Therapeutic Potential of Tralokinumab in the Treatment of Atopic Dermatitis: A Review on the Emerging Clinical Data

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease that greatly impacts patient quality of life. Type 2 cytokine interleukin (IL)-13 is integral to the pathogenesis of AD. Tralokinumab is a fully human IgG4 monoclonal antibody that specifically targets IL-13, preventing downstream signaling of inflammatory pathways that may contribute to AD. Tralokinumab was US Food and Drug administration (FDA) recently approved for the treatment of moderate to severe AD on December 28, 2021. In our review, we will explore the efficacy and adverse effects (AEs) of tralokinumab for the treatment of patients with moderate to severe AD. A PubMed search for key articles on the emerging clinical data of tralokinumab was performed. Six randomized controlled trials of tralokinumab identified improvements in disease severity measures, including Investigator’s Global Assessment (IGA) scores and Eczema Area Severity Index 75 (EASI75) scores. Four of these studies demonstrated improvements in quality of life measures with tralokinumab, including pruritus scores, sleep interference scores, Dermatology Life Quality Index, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure, and The Short Form 36 Health Survey (SF-36v2) scores. One study identified a similar immune response in patients taking tralokinumab to those taking the Tdap and meningococcal vaccines. Upper respiratory infection, conjunctivitis, and headaches were the most common adverse events. The varying criteria to assess changes in AD disease severity across different studies is a limitation of this review. Tralokinumab is another promising biologic option for the treatment of moderate to severe AD, which may reduce disease burden and improve patient quality of life.


Introduction
Atopic dermatitis (AD) is a chronic inflammatory skin disorder with an estimated prevalence of 2.1-4.9% of adults in North America. 1 AD is associated with pain, sleep disruption, anxiety, and depression and may contribute to a substantial disease burden among patients. 2 New treatments for AD target the inflammatory pathways driving its pathogenesis, improving the physical and mental well-being of patients. 2 The type 2 cytokine, interleukin (IL)-13, is a key factor in the pathogenesis of AD and is implicated in skin barrier disruption, inflammation, increased risk of skin infections, itch signaling, and epidermal hyperplasia. 1 Elevated IL-13 levels are associated with greater AD severity; reductions in IL-13 levels correlate with treatment response and improved clinical outcomes. 3 Tralokinumab is a fully human IgG4 monoclonal antibody that binds specifically to IL-13 and blocks downstream IL-13 signaling. 1 Tralokinumab was US Food and Drug administration (FDA) approved for the treatment of moderate to severe AD on December 28, 2021. 4 In this article, we review the efficacy and safety of tralokinumab for the treatment of moderate to severe AD.

Methods
PubMed and Google Scholar searches were performed using the key words tralokinumab, tralokinumab and atopic dermatitis, tralokinumab dermatology, tralokinumab efficacy, and tralokinumab adverse effects. Articles published between 2017 and 2022 were considered if they included efficacy or safety data related to tralokinumab for the treatment of AD. The authors prescreened abstracts from the search return to determine relevance to the topic. Additional articles were identified by reviewing reference lists from key articles.

Adverse Effects
In the ECZTRA 1 and 2 trials, AEs were reported in 76.4% and 61.5% of tralokinumab patients at week 16, respectively, compared to 77.0% and 66.0% of patients receiving placebo. 1 Among the AEs reported in ≥ 5% in any treatment group, upper respiratory infection and conjunctivitis occurred more frequently in the tralokinumab groups, while dermatitis and skin infection occurred more often in the placebo groups. 1 Conjunctivitis occurred in ≤ 10% of patients treated with tralokinumab in the initial treatment periods and in < 9% of those in the maintenance periods. 1 Most of the cases of conjunctivitis were mild or moderate, and only one case led to patient withdrawal (Table 1). 1 Similarly, in a meta-analysis of five randomized, placebo-controlled trials of tralokinumab in adult patients with moderateto-severe AD, the incidence of conjunctivitis was also higher with tralokinumab compared to placebo (7.5% vs 3.2%). 8 Most events were mild or moderate in severity and resolved during the trial in both treatment and placebo groups. 8 Two events led to discontinuation of tralokinumab. 8 An increased incidence of conjunctivitis was associated with more severe AD, a history of allergic conjunctivitis/atopic keratoconjunctivitis, and a number of atopic comorbidities regardless of treatment group. 6 Conjunctivitis has been observed in other studies of IL-4 or IL-13 inhibitors, but its etiology is still unknown. 1 In another study, the safety profile of tralokinumab in patients with AD was similar to that of asthma patients treated with tralokinumab. 3 Upper respiratory infections and headaches were the most common AEs; however, the majority of AEs were mild or moderate (Table 1). 3

Discussion
Tralokinumab has an acceptable efficacy and safety profile and provides early and sustained improvements in disease severity among patients with moderate-to-severe AD. 3 Clinical efficacy was greatest in participants treated with 300 mg of tralokinumab. 3 Tralokinumab presents another biologic option for the treatment of moderate to severe AD that, similar to dupilumab, exhibits improvements in EASI, SCORAD, pruritus, NRS, POEM, DLQI, and IGA and also targets the IL-13 proinflammatory pathway in adults (Table 2) (Figure 1). There are currently limited studies comparing tralokinumab to other systemic AD treatments, but the current data suggest tralokinumab improves subjective and objective measures of disease severity in AD patients. [1][2][3]9 Tralokinumab has the additional benefits of decreasing S. aureus colonization, reducing the need for systemic treatment of skin infections, and decreasing the frequency of eczema herpeticum. 1 These added benefits may be due to tralokinumab's ability to improve skin barrier integrity or its regulation of IL-13 leading to increased expression of antimicrobial genes. 1 Tralokinumab IGA and EASI responses were maintained over 36 weeks without active maintenance treatment or TCS, in the ECZTRA 1 and 2 trials, suggesting tralokinumab may induce remission of AD for some patients. 1 Some patients initially treated four times a week were able to maintain good disease control after stopping treatment, suggesting the possibility of less frequent maintenance dosing in some patients initially treated with a higher dose. 1 The objective improvements seen with tralokinumab treatment are clinically meaningful; patients treated with 300 mg tralokinumab two times a week had greater improvements in all 6 subscales of DLQI compared with placebo. 2 Among

Conclusion
Tralokinumab improves IGA, EASI 75, SCORAD, and POEM scores comparable to other systemic AD treatments (Table 2). 1,3,5,6 These improvements in symptom severity are apparent at both short and extended time points. 6 Tralokinumab's improvements in objective clinical outcomes is paralleled by improvements in multiple aspects of patients' quality of life. 2 Tralokinumab exhibits a good safety profile. Upper respiratory infection, conjunctivitis, and headaches are AEs commonly seen in patients treated with tralokinumab, but are usually mild to moderate. 1,3,8 Tralokinumab presents another promising biologic option for the treatment of AD which may directly target inflammatory pathways, reduce disease burden, and improve patient quality of life.

Funding
There is no funding to report.