Pharmacokinetics, Safety, Efficacy, and Biomarker Profiles During Nemolizumab Treatment of Atopic Dermatitis in Adolescents

Abstract

Introduction: Nemolizumab, a new monoclonal antibody that targets the receptor alpha of the neuroimmune cytokine interleukin-31 (IL-31), has shown efficacy in atopic dermatitis (AD) in adults. This study evaluated the pharmacokinetics (PK) and safety of nemolizumab in adolescents with moderate to severe AD as well as the relationship between nemolizumab concentrations and clinical efficacy and the effect of nemolizumab on protein biomarkers.

Methods: Open-label, 16-week study of nemolizumab in patients aged 12-17 years with moderate to severe AD (baseline EASI ≥ 16, IGA ≥ 3, and BSA ≥ 10%) and associated pruritus with baseline average daily peak pruritus numeric rating scale (PP-NRS) intensity of at least 4. Nemolizumab was administered subcutaneously as a loading dose of 60 mg at baseline, followed by 30 mg every 4 weeks until week 12 with background topical corticosteroids (TCS) or calcineurin inhibitors (TCI). Subsequently patients were followed for 8 weeks more. Stratum corneum (SC) and plasma samples were collected for biomarker assessments.

Results: Twenty patients participated, with a mean age of 14.8 ± 1.6 years. The PK of nemolizumab was described by a one-compartment model with linear elimination, a first-order absorption, and a mean half-life of 16.7 ± 4.1 days. Mean trough concentrations ranged from 2935 ± 1029 ng/mL to 3292 ± 2018 ng/mL over the 16-week treatment period. There was a marked improvement in rash, itch, and sleep with a decrease from baseline to week 16 in EASI by 66.5 ± 32.5%, in PP-NRS by 43.2 ± 37%, and in sleep disturbance numeric rating scale by 53.5 ± 47.8%. The popPK and PK/PD analyses confirmed that model-predicted exposure and efficacy of nemolizumab were similar in adolescents compared to adults receiving the same dosing regimens. Age did not impact PK parameters, while the main source of PK variability was body weight. Analyses of SC samples identified a panel of AD-related pro-inflammatory biomarkers that were upregulated in lesional skin (compared to non-lesional skin) and correspondingly downregulated in clinical responders to nemolizumab (based on EASI75 and PP-NRS ≥ 4). Four biomarkers (CCL20, CCL22, CCL27, and VEGF) had changes that were 1.9-3.5-fold higher in EASI responders than in EASI non-responders (all p < 0.05). Analysis showed no significant correlation between plasma biomarkers and clinical scores. Adverse events were experienced by 33.3% of subjects (n = 6) and were primarily mild or moderate in severity.

Conclusions: Nemolizumab PK and safety profiles in adolescents with moderate to severe AD are consistent with previous nemolizumab studies in adults. PK/PD models demonstrate similar exposure-response profiles in 12- to 17-year-old adolescents and adults for three clinical endpoints (EASI, IGA, and PP-NRS). Nemolizumab treatment reversed AD-related pro-inflammatory biomarkers in skin, indicating that the neuroimmune cytokine IL-31 is an important mediator of multiple pathways in AD.

Clinical trial registration: Clinicaltrials.gov NCT03921411.

Keywords: Adolescents; Atopic dermatitis; Biomarkers; Nemolizumab; Pharmacokinetics.

Fig. 1

Average predicted and observed nemolizumab concentrations in adolescents and adults

Fig. 2

Percentage change from baseline in EASI score at each study visit. ITT population

Fig. 3

Supervised analysis by mixed model repeated measures (MMRM) of significantly regulated protein biomarkers in stratum corneum with respect to EASI75. The p value corresponds to the interaction between sample type and EASI75 responders (Y; blue line) vs non responders (N; red line). Least-square estimated means (LS means) are shown with 95% confidence intervals for each treatment in each skin condition (lesional/non lesional baseline and week 16). For simplicity, only the interaction p value is mentioned in the figure, but the selection criterion is based on the minimum adjusted p value (interaction, main effect)

Fig. 4

Supervised analysis (MMRM) of the two significantly regulated protein biomarkers CCL17 and CCL20, in stratum corneum with respect to PP-NRS at week 12. The p value corresponds to the interaction between sample type and PP-NRS responders (Y; blue line) vs non responders (N; red line). Least-square estimated means (LS means) are shown with 95% confidence intervals for each treatment in each skin condition (lesional/non-lesional baseline and week 16). For simplicity, only the interaction p value is mentioned in the figure, but the selection criterion is based on the minimum adjusted p value (interaction, main effect)

Fig. 5

Unsupervised analysis by non-negative tensor factorization (NTF) on stratum corneum samples showing fitted values from the NTF model (red = high expression, blue = low expression, X = missing value). Proteins that show significant changes over time and skin condition appear in the left part of the heatmap, in contrast to more stable proteins that appear in the right part