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Abstract

Atopic dermatitis (AD) is a common, chronic, and recurrent inflammatory skin condition that affects a considerable portion of the population, and is particularly prevalent among children. The development of AD is influenced by environmental and genetic factors, which cause epidermal barrier dysfunction, immune dysregulation, and dysbiosis. In immune dysregulation, there is excessive production of cytokines. Among the cytokines, interleukin (IL)-13 plays a major role in the pathogenesis of AD. Searching for new and more selective treatments for moderate-to-severe cases is important because of the considerable effect of AD on the quality of life. Tralokinumab and lebrikizumab are selective IL-13 inhibitors that have demonstrated safety and efficacy as treatment options for AD in phase III trials. Tralokinumab is approved for use in Europe and the USA, while lebrikizumab is approved only in Europe. Cendakimab, which is another IL-13 selective inhibitor, has shown promising results in phase II trials, providing safe and effective outcomes. Eblasakimab, which disrupts IL-13 and IL-4 signaling pathways, is currently in phase II trials following well-tolerated administration in phase I studies. This narrative review aims to outline the current state of knowledge regarding the effectiveness and safety of these four biologic agents targeting IL-13 signaling.

Keywords

Atopic dermatitis monoclonal antibody interleukin-13 tralokinumab lebrikizumab cendakimab eblasakimab

Introduction

Atopic dermatitis (AD), also known as atopic eczema, is a prevalent, chronic, and recurrent inflammatory skin disease. While AD frequently manifests in childhood, it can persist into adulthood, affecting up to 25% of children and 2% to 10% of adults.^1,2 A family history of atopy is the main risk factor for AD, and it is estimated to increase a child’s risk of developing AD by 1.5 fold. This risk increases to approximately 3 fold if one parent has AD and up to 5 fold if both parents are affected by AD.³

Itchy, dry, and erythematous plaques are the main manifestations of AD. These symptoms often lead to sleep disturbances, decreased productivity, lower self-esteem, social withdrawal, and in severe cases, depression and suicidal thoughts.^4,5 AD is associated with various other atopic conditions, such as asthma, allergic rhinitis, food allergies, and eosinophilic esophagitis. Additionally, individuals with AD appear to have a higher susceptibility to cardiovascular issues and infections. This increased vulnerability is attributed to factors, such as compromised skin barrier function, immune dysregulation, reduced levels of antimicrobial peptides, enhanced bacterial colonization and skin infection, and the use of immunosuppressive medications.⁶

AD is an immune-mediated disorder, which is driven by the aberrant activation of type 2 T helper cells (Th2) and type 2 innate lymphoid cells, which are accompanied by elevated concentrations of inflammatory cytokines, notably interleukin-4 (IL-4) and interleukin-13 (IL-13).⁷ In recent years, the introduction of targeted biologic and small molecule therapies has greatly expanded the treatment options for individuals with moderate-to-severe AD. Dupilumab was the first biologic agent to be approved for the treatment of moderate-to-severe AD in 2017. Dupilumab acts as an inhibitor of IL-4 receptor α (IL-4Rα), effectively hindering IL-4 and IL-13 signaling pathways and inhibiting downstream inflammatory processes.⁸

Although IL-4 and IL-13 are implicated in the pathogenesis of AD, IL-13 has been suggested as the primary cytokine involved. This possibility has led to an increased research focus on IL-13 as a potential therapeutic target for treating AD.

This narrative review aims to outline the current state of knowledge regarding the effectiveness and safety of four biologic agents, tralokinumab, lebrikizumab, cendakimab, and eblasakimab, which target IL-13 signaling. Additionally, this review examines the role of IL-13 in the pathogenesis of AD.

Methods

A comprehensive literature search was conducted from 2011 to April 2024 to investigate the pathogenic role of IL-13 and the efficacy of IL-13 inhibitors in treating AD. This search was conducted in the PubMed, Google Scholar, Science Direct, and clinicaltrials.gov databases using the following search terms, alone or in combination: “atopic dermatitis,” “monoclonal antibodies,” “IL-13,” “tralokinumab,” “lebrikizumab,” “cendakimab,” and “eblasakimab,” with a focus on titles, abstracts, and article bodies.

The inclusion criteria encompassed original and review articles published in English, with a specific emphasis on the pathogenic mechanisms of IL-13 and the therapeutic applications of monoclonal antibodies against IL-13 in the context of AD. The bibliographic references of included articles were scrutinized to identify additional pertinent studies. This search yielded 47 articles and 21 clinical trials in clinicaltrials.gov.

Role of IL-13 in the pathogenesis of AD

The development of AD involves environmental and genetic factors, which interact to induce inflammation, dysbiosis, and immune dysregulation within the epidermis. This interaction enhances transepidermal water loss and promotes the penetration of irritants, microbes, and allergens into the skin.^7,9 These antigens trigger an abnormal type 2 immune response, prompting naïve T cells to commit to the Th2 lineage. This process results in an excessive production of cytokines crucial to the atopic manifestations of AD and itching, specifically IL-4, IL-5, IL-13, and IL-31. IL-4 and IL-13 contribute to dysfunction in the epidermal barrier by inducing the production of immunoglobulin E, attracting eosinophils, enhancing Th2 cell differentiation, and reducing filaggrin expression.⁷

IL-13 plays a major role in the pathogenesis of AD, with gene polymorphisms associated with a higher risk of AD.^10,11 IL-13 is a cytokine produced by Th2 cells, natural killer cells, mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. IL-13 shares structural similarities with IL-4, although their sequence homology is only 25%. The receptor for IL-13 is a heterodimeric complex comprising IL-4Rα and IL-13 receptor α1 (IL-13Rα1). Upon heterodimerization, this complex activates STAT6 signaling, which is crucial for initiating type 2 allergic responses. Additionally, IL-13 binds to IL-13Rα2, which has a limited cytoplasmic domain and functions as a decoy receptor, without mediating signaling. The expression of IL-13Rα2 can be induced by various pro-inflammatory cytokines, including IL-13, IL-4, and tumor necrosis factor, suggesting a negative feedback mechanism.^11,12

Overexpression of IL-13 compromises the integrity of the epithelial barrier by downregulating crucial components, including lipids and proteins (e.g., filaggrin, loricrin, and involucrin). Skin biopsy samples from patients with AD show notable overexpression of IL-13 in lesion and non-lesion skin, whereas only mild overexpression of IL-4 is detectable in 40% of AD lesions.^13–15

IL-13 inhibition in AD

IL-13 is a promising therapeutic target for effectively managing AD because of its substantial efficacy potential and minimal toxicity concerns.^5,15 The first biologic agent approved for AD, dupilumab, targets IL‐4Rα, thereby blocking the IL-13 pathway through the type 1 receptor and the IL-4 pathway through the type 1 and type 2 receptors.⁷ Randomized, controlled trials and real-world studies have demonstrated the efficacy and safety of subcutaneous (SC) dupilumab for treating AD. The safety profile of dupilumab is well documented, and the most relevant adverse events (AEs) are conjunctivitis, facial redness, arthralgia, and an immunological shift towards Th1/Th17.^16–19

Four other distinct monoclonal antibodies targeting IL-13 signaling are being developed or have already been approved. Tralokinumab has obtained approval from Health Canada, the Food and Drug Administration (FDA), and the European Medicines Agency (EMA), and is currently available for individuals with moderate-to-severe AD. Lebrikizumab has received approval from the EMA for treating AD, but it has yet to receive FDA approval. Cendakimab and eblasakimab are currently undergoing investigation in phase II trials.^20–22

Tralokinumab

Tralokinumab, a fully human immunoglobulin 4 monoclonal antibody originating from a human phage display library, was the first biologic approved in the European Union (EU) and the USA with a mechanism of targeting and selectively neutralizing IL-13. Tralokinumab effectively prevents IL-13 from binding to IL-13Rα1 (interleukin-13 receptor α1) and IL-13Rα2 receptors (Figure 1). IL-13Rα2 receptor, which is characterized by a short cytoplasmic tail lacking signaling motifs, serves as a decoy with an anti-inflammatory function by internalizing excess IL-13. By blocking IL-13-mediated signaling downstream of IL-4Rα/IL-13Rα1 heterodimerization, tralokinumab not only inhibits IL-13 activity but also potentially disrupts the endogenous regulation of IL-13 mediated by IL-13Rα2.^7,22–24

Figure 1.

(a) Tralokinumab binds to the cytokine IL‐13 at an epitope that overlaps with the binding site of IL‐13Rα, preventing IL‐13 from binding to both IL‐13Rα1 and IL‐13Rα2 and (b) Lebrikizumab binds to IL‐13 at an epitope that overlaps with the binding site of IL‐4Rα, preventing heterodimerization of the IL‐4Rα/IL‐13Rα1 subunits. IL‐13 can still bind to IL‐13Rα2. IL-4, interleukin-4; IL-13, interleukin-13; IL-4Rα, interleukin-4 receptor α; IL-13Rα1, interleukin-13 receptor α1. The image was retrieved from an article by Gonçalves et al.²⁴ This image is licensed under the Creative Commons Attribution-Non-commercial 4.0 International License. This license permits any non-commercial use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as appropriate credit is given to the original author(s) and the source, and a link to the Creative Commons license is provided. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/ (accessed 17 August 2024).

A phase I trial, which was a single-blind, randomized controlled study, examined the effects of SC tralokinumab at doses of 150, 300, or 600 mg in 30 healthy Japanese adults (Table 1).²⁵ This study showed dose-dependent increases in the observed maximum concentration, area under the serum concentration-time curve from time 0 to the last measurable time point (AUC_(0-t)), and area under the serum concentration-time curve from time 0 to infinity (AUC_(0-inf)) with tralokinumab administration. The incidence and nature of AEs were consistent across all dosage levels, and injection site pain was the most predominant treatment-related AE, reported by 83% to 100% of individuals across all treatment groups. The authors of this trial concluded that a single SC dose of tralokinumab ranging from 150 to 600 mg showed a favorable safety and pharmacokinetic profile in adults.²²

Table 1.

Completed clinical trials that investigated tralokinumab for the treatment of AD.

