Lebrikizumab Rapidly Lowers Inflammatory Biomarkers with Clinical Correlations in Moderate-to-Severe Atopic Dermatitis

Abstract

Lebrikizumab is a novel monoclonal antibody that selectively binds to interleukin (IL)-13 with high affinity and a slow dissociation rate. We assayed serum from select patients enrolled in ADvocate1 and ADvocate2 to determine the impact of lebrikizumab on circulating biomarkers and pathways relevant to atopic dermatitis (AD) and to assess the correlation between key biomarkers and clinical measures of improvement. At baseline, IL-13, CC motif chemokine ligand (CCL)13, CCL17, CCL22, total immunoglobulin (Ig)E, IL-5, and periostin were elevated in patients with moderate-to-severe AD versus healthy controls (p < 0.001). Baseline Eczema and Area Severity Index (EASI) and Investigator’s Global Assessment (IGA) scores were significantly correlated with IL-13, IL-5, CCL13, CCL22, and CCL26. Lebrikizumab induced rapid and progressive reductions in CCL13, CCL17, CCL22, and periostin at weeks 4, 16, and 52 compared with baseline (p < 0.05). AD-associated pathways linked to cytokine signaling were significantly improved at weeks 4 and 16. Improvements in EASI, IGA, and the Pruritus Numeric Rating Scale were correlated with reductions in CCL13, CCL17, CCL22, CCL26, and periostin across all time points. After multiple testing correction and adjusting for sex and race as covariates, we identified the chemokine CCL26 as a pharmacodynamic marker for lebrikizumab response at weeks 4 and 16. Selective inhibition of IL-13 with lebrikizumab monotherapy induced progressive inhibition of systemic biomarkers and pathways of type 2 inflammation, which correlated with clinical measures of improvement in patients with moderate-to-severe AD. NCT04146363 and NCT04178967. Atopic dermatitis (AD, also called atopic eczema) can cause various debilitating symptoms including red, scaly, and itchy skin that can worsen a person’s quality of life. Imbalance of normal immune system molecules, such as cytokines (substances released by cells involved in inflammation), play a central role in the development of AD. The aim of this study was to assess the impact of lebrikizumab, a treatment for AD that targets a cytokine called interleukin (IL)-13, on normalizing the levels of immune system molecules. Patients with AD were treated with lebrikizumab in two phase 3, placebo-controlled studies for 52 weeks. The results of this analysis demonstrated that numerous cytokines and other immune system molecules, including IL-13, were elevated in patients with moderate-to-severe AD at the start of the study compared with healthy controls (people who did not have AD). However, after patients with AD received treatment with lebrikizumab, rapid and progressive reductions in molecules associated with AD were observed through 52 weeks. In addition, the pathways that signal the cytokines associated with AD were significantly improved 4 and 16 weeks after receiving treatment. These improvements correlated with improved disease activity measures. Overall, this analysis demonstrated that treatment with lebrikizumab normalized several molecular pathways in patients with moderate-to-severe AD as compared with the levels of these molecules in healthy controls. These results suggest that lebrikizumab works in inhibiting IL-13 levels in patients with AD and is sufficient to improve the signs and symptoms of the disease.

Topics & Concepts