito Katoh has received honoraria as a speaker/consultant for Sanofi, Maruho, Abbvie, Ely-Lilly Japan, Taiho Pharmaceutical, Pfizer, Mitsubishi Tanabe Pharma, Jansen Pharma, Kyowa Kirin, Celgene Japan, Torii Pharmaceutical, and Otsuka Pharmaceutical, and has received grants as an investigator from Mitsubishi Tanabe Pharma, Torii Pharmaceutical, Maruho, Sun Pharma, Boehringer Ingelheim Japan, Eisai, and LEO Pharma. Richard G Langley has served and received compensation in the form of grants and/or honoraria as principal investigator for and is on the scientific advisory board or has served as a speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, Novartis, Pfizer, and UCB. Vivian Laquer has received grants from AbbVie, Eli Lilly, Galderma, LEO Pharma, and Novartis. Aleksandra Lesiak has participated in advisory boards and received speaker fees from Novartis, Lilly, Sanofi, Sandoz, Abbvie, Pierre Fabre, Alfa Sigma, Boehringer Ingelheim, and Pfizer. Additionally, she has served as a principal investigator for LEO Pharma, AnaptysBio, and Dermira, and received speaker fees from Galderma, UCB, and Janssen. Ketty Peris reports grants or personal fees for participation in advisory boards from AbbVie, Almirall, Galderma, Lilly, LEO Pharma, Novartis, Pierre Fabre, Sanofi, Sun Pharma, and Janssen. Julien Seneschal has served as an advisor, paid speaker, or participated in clinical trials (with honoraria paid to the institution) sponsored by: AbbVie, Almirall, Amgen, Bristol Myers Squibb, Eli Lilly, Galderma, Janssen-Cilag, LEO Pharma, Novartis, Pfizer, Pierre Fabre, Sanofi-Aventis, and UCB. Juan-Francisco Silvestre has served as a speaker, advisory board member, and/or investigator for: AbbVie, Almirall, Amgen, Apogee, Astra Zeneca, Bristol Myers Squibb, Celldex, Eli Lilly, Galderma, Incyte, LEO Pharma, Novartis, Pfizer, Regeneron, and Sanofi Genzyme. Richard B. Warren has received research grants or consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, Eli Lilly, GSK, Janssen, LEO Pharma, Medac, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and UNION. He is supported by the Manchester NIHR Biomedical Research Centre. Andreas Wollenberg has served as an advisor, paid speaker, or participated in clinical trials (with honoraria paid to the institution) sponsored by: AbbVie, Aileens, Almirall, Amgen, Apogee, Beiersdorf, Bioderma, Bioproject, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, DKSH, Eli Lilly, Galapagos, Galderma, Glenmark, GSK, Hans Karrer, Hexal, Incyte, Janssen-Cilag, Kyowa Kirin, LEO Pharma, L’Oreal, Maruho, MedImmune, MSD, Mylan, MSD, Nektar, Novartis, Pfizer, Pierre Fabre, Regeneron, Sandoz, Santen, Sanofi, and UCB. Matthew Zirwas has served as a speaker and/or consultant and/or investigator for Abbvie, Acrotech, Advanced Derm Solutions, Aldeyra, All Free Clear / Sun, Amgen, Anaptys Bio, Apogee, Arcutis, Basuch and Lomb, Beiersdorf, Biocon, Bristol Myers Squibb, Celldex, Cara Sun, Dermavant, Evommune, Evelo, Galderma, Google, Incyte, Janssen-Cilag, L’Oreal, LEO Pharma, Eli Lilly, LUUM, Meta, Nimbus, Novan’ Novartis, Pfizer, Q32 Bio, Regeneron, Sanofi, Supernus, Takeda, Trevi, Trifecta, UCB, and Verrica. Niels Højsager Bennike, Farzaneh Safavimanesh, and Ann-Marie Tindberg are employees and/or shareholders of LEO Pharma. Kristian Reich has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Forward Pharma, Gilead, Galderma, Janssen-Cilag, Kyowa Kirin, LEO Pharma, Lilly, Medac, Novartis, Ocean Pharma, Pfizer, Sanofi, and UCB; Professor Reich is co-founder of Moonlake Immunotherapeutics.

Ethical approval

The ECZTRA 1–8, TraSki, and ECZTEND trials were reviewed and approved by institutional review boards or ethics committees at each trial site and followed the Consolidated Standards of Reporting Trials guideline (Appendix in electronic Supplementary Material). The ECZTRA 1–8, TraSki, and ECZTEND trials were conducted in accordance with the ethical principles derived from international guidelines including the Declaration of Helsinki of 1964, and its later amendments, and Council for International Organizations of Medical Sciences International Ethical Guidelines, and in compliance with International Council for Harmonization guidelines for Good Clinical Practice. All participants provided written informed consent.

Consent to participants

The authors thank the ECZTEND investigators and all individuals who participated in the ECZTRA 1–8, TraSki, and ECZTEND studies.