Trial	Study design	Endpoints	Main results disclosed	Main AEs
Phase I²⁵	Single-blind, randomized, controlled trialN = 30 (20–55 years old)SC tralokinumab (150, 300, or 600 mg)	Primary: safety and tolerability of tralokinumab (monitoring the incidence of AEs and physical examinations, vital signs, electrocardiograms, and laboratory parameters)	SC tralokinumab 150 , 300, and 600 mg was well-toleratedAs the dosage of tralokinumab increased, there was a corresponding increase in C_max, AUC_(0-t), and AUC_(0-inf)	Injection-site pain (95.8% in the tralokinumab groups vs. 83.3% in placebo group), upper respiratory tract infection (16.7% vs. 0%), headache (8.3% vs. 0%), somnolence (8.3% vs. 0%), and toothache (8.3% vs. 0%)
Phase IIb²⁶	Randomized 1:1:1, double-blind, placebo-controlled trialN = 204 (≥18 years old)SC tralokinumab (45, 150, or 300 mg) or placebo q2w for 12 weeks with TCS	Primary: change in the EASI and the percentage of participants with an IGA response (0/1 and reduction of ≥2 points) at week 12Secondary: change in EASI and SCORAD scores at week 22, and the percentage of participants with a reduction of ≥50% in the EASI and a reduction of ≥50% in SCORAD at week 12; percentage of participants achieving an IGA response at week 22; and a change in PNRS and DLQI scores at week 12	Greater improvement in the EASI score in the 300 mg tralokinumab group vs. the placebo group (−15.72 vs. −7.81)A higher percentage of patients achieved an IGA score of 0/1 and better improvement in SCORAD, DLQI, and PNRS scores in the tralokinumab group vs. the placebo group	Upper respiratory tract infection (3.9% in the tralokinumab groups vs. 3.9% in the placebo group) and headache (2.0% vs. 2.0%)
ECZTRA 1 (phase III)²⁷	Randomized 3:1, double-blind, placebo-controlled trialN = 802 (≥18 years old)SC tralokinumab 300 mg q2w after an LD of 600 mg or placebo q2w	Primary: IGA 0/1 and EASI 75 at week 16Secondary: ≥4-point reduction in the weekly average worst daily PNRS score, and a change in SCORAD and DLQI scores at week 16Maintenance endpoints: IGA 0/1 at week 52 in patients randomized to tralokinumab with IGA 0/1 at week 16 without rescue TCS; EASI 75 at week 52 in patients randomized to tralokinumab with EASI 75 at week 16 without rescue TCS	A higher percentage of patients achieved an IGA score of 0/1 at week 16 in the tralokinumab group vs. the placebo group (15.8% vs. 7.1%)A higher percentage of patients achieved EASI 75 in the tralokinumab group vs. the placebo group (25.0% vs. 12.7%)Greater improvements in the PNRS, DLQI, and SCORAD scores in the tralokinumab groupPositive responses maintained up to week 52	Viral upper respiratory tract infection (23.1% in tralokinumab the group vs. 20.9% in the placebo group), conjunctivitis (7.1% vs. 2.0%), and pruritus (5.3% vs. 5.1%)
ECZTRA 2 (phase III)²⁷	Randomized 3:1, double-blind, placebo-controlled trialN = 794 (≥18 years old)SC tralokinumab 300 mg q2w after an LD of 600 mg or placebo q2w	Primary: IGA 0/1 and EASI 75 at week 16Secondary: ≥4-point reduction in the weekly average worst daily PNRS score, and a change in SCORAD and DLQI scores at week 16Maintenance endpoints: IGA 0/1 at week 52 in patients randomized to tralokinumab with IGA 0/1 at week 16 without rescue TCS; and EASI 75 at week 52 in patients randomized to tralokinumab with EASI 75 at week 16 without rescue TCS	A higher percentage of patients achieved an IGA score of 0/1 in the tralokinumab group vs. the placebo group at week 16 (22.2% vs. 10.9%)A higher percentage of patients achieved EASI 75 in the tralokinumab group vs. the placebo group (33.2% vs. 11.4%)Greater improvements in the PNRS, DLQI, and SCORAD scores in the tralokinumab groupPositive responses maintained up to week 52	Viral upper respiratory tract infection (8.3% in the tralokinumab group vs. 8.5% in the placebo group), upper respiratory tract infection (10.0% vs. 8.5%), and conjunctivitis (3.0% vs. 1.5%)
ECZTRA 3 (phase III)²⁸	Randomized 2:1, double-blind, placebo-controlled trialN = 380 (≥18 years old)SC tralokinumab 300 mg q2w or placebo q2w over 16 weeks with TCS as required	Primary: percentage of patients achieving IGA 0/1 and EASI 75 at week 16Secondary: a change in the SCORAD score and ≥ 4-point reduction in the weekly average worst daily PNRS and DLQI scores at week 16; percentage of patients achieving EASI 50 and EASI 90 or ≥4-point improvement in the DLQI, and a change in EASI and POEM scores at week 16; and worst daily pruritus and TCS useMaintenance endpoints: IGA 0/1 at week 32 in patients with IGA 0/1 at week 16, and EASI 75 at week 32 in patients with EASI 75 at week 16	A higher percentage of patients achieved IGA 0/1 in the tralokinumab group vs. the placebo group at week 16 (38.9% vs. 26.2%)A higher percentage of patients achieving EASI 75 in the tralokinumab group vs. the placebo group (56.0% vs. 35.7%)Greater improvements in PNRS, DLQI, and POEM scores in the tralokinumab groupPositive responses maintained up to week 32	Viral upper respiratory tract infection (19.4% in the tralokinumab group vs. 11.1% in the placebo group), conjunctivitis (11.1% vs. 3.2%), headache (8,7% vs. 4.8%), and upper respiratory tract infection (7.5% vs. 4.8%)
ECZTRA 7 (phase III)²⁹	Randomized 1:1, double-blind, parallel-group, placebo-controlled trialN = 277 (≥18 years old)SC tralokinumab 300 mg q2w or placebo q2w with TCS as required over 16 weeks	Primary: EASI 75 at week 16Secondary: ≥4-point reduction in the worst daily PNRS (weekly average), and a change in SCORAD and DLQI scores at weeks 16 and 26; EASI 75 at week 26; and EASI 90 and a change in EASI and POEM scores, eczema-related sleep, amount of TCS used, and the number of days without TCS use at weeks 16 and 26	A higher percentage of patients achieved EASI 75 in the tralokinumab group vs. the placebo group at week 16 (64.2% vs. 50.5%)Greater improvements in PNRS, DLQI, and POEM scores in the tralokinumab groupPositive responses maintained up to week 26	Viral upper respiratory tract infection (26.8% in the tralokinumab group vs. 25.5% in the placebo group), headache (15.2% vs. 9.5%), and upper respiratory tract infection (7.2% vs. 7.3%)
ECZTRA 8 (phase III)³⁰	Randomized, double-blind, placebo-controlled trialN = 106 (≥18 years old)SC LD of 600 mg tralokinumab followed by SC 300 mg q2w tralokinumab + TCS as required, or SC LD of placebo followed by SC placebo q2w + TCS as required over 26 weeks	Primary: IGA 0/1 and EASI 75 at week 16Secondary: change in SCORAD and DLQI scores at week 16; ≥4-point reduction in the worst PNRS score at week 16; EASI 50 and EASI 90 at week 16; percentage change in the EASI, change in the PNRS, change in the Eczema-related Sleep Numerical Rating Scale, and change in POEM at week 16; number of AEs at week 16; and number of patients with the presence of treatment-emergent anti-drug antibodies	A higher percentage of patients achieved IGA 0/1 in the tralokinumab group vs. the placebo group at week 16 (32.1% vs. 26.4%)A higher percentage of patients achieved EASI 75 in the tralokinumab group vs. the placebo group (71.7% vs. 56.6%)Greater improvements in SCORAD (−44.1 vs. −39.0) and DLQI (−10.0 vs. −8.8) scores at week 16 in the tralokinumab groupHigher percentage of patients achieved EASI 50 and EASI 90Greater improvements in the EASI, PNRS, Eczema-related Sleep Numerical Rating Scale, and POEM scores in the tralokinumab group at week 16	Injection site reaction (9.43% in the tralokinumab group vs. 0.0% in the placebo group), injection site erythema (5.66% vs. 0.0%), pyrexia (5.66% vs. 0.0%), nasopharyngitis (5.66% vs. 9.43%), and acne (11.32% vs. 7.55%)
ECZTRA 6 (phase III)³¹	Randomized 1:1:1, double-blind, parallel-group, placebo-controlled trialN = 301 (12–17 years old)SC tralokinumab (150 or 300 mg) q2w or placebo q2w over 16 weeks	Primary: IGA 0/1 and EASI 75 at week 16Secondary: ≥4-point reduction in the Adolescent worst PNRS score, and changes in SCORAD and Children’s DLQI scores at week 16	A higher percentage of patients achieved IGA 0/1 in the tralokinumab groups vs. the placebo group at week 16 (21.4% in the tralokinumab 150 mg group vs. 17.5% in the tralokinumab 300 mg group vs. 4.3% in the placebo group)A higher percentage of patients achieved EASI 75 in the tralokinumab groups vs. the placebo (28.6% vs. 27.8% vs. 6.4%)A higher percentage of patients with a ≥ 4-point reduction in the Adolescent worst PNRS score with tralokinumab 150 mg (23.2%) and tralokinumab 300 (25.0%) vs. placebo (3.3%)Greater improvements in SCORAD and Children’s DLQI scores in the tralokinumab groupPositive responses maintained up to week 52	Viral upper respiratory tract infection (19.44% in the tralokinumab 150 mg group vs. 12.4% in the tralokinumab 300 mg group vs. 8.5% in the placebo group), upper respiratory tract infection (8.2% vs. 11.3% vs. 4.3), headache (5.1% vs. 6.2% vs. 3.2%), and conjunctivitis (4.1% vs. 3.1% vs. 2.1%)
ECZTRA 5 (phase III)³³	Randomized 1:1, double-blind, placebo-controlled trialN = 215 (≥18 years old)SC tralokinumab 300 mg q2w or placebo q2w for 16 weeks Tdap and meningococcal vaccines at week 12	Primary: positive anti-tetanus response at week 16; and positive anti-meningococcal response at week 16Secondary: IGA 0/1 and EASI 75 at week 16; number of AEs; and presence of anti-drug antibodies	Similar immune responses: 91.9% of patients in the tralokinumab group had a positive anti-tetanus response vs. 96.1% in the placebo group at week 1686.0% of the patients in the tralokinumab group had a positive anti-meningococcal response vs. 84.2% in the placebo group at week 16A higher percentage of patients achieved IGA 0/1 in the tralokinumab group vs. the placebo group at week 16 (31.1% vs. 19.4%)A higher percentage of patients achieved EASI 75 in the tralokinumab group vs. the placebo group at week 16 (49.1% vs. 36.1%)	Viral upper respiratory tract infection (9.3% in the tralokinumab group vs. 1.9% in the placebo group) and AD (9.3% vs. 12.1%)

AD, atopic dermatitis; SC, subcutaneous, AEs, adverse events; C_Max, maximum concentration, AUC_(0-t), area under the serum concentration-time curve from time 0 to the last measurable time point; AUC_(0-inf), area under the serum concentration-time curve from time 0 to infinity; q2w, every 2 weeks; TCS, topical corticosteroid; EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; SCORAD, Scoring AD; PNRS, Pruritus Numeric Rating Scale; DLQI, Dermatology Life Quality Index; LD, loading dose; POEM, Patient Oriented Eczema Measure; Tdap, tetanus, diphtheria, and pertussis.

