Treatment With Tralokinumab Improved Epidermal Pathology, Reduced Systemic Markers In Type 2 Inflammation

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In an analysis of skin biopsies and blood samples of participants in the ECZTRA 1 (NCT03131648) and ECZTEND (NCT03587805) trials, researchers found that treatment with tralokinumab led to improvements in skin condition, decreased indicators of type 2 inflammation throughout the body, and altered the expression of important biomarkers associated with atopic dermatitis in the skin.

The analysis, published in Allergy,¹ also utilized gene expression assessment and protein expression assessment via RNA sequencing, immunohistochemistry, and immunoassay.

The identification of key cytokines involved in atopic dermatitis, particularly interleukin-4 (IL-4) and interleukin-13 (IL-13), has led to the development of targeted therapies aimed at mitigating the underlying inflammatory processes. One such therapy, dupilumab, which inhibits both IL-4 and IL-13 signaling, has shown promising results in reducing type 2 biomarkers and improving epidermal pathology in lesional skin.²

However, the specific impacts of selectively targeting IL-13 signaling on cellular and molecular changes in atopic dermatitis patients' and blood over time have not been thoroughly investigated, according to study authors Guttman-Yassky et al.

In this study, researchers delved into the short- and long-term effects of IL-13 neutralization on skin and serum biomarkers following treatment with tralokinumab in adult patients with moderate-to-severe atopic dermatitis.

The study utilized samples from a subset of patients enrolled in the phase 3 trial ECZTRA 1 trial and its open-label extension trial, ECZTEND. The study included 802 patients from ECZTRA 1, with a subset of 299 selected for serum biomarker analysis and 50 consenting to skin biopsies at week 16. Baseline characteristics of these subgroups were largely consistent with the overall trial population.

Patients were administered subcutaneous tralokinumab or placebo over the course of 16 weeks, with subsequent maintenance treatment for responders.

Researchers conducted various assessments, including biopsy and blood collection, at baseline and at multiple time points during the treatment period. In order to analyze molecular changes in lesion and non-lesion skin, researchers employed serum biomarkers, immunohistochemistry, and RNA extraction and sequencing techniques.

As a result, researchers found that treatment with tralokinumab led to significant reductions in serum biomarkers associated with the pathology of atopic dermatitis, including CCL17/TARC, periostin, IgE, and IL-22, compared to placebo. Clinical improvements, such as Eczema Area and Severity Index scores and pruritus Numerical Rating Scale scores, were also more pronounced in patients treated with tralokinumab.

Histological analysis revealed reduced epidermal thickness and expression of cell proliferation markers in lesional skin following treatment. Furthermore, gene expression profiling demonstrated a progressive shift towards a non-lesional transcriptional profile over 2 years of tralokinumab treatment. This, according to study authors, is indicative of sustained therapeutic effects.

Potential study limitations, as noted by authors, include the lack of a comparison group with healthy skin nor a placebo comparison group. Additionally, serum sample analysis was not conducted at the 2-year mark, and baseline characteristics of the 2-year biopsy cohort differed from the larger subgroups, possibly affecting observed changes. Bulk RNA sequencing cannot identify changes specific to certain cell types, potentially overlooking alterations in rare cell types. The use of topical corticosteroids as rescue medication may have influenced immune and barrier gene expression in the skin.

"Tralokinumab treatment significantly improved aberrant immune activation in skin and blood, epidermal barrier pathology, and markers of atherosclerosis in adult patients with moderate-to-severe AD," wrote Guttman-Yassky et al. "These data further support the central role of IL-13 in driving AD pathology and highlight that inhibition of IL-13 alone is sufficient for normalizing the molecular phenotype of AD."

References

1. Guttman-Yassky E, Kabashima K, Staumont-Salle D, et al. Targeting IL-13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years. Allergy. April 2, 2024. Accessed April 11, 2024. doi:10.1111/all.16108
2. Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019. Accessed April 11, 2024. doi:10.1016/j.jaci.2018.08.022