In a phase IIb trial, a cohort of 204 healthy adults with moderate-to-severe AD received treatment comprising 45, 150, or 300 mg of SC tralokinumab or placebo, administered every 2 weeks (q2w) over a span of 12 weeks with topical corticosteroid (TCS) (Table 1).²⁶ Individuals in the 300 mg tralokinumab group showed notable enhancement in the Eczema Area and Severity Index (EASI) score. Additionally, in this group, a higher proportion of patients achieved an Investigator Global Assessment (IGA) score of 0 or 1 and marked improvements in the Scoring Atopic Dermatitis (SCORAD), Dermatology Life Quality Index (DLQI), and Pruritus Numeric Rating Scale (PNRS) scores relative to those in the placebo group. The most significant clinical improvement was observed in the 300 mg cohort, with the most frequently reported AE of upper respiratory infections. Tralokinumab showed favorable safety and tolerability profiles, as well as early and sustained improvement in disease symptoms in patients with moderate-to-severe AD.²²

In the ECZTRA 1 (802 patients enrolled) and ECZTRA 2 (794 patients enrolled) trials, two extensive 52-week-long, randomized, double-blind, placebo-controlled, phase III studies were conducted to assess the safety and efficacy of tralokinumab (Table 1).²⁷ In these trials, the patients received SC tralokinumab 300 mg q2w or a placebo. Only the patients who achieved an IGA score of 0 or 1 and/or EASI 75 (proportion of patients achieving ≥75% improvement from baseline) with tralokinumab by week 16 underwent rerandomization to receive tralokinumab q2w, every 4 weeks (q4w), or placebo for an additional 36 weeks. In both clinical trials, patients who received tralokinumab showed higher rates of achieving an IGA score of 0/1 and EASI 75 at week 16 than those who received placebo. Additionally, patients treated with tralokinumab experienced improvements in pruritus, sleep, the DLQI, and SCORAD, with positive responses maintained up to week 52.²²

In the ECZTRA 3 study, a phase III trial was designed to evaluate the effectiveness and safety of tralokinumab in combination with TCS for patients who were diagnosed with moderate-to-severe AD and required systemic therapy (Table 1).²⁸ A double-blind methodology was used, and patients were randomly allocated in a 2:1 ratio to receive SC tralokinumab at a dosage of 300 mg or a placebo q2w, along with a TCS as required, over 16 weeks. This trial showed a notable increase in the proportion of patients who achieved an IGA score of 0 or 1 and EASI 75 at the end of the 16-week treatment period in those administered tralokinumab compared with those who had placebo. Following the initial treatment phase, a subset of patients from both arms of the study underwent rerandomization to receive SC tralokinumab q2w or q4w for an additional 16 weeks. A high percentage of patients maintained their positive response to treatment. A total of 89.6% of patients who received tralokinumab q2w sustained their IGA responses at 32 weeks. Additionally, 92.5% of patients who received tralokinumab q2w sustained EASI 75 responses at 32 weeks. A total of 77.6% and 90.8% of patients who received tralokinumab q4w sustained their IGA and EASI 75 responses at 32 weeks, respectively.²²

ECZTRA 7 was a phase III trial that evaluated the effectiveness and safety of tralokinumab combined with TCS in adults with severe AD who had contraindications for cyclosporin A (CyA) treatment or previously failed CyA treatment (Table 1).²⁹ In this multicenter, randomized, double-blind study, 277 adults received tralokinumab or placebo injections q2w for 26 weeks, along with TCS as required. A higher number of patients treated with tralokinumab plus TCS attained the primary efficacy target of EASI 75 by week 16 than those who received placebo plus TCS. This study suggests that combining tralokinumab with TCS on an as-needed basis notably enhances the signs and symptoms of AD in adults with severe disease refractory to CyA treatment.²²

ECZTRA 8 was a randomized, double-blind, placebo-controlled trial involving 106 participants (Table 1).³⁰ The primary endpoints of this trial were the percentage of patients who achieved an IGA score of 0 or 1 and EASI 75 at week 16. The participants received an SC 500-mg loading dose (LD) of tralokinumab followed by SC 300 mg q2w with TCS as required or a placebo. This trial showed the efficacy of tralokinumab, with a higher percentage of patients who achieved an IGA score of 0 or 1 (32.1% vs. 26.4%) and EASI 75 (71.7% vs. 56.6%) than those who had placebo.

ECZTRA 6 was a recent phase III trial, which evaluated tralokinumab monotherapy versus placebo in adolescents with moderate-to-severe AD who required systemic treatment (Table 1).³¹ This trial included 301 adolescents aged 12 to 17 years who received SC tralokinumab 150 or 300 mg or placebo q2w for 16 weeks. Tralokinumab resulted in an improvement in various patient-reported outcomes, such as eczema-related sleep, hospital anxiety, depression, and PNRS scores, compared with placebo. Overall, tralokinumab was well-tolerated and its efficacy and safety profiles in adolescents were similar to those observed in phase III trials involving adults.

Another phase III clinical trial evaluated the effectiveness of tralokinumab in adolescents (Table 2).³² This trial involved a single-arm design and focused on individuals aged 12 years and older. The participants received an initial SC dose of tralokinumab 600 mg, followed by self-administered doses of 300 mg q2w for a total duration of 14 weeks. This trial aimed to assess the safety and efficacy of tralokinumab in this age group. Although tralokinumab has already been approved by the FDA and EMA for treating AD in adults, it is not yet approved for use in adolescents.²²

The ECZTRA 5 trial was a randomized, double-blind, placebo-controlled phase II study, which aimed to investigate the potential effect of tralokinumab on the immune response to vaccines (Table 1).³³ Over 16 weeks, 107 adult patients were administered tralokinumab 300 mg, while 108 received a placebo q2w. At week 12, all participants received the tetanus, diphtheria, and pertussis vaccine (Tdap) and the meningococcal vaccine, and the primary endpoints focused on positive immune responses to either vaccine during weeks 12 and 16. This trial showed that the tralokinumab and placebo groups exhibited similar immune responses to those with the Tdap (91.9% vs. 96.1%) and meningococcal (86.0% vs. 84.2%) vaccines at week 16. This finding indicates that tralokinumab-treated adults with moderate-to-severe AD can continue their treatment without interruption because standard non-live vaccines have proven effective and safe in this population.²²

Some retrospective analyses have indicated the efficacy of tralokinumab in treating AD in patients who previously failed other systemic treatments. One study on 12 adults who did not achieve EASI 50 with 16-week dupilumab treatment showed that tralokinumab led to a rapid improvement, with patients reaching EASI 75 within 8 weeks and experiencing notable reductions in itch and sleep disturbances.³⁴ Another analysis of 10 patients who received tralokinumab for at least 26 weeks, after unsuccessful trials with CyA and dupilumab, demonstrated superior outcomes compared with tralokinumab phase III trials.³⁵ These superior outcomes included greater itch reduction and a higher proportion of patients who achieved EASI 75 and IGA 0/1. Additionally, a multicenter, retrospective study of 85 adult patients with severe AD showed that tralokinumab treatment for 16 weeks resulted in improvements in the EASI, SCORAD, and peak PNRS scores.³⁶ Additionally, a higher proportion of systemic treatment-naive patients showed achievement of EASI 75 than those with prior systemic therapy experience. These findings highlight tralokinumab’s real-world effectiveness in providing short-term relief for AD symptoms in patients who are unresponsive to other systemic treatments.²²

The ECZTRA 4 trial examined whether tralokinumab alters the metabolism of specific cytochrome P450 substrates in adults diagnosed with moderate-to-severe AD (Table 2).³⁷ This trial involved 14-week treatment with tralokinumab administration of a single dose (SD). This was an open-label, multicenter, drug–drug interaction study aimed at investigating the effects of tralokinumab on the pharmacokinetics of selected cytochrome P450 substrates in adult subjects with moderate-to-severe AD. The TraSki phase II trial included 16 patients who received an SC 600-mg LD of tralokinumab followed by 300 mg q2w (Table 2).³⁸ The primary outcome of this trial is to study skin barrier function, specifically the change in transepidermal water loss at one non-lesional and one lesional marker skin site at week 16. As of the date of the bibliographic review search, no results from these two trials have been posted.

Table 2.

Ongoing clinical trials investigating tralokinumab, lebrikizumab, and eblasakimab for the treatment of AD.

Treatment	ClinicalTrials.gov identifier	Title	Phase	Enrollment (N)	Status	Estimated study completion date
Tralokinumab	NCT05194540³²	Tralokinumab Administered with Device A in Adults and Adolescents with Moderate-to-severe Atopic Dermatitis (INJECZTRA)	III	136 (actual)	Completed (waiting for results)	June 2023
	NCT03556592³⁷	Drug-drug Interaction Trial with Tralokinumab in Moderate to Severe Atopic Dermatitis - ECZTRA 4	III	40 (actual)	Completed (waiting for results)	June 2020
	NCT04556461³⁸	Effects of Tralokinumab Treatment of Atopic Dermatitis on Skin Barrier Function (TraSki)	II	16 (actual)	Completed (waiting for results)	March 2023
	NCT03587805⁶³	Long-term Extension Trial in Subjects with Atopic Dermatitis Who Participated in Previous Tralokinumab Trials – ECZTEND	III	1672 (actual)	Active, not Recruiting	July 2027
	NCT05388760⁶⁴	Tralokinumab Monotherapy for Children with Moderate-to-severe Atopic Dermatitis - TRAPEDS 1 (TRAlokinumab PEDiatric Trial no. 1)	III	53 (estimated)	Active, not Recruiting	September 2025
	NCT05958407⁶⁵	A 32-week Trial to Evaluate the Efficacy and Safety of Tralokinumab in Subjects with Moderate-to-severe Atopic Hand Eczema Who Are Candidates for Systemic Therapy (ADHAND)	III	402 (estimated)	Recruiting	March 2026
	NCT05938478⁶⁶	Monitoring Pregnancy and Infant Outcomes Following Tralokinumab Exposure During Pregnancy in the US and Canada - PROTECT (PROTECT)	III	900 (estimated)	Recruiting	September 2035
	NCT05378698⁶⁷	Effects of Tralokinumab in the Skin: an Immunologic and Molecular Investigation (TRALIS)	III	25 (estimated)	Not yet recruiting	June 2025
	NCT05682976⁶⁸	Ophthalmological Adverse Events of Tralokinumab in AD (TRALO-Oeil)	III	100 (estimated)	Not yet recruiting	March 2026
Lebrikizumab	ADjoin⁴⁹	Long-term Safety and Efficacy Study of Lebrikizumab (LY3650150) in Participants with Moderate-to-Severe Atopic Dermatitis (ADjoin)	III	1188 (actual)	Active, not Recruiting	April 2025
	NCT05369403⁶⁹	A Study of Lebrikizumab in Adult and Adolescent Participants with Moderate-to-Severe Atopic Dermatitis Previously Treated with Dupilumab	III	120 (estimated)	Active, not Recruiting	December 2024
	NCT05149313⁷⁰	A Study of Lebrikizumab in Combination with Topical Corticosteroids in Participants Having Atopic Dermatitis (AD) that Are Not Adequately Controlled or Non-eligible for Cyclosporine	III	331 (actual)	Active, not recruiting	April 2024
	NCT05372419⁷¹	A Study of Lebrikizumab to Assess the Safety and Efficacy of Adult and Adolescent Participants with Moderate-to-Severe Atopic Dermatitis and Skin of Color	III	80 (estimated)	Recruiting	December 2024
	NCT05559359⁷²	A Study of Lebrikizumab (LY3650150) in Participants 6 Months to <18 Years of Age with Moderate-to-Severe Atopic Dermatitis	III	300 (estimated)	Recruiting	June 2025
	NCT05916365⁷³	Long-term Safety and Efficacy of Lebrikizumab in Adult and Adolescent Participant with Moderate-to-Severe Atopic Dermatitis (ADlong)	III	200 (estimated)	Recruiting	April 2026
	NCT05990725⁷⁴	Effectiveness and Safety of Lebrikizumab Treatment in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis (ADhope)	III	240 (estimated)	Not yet recruiting	May 2025
Eblasakimab	TREX-DX (NCT05694884)⁵⁹	Study of Eblasakimab in Male or Female Moderate-to-Severe Atopic Dermatitis Patients Previously Treated with Dupilumab	II	75 (estimated)	Recruiting	February 2025

AD, atopic dermatitis.

Overall, tralokinumab demonstrated a favorable safety profile across all studies, with no important life-threatening AEs reported. The most frequent systemic AEs observed included upper respiratory tract infection, headache, somnolence, toothache, conjunctivitis, pruritus, pyrexia, nasopharyngitis, and acne. Locally, cases of an injection site reaction with pain and erythema were reported.^25–31,33

Lebrikizumab

Lebrikizumab is a humanized monoclonal antibody and shows high affinity for soluble IL-13 by binding to its non-receptor binding domain. When IL-13 is bound by lebrikizumab, it retains the capacity to form a complex with IL-13Rα1, but impedes its heterodimerization with IL-4Rα, thereby blocking signal transduction. Consequently, lebrikizumab effectively inhibits the formation of the IL-4Rα/IL-13Rα1 signaling complex, while concurrently modulating endogenous IL-13 through the stimulation of IL-13Rα2 (Figure 1).^7,39

Two phase II trials studied the safety and efficacy of lebrikizumab for the treatment of moderate-to-severe AD.^40–42 In the TREBLE trial, the efficacy and safety of lebrikizumab as an adjunct therapy to TCS were evaluated in 209 adults with AD (Table 3).⁴⁰ This trial demonstrated that lebrikizumab 125 mg administered q4w for 12 weeks improved the primary endpoint of achieving a 50% reduction in the EASI score compared with placebo (82.4% vs. 62.3%). Additionally, the lebrikizumab group showed significant improvements in secondary endpoints, including EASI 75, SCORAD 50, and an IGA score of 0/1. While SD groups did not show significant responses at week 12, the results on the 250-mg SD group suggested a potential dose–response relationship. A phase IIb trial investigated the efficacy, dose–response relationship, and safety of lebrikizumab monotherapy, with TCS used if necessary, in 280 adults with AD who were unresponsive to standard topical treatment (Table 3).⁴² The patients were randomized into four arms: lebrikizumab with an LD of 250 mg followed by 125 mg q4w, lebrikizumab with an LD of 500 mg followed by 250 mg q4w, lebrikizumab with an LD of 500 mg at baseline and at week 2 followed by 250 mg q2w and placebo q2w. In the primary endpoint, a dose-dependent reduction in EASI scores across all lebrikizumab groups compared with placebo was observed at week 16, with significant differences observed as early as week 4. Specifically, the lebrikizumab 250 mg groups showed superior response rates in secondary endpoints, including IGA 0/1 EASI 50, EASI 75, and EASI 90 responses. Furthermore, placebo-treated patients required approximately three times more rescue TCS use, which was initiated earlier and sustained for a longer duration, than in lebrikizumab-treated patients.

Table 3.

Completed clinical trials that investigated lebrikizumab for the treatment of AD.

Trial	Study design	Endpoints	Main results disclosed	Main AEs
TREBLE (phase II)⁴⁰	Randomized 1:1:1:1, double-blind, placebo-controlled trialN = 209 (≥18 years old)125 mg SD, 250 mg SD, 125 mg q4w, or placebo q4w over 12 weeks with concomitant use of TCS	Primary: percentage of patients achieving EASI 50 at week 12Secondary: percentage of patients achieving EASI 75, IGA 0/1, and SCORAD 50 at week 12	A higher percentage of patients achieved EASI 50 in those with 125 mg q4w vs. placebo at week 12 (82.4% vs. 62.3%)A higher percentage of patients achieved EASI 75 in those with 125 mg q4w vs. placebo at week 12 (54.9% vs. 34.0%)A higher percentage of patients achieved IGA 0/1 in those with 125 mg q4w vs. placebo at week 12 (33.3% vs. 18.9%)A higher percentage of patients achieved SCORAD 50 in those with 120 mg q4w (47.2%) and 250 mg SD (51%) vs. placebo (26.4%)	Conjunctivitis (9.6% in the lebrikizumab group vs. 7.5% in the placebo group), herpes infections (3.8% vs. 0%), peripheral eosinophilia (3.2%), injection site reactions (1.3% vs. 1.9%)
Phase IIb⁴²	Randomized 3:3:3:2, double-blind, parallel-group, placebo-controlled trialN = 280 (≥18 years old)250 mg LD plus 125 mg q4w, 500 mg LD plus 250 mg q4w, 500 mg LD plus 500 mg at week 2 plus 250 mg q2w, or placebo q2w over 16 weeks with TCS as required	Primary: percentage change in EASI at week 16Secondary: percentage of patients with EASI 75, EASI 50, EASI 90, and a ≥2-point reduction in the IGA score, and the percentage change in the PNRS score	A higher percentage change was achieved in the EASI in the lebrikizumab groups (−62.3% in 125 mg q4w, −69.2% in 250 mg q4w, and −72.1% in 250 mg q2w) vs. placebo (−41.1%)Superior response in IGA 0/1, EASI 50, EASI 75, and EASI 90 in the lebrikizumab 250 mg group vs. placeboGreater improvement in the PNRS score (35.9% in 125 mg q4w, 49.6% in 250 mg q4w, and 60.6% in 250 mg q2w) vs. placebo (−4.3%)	Upper respiratory tract infections (7.5% in the lebrikizumab groups vs. 5.8% in the placebo group), nasopharyngitis (6.6% vs. 3.8%), injection site reactions (5.7% vs. 1.9%), herpes virus infections (3.5% vs. 3.8%), and conjunctivitis (2.6% vs. 0%)
Adhere (phase III)⁴³	Randomized 2:1, double-blind, parallel-group, placebo-controlled trial N = 211 (≥12 years old)50 mg LD plus 500 mg at week 2, and then 250 mg q2w + TCS vs. placebo q2w + TCS over 16 weeks	Primary: percentage of patients achieving EASI 75 and IGA 0/1 with a ≥2-point reduction at week 16Secondary: EASI 90; and improvement in PNRS, DLQI, and Sleep-Loss Scale scores at week 16	A higher percentage of patients who received lebrikizumab + TCS achieved IGA 0/1 (41.4%) vs. those with placebo (22.7%) at week 16A higher percentage of patients who received lebrikizumab + TCS achieved EASI 75 (69.7%) vs. those with placebo (42.4%) at week 16A higher percentage of patients who received lebrikizumab + TCS showed improvements in PNRS (51% vs. 36%), DLQI (79% vs. 57%), and Sleep-Loss Scale (35% vs. 17%) scores vs. placebo + TCS at week 16	Conjunctivitis (4.8% in the lebrikizumab group vs. 0.0% in the placebo group), headache (4.8% vs. 1.5%), herpes infection (3.4% vs. 1.5%), and injection site reactions (2.8% vs. 1.5%)
ADvocate 1 (phase III) and ADvocate 2 (phase III)^44,45	Randomized 2:1, double-blind, parallel-group, placebo-controlled trialN (ADv1) = 424 (≥12 years old)N (ADv2) = 445 (≥12 years old)Induction period (16 weeks): 500 mg LD + 500 mg at week 2 + 250 mg q2w or placebo q2wMaintenance period (36 weeks) - re-randomization (2:2:1) of responders: 250 mg q2w, 250 mg q4w, or placebo q2w (rescue medication as required)	Primary: percentage of patients achieving EASI 75 and IGA 0/1 with a ≥2-point reduction at week 16Secondary: percentage of patients achieving IGA/01 with a ≥2-point reduction at weeks 2 and 4; percentage of patients achieving EASI 90; ≥4-point reduction in the PNRS score at weeks 1, 2, 4, and 16; change in the Sleep-Loss Scale and DLQI scores; and maintenance of IGA 0/1, EASI 75, and a ≥4-point reduction in the PNRS score at week 52	A higher percentage of patients who received lebrikizumab achieved IGA 0/1 with a ≥2-point reduction vs. placebo (ADv1: 43.1% vs. 12.7%; ADv2: 33.2% vs. 10.8%)A higher percentage of patients who received lebrikizumab achieved EASI 75 vs. placebo (ADv1: 58.8% vs. 16.2%; ADv2: 52.1% vs. 18.1%)A higher percentage of patients who received lebrikizumab achieved EASI 75 vs. placebo (ADv1: 38.3% vs. 9.0%; ADv2: 30.7% vs. 9.5%)A higher percentage of patients who received lebrikizumab maintained an IGA 0/1 than those in the withdrawal arm (65%–81% vs. 47 to 50%)A higher percentage of patients who received lebrikizumab maintained an EASI 75 than those in the withdrawal arm (77%–85% vs. 61%–72%)A higher percentage of patients who received lebrikizumab maintained a ≥4-point reduction in the PNRS score at week 52 than those in the withdrawal arm (80%–90% vs. 65%–68%)	Conjunctivitis (8.3% in ADv1 and 8.1% in ADv2), nasopharyngitis (6.8% in ADv1 and 9.6% in ADv2) headache (3.3% in ADv1 and 5.7% in ADv2), herpes infection (5.0% in ADv1 and 4.9% in ADv2), injection site reactions (1.8% in ADv1 and 2.9% in ADv2), and eosinophilia (1.3% in ADv1 and 1.7% in ADv2)
ADore (phase III)⁴⁶	Open-label, single-arm trialN = 206 (≥12 to <18 years old)SC LD of lebrikizumab 500 mg + SC 500 mg at week 2 + 250 mg q2w for 52 weeks	Primary: percentage of patients who discontinued treatment because of AEsSecondary: percentage of patients achieving IGA 0/1 with ≥2 points of improvement; percentage of patients achieving EASI 75, EASI 50, and EASI 90; percentage change in the EASI; and changes in body surface area (BSA), Patient-Reported Outcomes Measurement Information System measures of anxiety and depression, DLQI scores, and Children’s DLQI scores	172 patients completed the treatment (83.5%) and 34 discontinued treatment (16.5%)62.6% of patients achieved IGA 0/1 with ≥2 points of improvement73.2% of patients achieved EASI 75 at week 16 and 81.9% at week 52The mean percentage improvement in the EASI was 86.0% by week 52BSA decreased from 45.4% at baseline to 8.4% by week 52Improvements reported in the Patient-Reported Outcomes Measurement Information System measures of anxiety and depression, DLQI, and Children’s DLQI	AD (13.1%), nasopharyngitis (9.7%), COVID-19 (8.7%), upper respiratory tract infection (6.3%), headache (5.8%), oral herpes (5.3%), and conjunctivitis (4.9%)
ADopt-VA (phase III)⁴⁷	Randomized, double-blind, parallel-group, placebo-controlled trialN = 254 (≥18 years old)SC LD of lebrikizumab 500 mg + SC 500 mg at week 2 + 250 mg q2w from week 4 to week 14	Primary: positive anti-tetanus response at week 16; and positive anti-meningococcal response at week 16Secondary: IGA 0/1 with ≥2 points of improvement, and EASI 75 and EASI 90 at week 16; percentage of patients with ≥4 points of improvement in the PNRS; and changes from baseline in BSA and the Sleep-Loss Scale score	73.6% of the patients in the lebrikizumab group had a positive anti-tetanus response at week 16 vs. 73.4% in the placebo group86.9% of patients in the lebrikizumab group had a positive anti-meningococcal response at week 16 vs. 75.0% in the placebo groupA higher percentage of patients achieved IGA 0/1 with ≥2 points of improvement in the lebrikizumab group vs. the placebo group at week 16 (40.6% vs. 18.9%)A higher percentage of patients achieved EASI 75 in the lebrikizumab group vs. the placebo group at week 16 (58.0% vs. 32.7%); and a higher percentage of patients had ≥4 points of improvement in the PNRS in the lebrikizumab group vs. the placebo group (51.7% vs. 33.2%)Higher changes from baseline in BSA and the Sleep-Loss Score in patients who received lebrikizumab	AD (4.72% in the lebrikizumab group vs. 6.3% in the placebo group), COVID-19 (5.51% vs. 3.94%), headache (3.15% vs. 0.79%), nasopharyngitis (3.15% vs. 2.36%), and conjunctivitis (2.36% vs. 0.0%)
ADhere-j (phase III)⁴⁸	Randomized, double-blind, placebo-controlled trialN = 286 (≥12 years old)SC LD of lebrikizumab 500 mg + 250 mg q4w + TCS until week 14, SC LD of lebrikizumab 500 mg + 250 mg q2w + TCS until week 14, or LD of placebo + placebo q2w + TCS until week 14Week 16 responders: randomly assigned 1:1 and allocated to 250 mg lebrikizumab q2w or 250 mg lebrikizumab q2w Non responders: escape arm, lebrikizumab 250 mg q2w until week 68	Primary: percentage of patients achieving EASI 75 and IGA 0/1 with a ≥ 2-point reduction at week 16Secondary: percentage change in EASI at week 16; percentage of patients achieving EASI 90 at week 16; percentage of patients with an Itch Numeric Rating Scale score of ≥4 points at baseline achieving a ≥4-point reduction at weeks 1, 2, 4, and 16	A higher percentage of patients achieved EASI 75 in the lebrikizumab groups (33.4% in the 250 mg q2w group and 29.1% in the 250 mg q4w group) vs. placebo (6.1%)A higher percentage of patients achieved IGA 0/1 with a ≥2-point reduction in the lebrikizumab groups (51.2% and 47.2%) vs. placebo (13.4%)A higher percentage change in the EASI was observed in the lebrikizumab groups (−64.23% and −59.74%) vs. placebo (−25.25%)A higher percentage of patients with an Itch Numeric Rating Scale score of ≥4 points at baseline achieved a ≥4-point reduction in the lebrikizumab groups vs. placebo at week 16	Allergic conjunctivitis (17.07% in the lebrikizumab 250 mg q2w group vs. 12.35% in the lebrikizumab 250 mg q2w group vs. 4.88% in the placebo group), pyrexia (20.33% vs. 18.52% vs. 15.85%), vaccination site pain (3.25% vs. 3.70% vs. 4.88%), conjunctivitis (9.76% vs. 6.17% vs. 2.44%), folliculitis (5.69% vs. 6.17% vs. 9.76%), nasopharyngitis (5.69% vs. 6.17% vs. 2.44%), and headache (3.25% vs. 3.70% vs. 10.98%)

AD, atopic dermatitis; SD, single dose; q4w, every 4 weeks; TCS, topical corticosteroid; EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; SCORAD, Scoring AD; LD, loading dose; q2w, every 2 weeks; PNRS, Pruritus Numeric Rating Scale; DLQI, Dermatology Life Quality Index; SC, subcutaneous; AEs, adverse events; BSA, body surface area; COVID-19, coronavirus disease 2019.

Four major phase III trials have been completed to thoroughly assess the efficacy and safety profile of lebrikizumab (Table 3). These trials were ADhere, ADvocate 1, ADvocate 2, and ADore.^41,43–46 The ADhere trial was a multicenter, double-blind, placebo-controlled study of 211 adolescents aged 12 to 16 years and adults (Table 3).⁴³ The participants were randomized to receive SC lebrikizumab with an LD of 500 mg at baseline and week 2, followed by 250 mg q2w or a placebo. Both groups received treatment in combination with a low- to mid-potency TCS. The primary endpoints included achieving an IGA score of 0 or 1 with a reduction of at least 2 points from baseline and EASI 75 at 16 weeks. The secondary endpoints included improvements in the EASI score, PNRS score, sleep loss due to pruritus, and the DLQI score. At week 16, improvement was observed in the lebrikizumab plus TCS group compared with the placebo group. Specifically, 41.2% of patients in the lebrikizumab group achieved an IGA score of 0 or 1 with a reduction of at least 2 points from baseline compared with 22.1% in the placebo group. Additionally, 69.5% of patients in the lebrikizumab group achieved EASI 75 compared with 42.2% in the placebo group. Clinically meaningful improvements across all key secondary endpoints were also observed in the lebrikizumab group as early as 4 weeks.

In the ADvocate 1 and ADvocate 2 trials, lebrikizumab administered q2w showed improvements in primary and secondary endpoints, including skin clearance, pruritus, sleep interference, and quality of life, compared with placebo (Table 3).^44,45 At week 16, a higher proportion of lebrikizumab-treated patients achieved an IGA score of 0 or 1 with a reduction of at least 2 points from baseline compared with placebo. Similarly, more lebrikizumab-treated patients achieved EASI 75 and EASI 90 responses than those with placebo at week 16. During the maintenance period, patients who maintained their response to lebrikizumab q2w or q4w showed sustained improvements in IGA scores, EASI 75 and EASI 90 responses, and PNRS scores compared with those in the withdrawal arm.

The ADore study was a single-arm trial that evaluated the safety and efficacy of lebrikizumab in adolescents with moderate-to-severe AD (Table 3).⁴⁶ The patients received two doses of lebrikizumab of 250 mg initially and at week 2, followed by a single injection q4w from weeks 4 to 52. Throughout the 52-week treatment period, lebrikizumab showed clinically meaningful improvements in skin clearance, which were noticeable as early as the first assessment at week 4, and an increasing number of patients experienced improvement over time. The positive results of the study indicate that treating moderate-to-severe AD in adolescents by targeting IL-13 with lebrikizumab is a promising approach. Clinically significant improvements were observed across all primary and secondary endpoints in the four above-mentioned studies.

The ADopt trial was a phase III randomized, double-blind, placebo-controlled study of a cohort of 254 participants that aimed to investigate the effect of lebrikizumab on vaccine immune responses in adults diagnosed with moderate-to-severe AD (Table 3).⁴⁷ The primary endpoints were a positive anti-tetanus response and a positive anti-meningococcal response at week 16. This study showed that the immune response was similar in both groups. A total of 73.6% of participants who took lebrikizumab achieved a positive anti-tetanus response compared with 73.4% of participants who received placebo. A positive anti-meningococcal immune response was achieved by 86.9% of the participants who took lebrikizumab and 75.0% of participants who had placebo.

The ADhere-J trial was a randomized, double-blind, placebo-controlled study, which was designed to assess the efficacy and safety of lebrikizumab combined with TCS in Japanese individuals with moderate-to-severe AD (Table 3).⁴⁸ In the lebrikizumab treatment groups, a higher percentage of patients achieved considerable improvement than those in the placebo group across all of the measures. Specifically, a greater proportion of patients achieved EASI 75, with 33.4% in the 250 mg q2w group and 29.1% in the 250 mg q4w group, compared with only 6.1% in the placebo group. Additionally, a higher percentage of patients in the lebrikizumab groups achieved IGA scores of 0 or 1 with at least a 2-point reduction from baseline. A total of 51.2% of patients in the 250 mg q2w group and 47.2% in the 250 mg q4w group achieved IGA 0/1 compared with 13.4% in the placebo group.

ADjoin is an ongoing phase III study focusing on evaluating the long-term efficacy and safety of lebrikizumab (Table 2). With a participant pool of 1000 individuals, the study spans 110 weeks. The primary aim of this study is to assess the long-term effectiveness of lebrikizumab and to monitor any safety concerns that may arise over the extended period. This long-term extension study encompasses patients who have completed their involvement in a previous lebrikizumab trial.⁴⁹

Overall, lebrikizumab showed a favorable safety profile across all studies, with no major life-threatening AEs. The most frequent systemic AEs observed included upper respiratory tract infections, nasopharyngitis, headache, coronavirus disease 2019 (COVID-19), oral herpes, and conjunctivitis. Locally, injection site reactions were reported, with frequencies ranging from 1.3% to 5.7% in the lebrikizumab groups.^40,42–48

Lebrikizumab was approved by the EMA for use in AD in November 2023 but it is still waiting for FDA approval.^20,21

Cendakimab

Cendakimab (RPC-4046) is a recombinant humanized anti-IL-13 monoclonal antibody. Cendakimab binds to IL-13 at an epitope overlapping with the binding sites of the IL-13Rα1 and IL-13Rα2 subunits, thereby preventing their interaction and blocking subsequent signaling (Figure 2).⁵⁰

Figure 2.

a) Cendakimab binds to the cytokine IL‐13, preventing IL‐13 from binding to IL‐13Rα1 and IL‐13Rα2. b) Eblasakimab binds to IL-13Rα1, blocking IL-4 and IL-13 signaling through the type 2 receptor. This prevents IL‐13 from binding to both IL‐13Rα1 and IL‐13Rα2, and IL-4 to IL‐13Rα1. IL‐4 can still bind and signal through the type 1 receptor. IL-4, interleukin-4; IL-13, interleukin-13; IL-4Rα, interleukin-4 receptor α; IL-13Rα1, interleukin-13 receptor α1. The image was retrieved from Gonçalves et al. 2021.²⁴ This image is licensed under the Creative Commons Attribution-Non-commercial 4.0 International License. This license permits any non-commercial use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as appropriate credit is given to the original author(s) and the source, and a link to the Creative Commons license is provided. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/ (accessed on 17 August 2024).

A phase II multicenter, randomized, double-blind, parallel-group, placebo-controlled trial (NCT04800315) evaluated the effectiveness and safety of three dosing regimens of cendakimab in adult participants with moderate-to-severe AD (Table 4).^51,52 This study consisted of four experimental groups. In group 1, the participants received SC cendakimab 720 mg once weekly (qw) for 16 weeks. In group 2, the participants were administered SC cendakimab 720 mg q2w, with placebo administered alternately q2w. The participants in group 3 received SC cendakimab 360 mg q2w, with placebo administered SC weekly. The participants in the placebo group received SC placebo qw. The primary outcome of the study was the mean percentage change in the EASI score from baseline to week 16. This trial showed a greater decrease in the EASI score in the cendakimab 720 mg qw group (−84.41%) than in the cendakimab 720 mg q2w group (−76.03%), cendakimab 360 mg q2w group (−78.93%), and the placebo group (−62.7%). The highest proportion of patients who achieved an IGA score of 0 or 1 was observed in the cendakimab 360 mg q2w group (38.2%) compared with 33.3% in the 720 mg qw group and 24.4% in the 720 mg q2w group. The most reported AEs in this study were upper respiratory tract infection, allergic conjunctivitis, COVID-19, and headache.

Table 4.

Completed clinical trials that investigated cendakimab for the treatment of AD

Trial	Study Design	Endpoints	Main results disclosed	Main AEs
NCT04800315 (phase 2)^51,52	Randomized, placebo-controlled, parallel-group, double-blind trialN = 221Dose 1: 720 mg SC cendakimab qw over 16 weeksDose 2: 720 mg SC cendakimab q2w and placebo q2w over 16 weeksDose 3: 360 mg SC cendakimab q2w and placebo qw over 16 weeksPlacebo group: SC placebo qw over 16 weeks	Primary: percentage change in the EASI at week 16Secondary: percentage of patients with IGA 0/1 with a reduction of ≥2 points at week 16; percentage of patients with EASI 75 and EASI 90 at week 16; percentage change in the mean SCORAD and PNRS scores at week 16; percentage of patients with a change in the PNRS score ≥4 points; time to achieve at least 4 points of improvement in the severity of the PNRS; percentage change in BSA at week 16; number of patients with AEs; number of patients with the presence of serum antibodies to cendakimab; serum trough concentration of cendakimab at week 16; and number of patients with clinically significant laboratory abnormalities	A higher decrease in the EASI was achieved at week 16 in the cendakimab groups vs. the placebo group (−84.41% in the 720 mg qw group vs. −76.03% in the 720 mg q2w group vs. −78.93% in the 360 mg q2w group vs. −62.7% in the placebo group)A higher percentage of participants achieved IGA 0/1 (33.3% vs. 24.4% vs. 38.2% vs. 9.4%)A higher percentage of patients achieved EASI 75 and EASI 90 at week 16 (50.0%/31.5% vs. 48.2%/24.0% vs. 52.7%/29.1% vs. 26.3%/13.4%)A higher change in the SCORAD score was achieved at week 16 (−69.28% vs. −55.47% vs. −60.19% vs. −41.11%)A higher percentage change in the PNRS score was achieved at week 16 (−55.48% vs. −46.15% vs. −49.30% vs. −32.98%)A higher percentage of patients had a response and change in the PNRS score ≥4 points (33.3% vs. 34.5% vs. 32.7% vs. 14.8%)Less days were required to achieve at least 4 points of improvement in the PNRS (54 vs. 76 vs. 50 vs. 123 days)	Upper respiratory tract infection (7.41% in the 720 mg qw group vs. 10.91% in the 720 mg q2w group vs. 9.09% in the 360 mg q2w group vs. 8.93% in the placebo group), allergic conjunctivitis (7.41% vs. 12.73% vs. 9.09% vs. 3.57%), COVID-19 (7.41% vs. 7.27% vs. 5.45% vs. 16.07%), headache (3.70% vs. 7.27% vs. 3.64% vs. 3.57%), and an increase in blood creatine phosphokinase concentrations (5.56% vs. 5.45% vs. 1.82% vs. 0.00%)

SC, subcutaneous; qw, every week; q2w, every 2 weeks; EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; SCORAD, Scoring AD; PNRS, Pruritus Numeric Rating Scale; BSA, body surface area; AEs, adverse events; COVID-19, coronavirus disease 2019.

The development of cendakimab has been discontinued, even after successfully completing its phase II trial. Despite achieving the primary endpoint, the company that produced cendakimab noted that the treatment landscape for AD is highly competitive, and cendakimab did not provide a considerable advantage over existing therapies.⁵³

Eblasakimab

Eblasakimab is a monoclonal antibody designed to specifically bind with high affinity to IL-13Rα1. Unlike other monoclonal antibodies, the mechanism of eblasakimab involves disrupting the signaling pathways of IL-13 and IL-4 (Figure 2).^54,55

A phase Ia study, which featured an open-label, single ascending dose design, examined the mechanistic actions of eblasakimab and its effect on IL-13Rα1 signaling (Table 5).⁵⁵ In this study, 44 healthy male volunteers of Asian descent received single ascending doses of eblasakimab via intravenous or SC injection. The data obtained showed that eblasakimab was safe and well tolerated, regardless of the route of administration. Notably, eblasakimab effectively blocked IL-13Rα1 and impeded IL-13-induced activation of STAT6 (at an SD of 3 mg/kg intravenously and 300 mg SC), which is a pivotal transcription factor responsible for the expression of Th2 effector cytokines. In the intravenous cohorts, the most frequent AEs were upper respiratory tract infection, decreased appetite, headache, oropharyngeal pain, and pyrexia. In the SC cohorts, headache, elevated C-reactive protein concentrations, and pruritus at the injection site were the most commonly related AEs.

Table 5.

Completed clinical trials that investigated eblasakimab for the treatment of AD.

Trial	Study design	Endpoints	Main results disclosed	Main AEs
Phase Ia⁵⁵	Open-label, single ascending dose trialN = 44 (healthy male adults)Two parts:^aA – SD mg/kg IV eblasakimab in 5 cohortsB- Single fixed SC eblasakimab in 4 cohorts	Primary: safety of eblasakimab (the incidence of AEs was monitored from day 1 to completion of the study)Secondary: AUC_(0-t), volume of distribution at steady state, SC bioavailability, dose-normalized C_max, and AUC_(0-inf)/dose	Well tolerated to doses up to 10 mg/kg IV and 600 mg SC No serious AEs	IV cohorts: upper respiratory tract infection (20%), decreased appetite (15%), headache (15%), oropharyngeal pain (15%), and pyrexia (15%)SC cohorts: headache (8.3%), elevated C-reactive protein concentrations (8.3%), and pruritus at the injection site (4.2%)
Phase Ib⁵⁶	Double-blind, randomized 3:1 controlled trialN = 52 (≥18 years old)SC 200 mg eblasakimab qw, SC 400 mg eblasakimab, SC 600 mg eblasakimab mg, or placebo over 8 weeks	Primary: incidence of AEsSecondary: percentage change in the EASI from baseline; percentage of patients achieving EASI 75, EASI 50, and EASI 90; percentage of patients achieving IGA 0/1; percentage change in BSA; percentage change in the peak PNRS score from baseline; percentage of patients with ≥4 points of improvement in the PNRS score; and improvement in the POEM score	AEs occurred in 47% of patients who received placebo and in 71% of those who received eblasakimabMost AEs were mild or moderateThe percentage change in the EASI score was significant in the 600 mg SC eblasakimab group vs. the placebo group (−65% vs. −27%)	Pruritus (20.8% in the eblasakimab groups vs. 7.7% in the placebo group), injection site erythema (14.8% vs. 7.7%), injection site swelling (14.8% vs. 0%), eye pruritus (11.1% vs. 7.7%), rhinorrhea (11.1% vs. 7.7%), injection site pruritus (11.1% vs. 0%), headache (11.1% vs. 0%), and lethargy (11.1% vs. 0%)
TREX-AD (NCT05158023) (phase IIb)^57,58,62	Randomized, double-blind, placebo-controlled trial300 mg eblasakimab q2w400 mg eblasakimab q2w400 mg eblasakimab q4w600 mg eblasakimab q4wPlacebo q2w	Primary: percentage change from baseline in the EASI at week 16Secondary: proportion of patients achieving a validated IGA response of 0 (clear) or 1 (almost clear); patients achieving EASI 50, 75, and 90; patients with an EASI score <7; percentage change in the EASI score; absolute and percentage change in the PNRS score over time; proportion of patients achieving a 4-point reduction in the PNRS score; change in BSA affected by AD; changes in SCORAD, DLQI, and POEM scores, the European Quality of Life-5 Dimensions-5 Levels Index Score by the United States and United Kingdom algorithms, and the Hospital Anxiety Depression Scale; absolute and percentage change in the SD-NRS; and the proportion of patients achieving a 4-point reduction in the SD-NRS score; number of treatment-emergent AEs and treatment-emergent serious AEs	The 600-mg monthly dose of eblasakimab for 16 weeks led to a 74.5% reduction in EASI scores compared with 38.0% with placebo53.6% of patients achieved EASI 75 compared with 12.9% with those who had placeboEblasakimab demonstrated rapid efficacy, with improvement in EASI scores by week 4	Generally well-tolerated, with low rates of conjunctivitis and injection site reactions

In the IV route (6 cohorts), the doses were 0.1, 0.3, 1, 3, 10, and 20 mg/kg (optional). In the SC route (4 cohorts), the doses were 75, 150, 300, and 600 mg (optional).

SD, single dose; IV, intravenous; SC, subcutaneous; AEs, adverse events; AUC_(0-t), area under the serum concentration-time curve from time 0 to the last measurable time point; C_Max, maximum concentration, AUC_(0-inf), area under the serum concentration-time curve from time 0 to infinity; BSA, body surface area, EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; PNRS, Pruritus Numeric Rating Scale; POEM, Patient Oriented Eczema Measure; q2w, every 2 weeks; q4w, every 4 weeks; AD, atopic dermatitis; SCORAD, Scoring AD; DLQI, Dermatology Life Quality Index; SD-NRS, Sleep Disturbance Numerical Rating Scale.

A phase Ib randomized, double-blinded study evaluated the efficacy of eblasakimab in patients with AD (Table 5). The preliminary data included 52 patients who were randomized to receive eblasakimab at doses of 200, 400, or 600 mg compared with a placebo group. After 8 weeks of treatment, considerable improvement was observed in the eblasakimab groups compared with the placebo group. A reduction in the EASI score was notable across all dose groups as follows: 50% in the 200 mg group, 63% in the 400 mg group, and 61% in the 600 mg group compared with 32% in the placebo group. Similarly, EASI 50 and EASI 75 responses were higher in the eblasakimab groups than in the placebo group. The peak PNRS score was lower in the 600 mg eblasakimab group than in the placebo group. A further analysis indicated that the 400 mg and 600 mg doses of eblasakimab produced greater clinical responses than the 200 mg dose. At week 8, eblasakimab 600 mg resulted in considerable improvement in the mean percentage change in the EASI regarding the proportion of patients achieving EASI 50 and EASI 75 compared with placebo. This study also showed improvements in the PNRS and Patient Oriented Eczema Measure (POEM) scores and sleep disturbance with eblasakimab treatment compared with placebo. The most reported AEs were pruritus, injection site erythema, and injection site swelling.⁵⁶

Overall, the phase I studies suggested that the administration of eblasakimab to adults with moderate-to-severe AD was well tolerated. The data from these trials demonstrate considerable clinical enhancement compared with placebo, as shown by physician- and patient-reported outcomes. These findings highlight the promising therapeutic potential of eblasakimab in managing AD. Consequently, further investigation through phase II trials is warranted to better understand the efficacy and safety profile of eblasakimab in larger patient populations and to determine its potential as a treatment option for this inflammatory skin condition.

TREX-AD (NCT05158023) was a phase IIb, randomized, double-blind, placebo-controlled study that highlighted eblasakimab’s efficacy and potential for monthly dosing from initiation (Table 5).^57,58 This study included a post-hoc analysis of patients with severe AD, representing 63% of the intent-to-treat population. A 600-mg monthly dose of eblasakimab for 16 weeks led to a 74.5% reduction in EASI scores compared with 38.0% with placebo. Additionally, 53.6% of patients achieved EASI 75 compared with 12.9% on placebo. Eblasakimab demonstrated rapid efficacy, with a considerable improvement in EASI scores by week 4. The study's primary endpoint showed statistical significance across three dosing arms. Eblasakimab was generally well-tolerated, with low rates of conjunctivitis and injection site reactions.

TREX-DX (NCT05694884) is an ongoing phase II multicenter, randomized, double-blind, placebo-controlled, parallel-arm clinical trial. This trial aimed to assess the effectiveness and safety of eblasakimab in individuals with moderate-to-severe AD who stopped dupilumab treatment owing to non-response, intolerance, or AEs (Table 2). The trial spans a 16-week treatment period followed by an 8-week follow-up period for 24 weeks. Approximately 75 participants are estimated to be enrolled in the study. The study officially began in December 2022 and is expected to reach its primary completion by December 2024.⁵⁹

New positive data from the TREK-DX study showed that 60% of patients treated with 400 mg eblasakimab weekly achieved EASI 90 and 66.7% reached a validated Investigator’s Global Assessment score of 0 or 1 (clear or almost clear skin) compared with only 14.3% of patients who had placebo after 16 weeks.⁶⁰ These results indicate the efficacy of eblasakimab even in patients who do not respond adequately to dupilumab. New data also showed that eblasakimab led to a rapid improvement, with over half of the patients achieving EASI 75 by week 6 and 73% by week 16. Pruritus scores showed a rapid reduction in itch, which was evident as early as week 2. Discontinuation rates were notably lower in eblasakimab-treated patients (13%) than in those who had placebo (43%).

Discussion

AD is a chronic disease with considerable implications for patients’ quality of life. Therefore, there is a continuous need for the development of new, more effective, and targeted therapies for AD. Opting for selective IL-13 inhibitors in AD treatment appears to offer advantages over broadly targeting IL-4 and IL-13. By specifically inhibiting IL-13, these medications can potentially avoid interfering with the functions of IL-4, which plays a role in a range of immune and non-immune cells. This specificity allows for a more refined approach to modulating the immune response, potentially reducing the risk of AEs associated with broader cytokine inhibition.

Among the selective IL-13 inhibitors, tralokinumab, lebrikizumab, and cendakimab show distinct mechanisms of action. Tralokinumab, which is a fully human immunoglobulin 4 monoclonal antibody, selectively binds to IL-13, neutralizing its signaling activity by preventing its binding to IL-13Rα1 and IL-13Rα2. In contrast, lebrikizumab, which is a high-affinity monoclonal antibody, targets IL-13 by binding to a different epitope. This binding prevents IL-4Rα/IL-13Rα1 heterodimerization, thus blocking downstream signaling pathways. However, unlike tralokinumab, lebrikizumab does not inhibit the binding of IL-13 to IL-13Rα2, allowing for endogenous regulation of IL-13 to continue. Similarly, cendakimab is a selective, high-affinity monoclonal antibody, which blocks IL-13 binding to both IL-13 receptors (IL-13Rα1 and IL-13Rα2) with potent efficacy, thereby inhibiting downstream signaling pathways involved in the pathogenesis of AD.^7,39,50

A study compared the in vitro binding affinities and cell-based functional activities of the clinical IL-13 monoclonal antibodies lebrikizumab, tralokinumab, and cendakimab.¹¹ This study showed that lebrikizumab had a higher binding affinity to glycosylated and aglycosylated forms of IL-13 than tralokinumab and cendakimab. This stronger binding affinity is driven by a slower dissociation rate. In cell-based neutralization assays, lebrikizumab showed higher potency in inhibiting IL-13 induced effects than tralokinumab and cendakimab.¹¹ Furthermore, lebrikizumab binds to a distinct epitope on IL-13 that does not impede the natural clearance of IL-13 through the IL-13Rα2 receptor, unlike tralokinumab and cendakimab. These in vitro findings highlight molecular and mechanistic distinctions among lebrikizumab, tralokinumab, and cendakimab, which may lead to differences in clinical efficacy for patients with AD.

Eblasakimab and dupilumab block IL-13 and IL-4 pathways, but they have distinct mechanisms of action. Eblasakimab selectively binds to the IL-13Rα1 subunit of the type 2 receptor, preventing the formation of the IL-13Rα1/IL-4Rα heterodimer receptor signaling complex. This approach exclusively blocks IL-4 and IL-13 signaling via the type 2 receptor, while sparing the type 1 receptor, potentially reducing unwanted effects associated with broad cytokine inhibition. In contrast, dupilumab, which is a fully human immunoglobulin 4κ monoclonal antibody, targets the α subunit in the IL‐4 receptor, blocking IL‐4 and IL-13 signaling through the type 2 receptor (IL-4Rα/IL-13Rα1), and also inhibiting IL-4 signaling via the type 1 receptor (IL-4Rα/common γ chain). This broader inhibition may lead to more widespread effects on the immune response. Eblasakimab’s selective targeting of the type 2 receptor may offer advantages in modulating Th2 cytokines without inducing an increase in Th1 cytokines compared with the broader inhibition achieved by blocking the IL-4 receptor entirely with dupilumab.^7,16,54,55

Conjunctivitis is an important AE associated with the use of dupilumab, reported in up to 25% of patients in clinical trials and real-world studies. The exact mechanism behind this occurrence is not fully understood. However, dupilumab, by targeting IL-4, may induce a Th1 response, leading to interferon γ-mediated goblet cell apoptosis and reduced mucin production, resulting in eye dryness and conjunctivitis.⁶¹

The prevalence of conjunctivitis with IL-13 selective inhibitors is lower than that with Dupilumab, which affects the IL-4 and IL-13 signaling pathways. In clinical trials of tralokinumab, the prevalence of conjunctivitis was 11.1% in ECZTRA 3 and less than 10% in all other studies.^25–33 Lebrikizumab showed a prevalence of conjunctivitis as an AE of only up to 9.76%.^40–48 Additionally, up to 12.73% of patients treated with cendakimab experienced conjunctivitis.⁵¹ In all three selective IL-13 inhibitors, the prevalence of conjunctivitis as an AE was slightly higher in the treatment groups than in the placebo groups.⁴¹

Direct comparisons between different IL-13 inhibitors or between IL-13 inhibitors and other therapies, such as dupilumab and Janus kinase inhibitors, are challenging because no head-to-head studies have been conducted, and individual studies have different designs. This gap in knowledge needs to be addressed in future trials and network meta-analyses to establish the place-in-therapy of selective IL-13 inhibitors in managing AD.

Conclusion

AD represents a major health issue with profound implications for patients’ quality of life. The pivotal role of IL-13 in the pathogenesis of AD has been indicated by the clinical success of therapies targeting this cytokine.

Tralokinumab and lebrikizumab have emerged as effective and safe treatment options for individuals with moderate-to-severe AD, and show notable efficacy and safety in clinical settings. Two other IL-13 inhibitors, eblasakimab and cendakimab, each with slightly different mechanisms of action, are currently under study. Further investigations are warranted to determine their therapeutic efficacy. Because of the scarcity of sustainable therapeutic options for severe and refractory AD, the outcomes achieved through selective IL-13 inhibition shed light on the path forward in managing this disease.

Footnotes

Author contributions

All of the authors contributed equally to the preparation of this review. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Data availability

Data availability is not applicable to this article because no new data were created or analyzed in this study. This is a narrative review, and all sources of information are cited appropriately in the manuscript.

Declaration of conflicting interest

Orhan Yilmaz, Carlos Teixeira, and Diana Bernardo declare that there is no conflict of interest. Tiago Torres has received consultancy and/or speaker’s honoraria from and/or participated in clinical trials sponsored by AbbVie, Amgen, Almirall, Amgen, Arena Pharmaceuticals, Biocad, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Fresenius-Kabi, Janssen, LEO Pharma, Eli Lilly, MSD, Mylan, Novartis, Pfizer, Samsung-Bioepis, Sanofi-Genzyme, Sandoz, and UCB.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iDs

Orhan Yilmaz

Tiago Torres

References

Amat

Soria

Tallon

, et al. New insights into the phenotypes of atopic dermatitis linked with allergies and asthma in children: An overview. Clin Exp Allergy 2018; 48: 919–934. DOI: 10.1111/cea.13156.

Chiricozzi

Gori

Maurelli

, et al. Biological agents targeting interleukin-13 for atopic dermatitis. Expert Opin Biol Ther 2022; 22: 651–659. DOI: 10.1080/14712598.2022.2035356.

Weidinger

Beck

Bieber

, et al. Atopic dermatitis. Nat Rev Dis Primers 2018; 4: 1. DOI: 10.1038/s41572-018-0001-z.

Rønnstad

ATM

Halling-Overgaard

Hamann

, et al. Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: A systematic review and meta-analysis. J Am Acad Dermatol 2018; 79: 448–456.e30. DOI: 10.1016/j.jaad.2018.03.017.

Lytvyn

Gooderham

Targeting Interleukin 13 for the Treatment of Atopic Dermatitis. Pharmaceutics 2023; 15: 568. DOI: 10.3390/pharmaceutics15020568.

Silverberg

JI.

Comorbidities and the impact of atopic dermatitis. Ann Allergy Asthma Immunol 2019; 123: 144–151. DOI: 10.1016/j.anai.2019.04.020.

Moyle

Cevikbas

Harden

, et al. Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches. Exp Dermatol 2019; 28: 756–768. DOI: 10.1111/exd.13911.

Bieber

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis. Allergy 2020; 75: 54–62. DOI: 10.1111/all.13954.

Napolitano

Marasca

Fabbrocini

, et al. Adult atopic dermatitis: new and emerging therapies. Expert Rev Clin Pharmacol 2018; 11: 867–878. DOI: 10.1080/17512433.2018.1507734.

10.

Brunner

Guttman-Yassky

Leung

DYM.

The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol 2017; 139: S65–S76. DOI: 10.1016/j.jaci.2017.01.011.

11.

Okragly

Ryuzoji

Wulur

, et al. Binding, Neutralization and Internalization of the Interleukin-13 Antibody, Lebrikizumab. Dermatol Ther (Heidelb) 2023; 13: 1535–1547. DOI: 10.1007/s13555-023-00947-7.

12.

Hershey

GKK.

IL-13 receptors and signaling pathways: An evolving web. J Allergy Clin Immunol 2003; 111: 677–690; quiz 691. DOI: 10.1067/mai.2003.1333.

13.

Howell

Kim

Gao

, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2009; 124: R7–R12. DOI: 10.1016/j.jaci.2009.07.012.

14.

Kim

Leung

DYM

Boguniewicz

, et al. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol 2008; 126: 332–337. DOI: 10.1016/j.clim.2007.11.006.

15.

Tsoi

Rodriguez

Degenhardt

, et al. Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis. J Invest Dermatol 2019; 139: 1480–1489. DOI: 10.1016/j.jid.2018.12.018.

16.

David

Ungar

Renert‐Yuval

, et al. The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective. Clin Exp Allergy 2023; 53: 156–172. DOI: 10.1111/cea.14263.

17.

Kraft

Worm

Dupilumab in the treatment of moderate-to-severe atopic dermatitis. Expert Rev Clin Immunol 2017; 13: 301–310. DOI: 10.1080/1744666X.2017.1292134.

18.

Kychygina

Cassagne

Tauber

, et al. Dupilumab-Associated Adverse Events During Treatment of Allergic Diseases. Clin Rev Allergy Immunol 2022; 62: 519–533. DOI: 10.1007/s12016-022-08934-0.

19.

Wijs

LEM

Waa

Jong

PHP

, et al. Acute arthritis and arthralgia as an adverse drug reaction to dupilumab. Clin Exp Dermatol 2020; 45: 262–263. DOI: 10.1111/ced.14050.

20.

Ebglyss | European Medicines Agency, https://www.ema.europa.eu/en/medicines/human/EPAR/ebglyss (accessed 30 November 2023).

21.

U.S. Food and Drug Administration Issues Complete Response Letter for Lebrikizumab Based on Inspection Findings at Third-Party Manufacturer | Eli Lilly and Company, https://investor.lilly.com/news-releases/news-release-details/us-food-and-drug-administration-issues-complete-response-2 (accessed 28 February 2024).

22.

Ewulu

Prajapati

Feldman

SR.

The role of tralokinumab in the treatment of atopic dermatitis and future perspectives for adolescents. Immunotherapy 2023; 15: 1341–1349. DOI: 10.2217/imt-2022-0307.

23.

Simpson

Guttman‐Yassky

Eichenfield

, et al. Tralokinumab therapy for moderate‐to‐severe atopic dermatitis: Clinical outcomes with targeted IL‐13 inhibition. Allergy 2023; 78: 2875–2891. DOI: 10.1111/all.15811.

24.

Gonçalves

Freitas

Torres

Selective IL-13 inhibitors for the treatment of atopic dermatitis. Drugs Context 2021; 10: 2021–1–7. DOI: 10.7573/dic.2021-1-7.

25.

Baverel

She

Piper

, et al. A randomized, placebo-controlled, single ascending-dose study to assess the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tralokinumab in Japanese healthy volunteers. Drug Metab Pharmacokinet 2018; 33: 150–158. DOI: 10.1016/j.dmpk.2017.12.001.

26.

Wollenberg

Howell

Guttman-Yassky

, et al. Treatment of atopic dermatitis with tralokinumab, an anti–IL-13 mAb. J Allergy Clin Immunol 2019; 143: 135–141. DOI: 10.1016/j.jaci.2018.05.029.

27.

Wollenberg

Blauvelt

Guttman‐Yassky

, et al; ECZTRA 1 and ECZTRA 2 study investigators. Tralokinumab for moderate‐to‐severe atopic dermatitis: results from two 52‐week, randomized, double‐blind, multicentre, placebo‐controlled phase III trials (ECZTRA 1 and ECZTRA 2. Br J Dermatol 2021; 184: 437–449. DOI: 10.1111/bjd.19574.

28.

Silverberg

Toth

Bieber

, et al; ECZTRA 3 study investigators. Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial. Br J Dermatol 2021; 184: 450–463. DOI: 10.1111/bjd.19573.

29.

Gutermuth

Pink

Worm

, et al. Tralokinumab plus topical corticosteroids in adults with severe atopic dermatitis and inadequate response to or intolerance of ciclosporin A: a placebo‐controlled, randomized, phase III clinical trial (ECZTRA 7). Br J Dermatol 2022; 186: 440–452. DOI: 10.1111/bjd.20832.

30.

Tralokinumab in Combination With Topical Corticosteroids in Japanese Subjects With Moderate-to-severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04587453 (accessed 28 November 2024).

31.

Paller

Flohr

Cork

, et al. Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial. JAMA Dermatol 2023; 159: 596–605. DOI: 10.1001/jamadermatol.2023.0627.

32.

Tralokinumab Administered With Device A in Adults and Adolescents With Moderate-to-severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05194540 (accessed 29 November 2023).

33.

Merola

Bagel

Almgren

, et al. Tralokinumab does not impact vaccine-induced immune responses: Results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis. J Am Acad Dermatol 2021; 85: 71–78. DOI: 10.1016/j.jaad.2021.03.032.

34.

Pezzolo

Naldi

Tralokinumab in the treatment of resistant atopic dermatitis: An open‐label, retrospective case series study. J Eur Acad Dermatol Venereol 2023; 37: e644–e645. DOI: 10.1111/jdv.18753.

35.

Gargiulo

Ibba

Vignoli

, et al. Tralokinumab rapidly improves subjective symptoms and quality of life in patients with moderate-to-severe atopic dermatitis: a real-life 16-week experience. J Dermatolog Treat 2023; 34: 2216815. DOI: 10.1080/09546634.2023.2216815.

36.

Pereyra-Rodríguez

Herranz

Ruiz-Villaverde

, et al. Treatment of severe atopic dermatitis with tralokinumab in clinical practice: short-term effectiveness and safety results. Clin Exp Dermatol 2023; 48: 991–997. DOI: 10.1093/ced/llad153.

37.

Drug-drug Interaction Trial With Tralokinumab in Moderate to Severe Atopic Dermatitis – ECZTRA 4 | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT03556592 (accessed 29 November 2023).

38.

Effects of Tralokinumab Treatment of Atopic Dermatitis on Skin Barrier Function | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04556461 (accessed 29 November 2023).

39.

Ultsch

Bevers

Nakamura

, et al. Structural Basis of Signaling Blockade by Anti-IL-13 Antibody Lebrikizumab. J Mol Biol 2013; 425: 1330–1339. DOI: 10.1016/j.jmb.2013.01.024.

40.

Simpson

Flohr

Eichenfield

, 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). J Am Acad Dermatol 2018; 78: 863–871.e11. DOI: 10.1016/j.jaad.2018.01.017.

41.

Bernardo

Bieber

Torres

Lebrikizumab for the Treatment of Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol 2023; 24: 753–764. DOI: 10.1007/s40257-023-00793-5.

42.

Guttman-Yassky

Blauvelt

Eichenfield

, et al. Efficacy and Safety of Lebrikizumab, a High-Affinity Interleukin 13 Inhibitor, in Adults With Moderate to Severe Atopic Dermatitis: A Phase 2b Randomized Clinical Trial. JAMA Dermatol 2020; 156: 411–420. DOI: 10.1001/jamadermatol.2020.0079.

43.

Simpson

Gooderham

Wollenberg

, et al; ADhere Investigators. Efficacy and Safety of Lebrikizumab in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial (ADhere). JAMA Dermatol 2023; 159: 182–191. DOI: 10.1001/jamadermatol.2022.5534.

44.

Blauvelt

Thyssen

Guttman-Yassky

, et al. Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials. Br J Dermatol 2023; 188: 740–748. DOI: 10.1093/bjd/ljad022.

45.

Silverberg

Guttman-Yassky

Thaçi

, et al; ADvocate1 and ADvocate2 Investigators. Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis. N Engl J Med 2023; 388: 1080–1091. DOI: 10.1056/NEJMoa2206714.

46.

Paller

Flohr

Eichenfield

, et al. Safety and Efficacy of Lebrikizumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis: A 52-Week, Open-Label, Phase 3 Study. Dermatol Ther (Heidelb) 2023; 13: 1517–1534. DOI: 10.1007/s13555-023-00942-y.

47.

A Study of Lebrikizumab (LY3650150) on Vaccine Response in Adults With Atopic Dermatitis (ADopt-VA) | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04626297 (accessed 28 November 2023).

48.

A Study of Lebrikizumab (LY3650150) in Combination With Topical Corticosteroids in Japanese Participants With Moderate-to-Severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04760314 (accessed 28 November 2023).

49.

Long-term Safety and Efficacy Study of Lebrikizumab (LY3650150) in Participants With Moderate-to-Severe Atopic Dermatitis (ADjoin) | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04392154 (accessed 28 November 2023).

50.

Tripp

Cuff

Campbell

, et al. RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study. Adv Ther 2017; 34: 1364–1381. DOI: 10.1007/s12325-017-0525-8.

51.

A Study to Evaluate Safety and Effectiveness of Cendakimab (CC-93538) in Participants With Moderate to Severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04800315 (accessed 9 January 2024).

52.

Blauvelt

Guttman-Yassky

Lynde

, et al. Cendakimab in Patients With Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol 2024; 160: 856–864. DOI: 10.1001/jamadermatol.2024.2131.

53.

Drug Discovery and Development. Buntz B. Big Pharma companies trimming pipelines in 2023, https://www.drugdiscoverytrends.com/big-pharma-companies-trimming-pipelines-in-2023/. (accessed 23 August 2024).

54.

Redpath

Wilson

, et al. Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1. Biochem J 2013; 451: 165–175. DOI: 10.1042/BJ20121819.

55.

Cevikbas

Ward

Firth

, et al. Eblasakimab, a novel IL-13 receptor alpha 1 monoclonal antibody, blocks STAT6 phosphorylation with low dose in human volunteers. Clin Immunol 2023; 253: 109677. DOI: 10.1016/j.clim.2023.109677.

56.

Veverka

Thng

STG

Silverberg

, et al. Safety and efficacy of eblasakimab, an interleukin 13 receptor α1 monoclonal antibody, in adults with moderate-to-severe atopic dermatitis: A phase 1b, multiple-ascending dose study. J Am Acad Dermatol 2023; 90: 504–511. DOI: 10.1016/j.jaad.2023.10.026.

57.

National Eczema Association. ASLAN Pharmaceuticals Presents New Data From Phase 2b Study of Eblasakimab in Atopic Dermatitis in Late Breaker Presentation at 32nd European Academy of Dermatology and Venereology Congress, https://nationaleczema.org/blog/aslan-101323/ (accessed 2 June 2024).

58.

Simpson

Gooderham

Kircik

, et al. Topline results from TREK-AD: A randomized, double-blind, placebo-controlled, Phase 2b study of eblasakimab in adult patients with moderate-to-severe atopic dermatitis [Abstract No. 6703]. 32nd EADV Congress 2023, 11-14 October 2023, https://aslanpharma.com/wp-content/uploads/lana-downloads/2023/11/2023-EADV_Eblasakimab-Phase2b-topline-data-abstract.pdf (accessed 2 June 2024).

59.

Study of Eblasakimab in Male or Female Moderate-to-Severe Atopic Dermatitis Patients Previously Treated With Dupilumab | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05694884 (accessed 9 November 2023).

60.

GlobeNewswire. San Francisco. ASLAN Pharmaceuticals to Present Additional Data From Interim Analysis of TREK-DX Phase 2 Study of Eblasakimab in Dupilumab-Experienced Atopic Dermatitis Patients During Virtual KOL Event, https://www.globenewswire.com/news-release/2024/05/07/2876615/0/en/ASLAN-Pharmaceuticals-to-Present-Additional-Data-From-Interim-Analysis-of-TREK-DX-Phase-2-Study-of-Eblasakimab-in-Dupilumab-Experienced-Atopic-Dermatitis-Patients-During-Virtual-KO.html (accessed 2 June 2024).

61.

Ferreira

Torres

Conjunctivitis in patients with atopic dermatitis treated with dupilumab. Drugs Context 2020; 9: 1–8. DOI: 10.7573/dic.2020-2-3.

62.

Phase 2b Study of ASLAN004 in Adults With Moderate-to-Severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05158023 (accessed 2 June 2024).

63.

Long-term Extension Trial in Subjects With Atopic Dermatitis Who Participated in Previous Tralokinumab Trials – ECZTEND | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT03587805 (accessed 29 November 2023).

64.

Tralokinumab Monotherapy for Children With Moderate-to-severe Atopic Dermatitis – TRAPEDS 1 (TRAlokinumab PEDiatric Trial no. 1) | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05388760 (accessed 27 November 2023).

65.

A 32-week Trial to Evaluate the Efficacy and Safety of Tralokinumab in Subjects With Moderate-to-severe Atopic Hand Eczema Who Are Candidates for Systemic Therapy | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05958407 (accessed 29 November 2023).

66.

Monitoring Pregnancy and Infant Outcomes Following Tralokinumab Exposure During Pregnancy in the US and Canada – PROTECT | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05938478 (accessed 29 November 2023).

67.

Effects of Tralokinumab in the Skin: an Immunologic and Molecular Investigation | ClinicalTrials.gov, 2023. https://clinicaltrials.gov/study/NCT05378698 (accessed 29 November 2023).

68.

Ophthalmological Adverse Events of Tralokinumab in AD | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05682976 (accessed 29 November 2023).

69.

A Study of Lebrikizumab (LY3650150) in Adult and Adolescent Participants With Moderate-to-Severe Atopic Dermatitis Previously Treated With Dupilumab | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05369403 (accessed 28 November 2023).

70.

A Study of Lebrikizumab in Combination With Topical Corticosteroids in Participants Having Atopic Dermatitis (AD) That Are Not Adequately Controlled or Non-eligible for Cyclosporine | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05149313 (accessed 28 November 2023).

71.

A Study of (LY3650150) Lebrikizumab to Assess the Safety and Efficacy of Adult and Adolescent Participants With Moderate-to-Severe Atopic Dermatitis and Skin of Color | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05372419 (accessed 28 November 2023).

72.

A Study of Lebrikizumab (LY3650150) in Participants 6 Months to <18 Years of Age With Moderate-to-Severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05559359 (accessed 28 November 2023).

73.

Long-term Safety and Efficacy of Lebrikizumab in Adult and Adolescent Participant With Moderate-to-Severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05916365 (accessed 28 November 2023).

74.

Effectiveness and Safety of Lebrikizumab Treatment in Adults and Adolescents With Moderate-to-Severe Atopic Dermatitis | ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT05990725 (Accessed February 28, 2024).

IL-13 inhibition in the treatment of atopic dermatitis – new and emerging biologic agents

Abstract

Keywords

Introduction

Methods

Role of IL-13 in the pathogenesis of AD

IL-13 inhibition in AD

Tralokinumab

Lebrikizumab

Cendakimab

Eblasakimab

Discussion

Conclusion

Footnotes

Author contributions

Data availability

Declaration of conflicting interest

Funding

ORCID iDs

References