Eblasakimab treatment in adults with moderate-to-severe AD resulted in marked reductions in serum biomarker levels, consistent with the marked reductions in AD severity as assessed by EASI and IGA endpoints reported in a previous publication [18]. Eblasakimab treatment was also associated with marked improvements in patient-reported outcomes such as patient-oriented eczema measure (POEM) and pruritus [18], which is a disease hallmark and known to negatively impact quality of life in patients with AD [28, 29]. These observations are similar to those generated for other type 2 cytokine inhibitors that have demonstrated benefit in AD [16, 30]. They further support the role that eblasakimab plays in blocking both IL-13 and IL-4-mediated Th2 inflammation by specifically binding the IL-13Rα1 subunit of the type 2 receptor complex.

These data extend our understanding of the clinical benefit of eblasakimab treatment in improving markers of inflammation and AD severity. The data also fill a gap left by other studies of new targeted strategies in AD that have failed to investigate the effects of treatment on biomarker levels or evaluated the potential of these biomarkers as means of assessing treatment efficacy [6]. Results from the present study show that patients dosed weekly for 8 weeks with eblasakimab 400 mg or 600 mg experienced reductions in serum levels of TARC, total IgE, and LDH. These reductions in AD biomarkers further validate published results showing significant impacts of eblasakimab 400 mg and 600 mg on AD outcomes, including higher proportions of patients receiving eblasakimab 600 mg treatment achieving EASI-50, EASI-75, and IGA 0/1 at Week 8 compared with placebo [18, 31]. There is a strong link between the biomarkers assessed in this study and the inflammation and allergic symptomatology underlying AD pathophysiology and clinical manifestations, which might explain the connections between the changes in biomarker levels and improvement in symptoms [6]. For instance, TARC is a byproduct of the Th2-mediated immune pathway which predominates in the pathophysiology of AD [1, 32]. Serum LDH and IgE levels are associated with the general inflammatory response typical of AD, which correlates with disease severity assessed using EASI and IGA scores [32]. Also, patients have been shown to experience improvements in EASI and IGA scores when skin Th2 inflammatory markers decrease [4].

Among the biomarkers analyzed, TARC showed the greatest decreases from baseline levels with eblasakimab treatment, achieving significance from placebo within the first week of treatment. This early response is in line with evidence pointing to TARC as the most reliable biomarker of AD (including a meta-analysis showing serum TARC levels correlated significantly with disease severity) [7], and similar reductions observed among patients receiving tralokinumab [22]. In addition to reduction in TARC levels, patients receiving eblasakimab experienced early and sustained reductions in serum IgE levels. However, change in serum levels of IgE was not as marked as in TARC. Evidence shows serum IgE may be a less reliable AD biomarker as about 20% of individuals with AD, especially intrinsic AD, do not experience elevated serum IgE levels [13]. Some individuals with severe AD have total serum IgE within reference levels while others with multiple non-atopic conditions have elevated total serum IgE levels [13, 33]. Another potential explanation for the slower rate of reduction in serum IgE level compared with TARC may be as a result of the longer half-life of IgE [24]. The measurement of serum IgE in this study was exploratory to assess eblasakimab’s efficacy in reducing serum IgE levels within the context of AD as reported in other systemic AD treatments [34, 35]. While other drugs, including those targeting IgE such as omalizumab, reduce free and surface IgE [35], the changes to the level of serum IgE recorded in this study are similar to those observed for dupilumab [36] and tralokinumab [22].

Similarly, early and sustained reductions in serum LDH level were recorded among patients receiving eblasakimab. However, like the observed changes to serum IgE levels, the reduction in serum LDH level was not as marked as in TARC. This could be due to the relatively lower specificity of LDH as a marker in AD compared with TARC, which is produced more directly downstream of the Th2 IL-4/IL-13 immune-mediated pathway [11, 14].

Following a course of AD treatment, especially one that exerts control on the underlying type 2 inflammatory process typical of the disease, it is expected that serum biomarker levels should gradually return to baseline levels following treatment discontinuation. In the case of patients who received eblasakimab 400 mg and 600 mg in this study, serum biomarker levels were reduced to the extent characterized for other Th2 inhibitors dosed for a longer period (dupilumab, 16 weeks) during the 8 weeks of active eblasakimab treatment and remained suppressed up to 6 weeks following the last dose [36]. This suggests a potential longer and more sustainable effect of eblasakimab following cessation of treatment and may result in less frequent dosing.

Additionally, considerable fluctuations were observed in biomarker levels in the weeks following treatment completion, especially between Weeks 12 and 20 (Figs 4–5). Possible reasons for the fluctuations include the heterogenous pathophysiology of AD, differences in patients’ response to loss of disease control in the weeks following dosing discontinuation, and differences in patients’ biomarker expression [6, 13]. With treatment cessation, the state of inflammation generally returns in a highly individual and heterogeneous manner, with substantial variability in each patient’s response. Also, it has been reported that some patients with the same disease severity have different serum TARC levels [32] and some with severe disease have normal or low serum TARC levels [6]. Variability within a group is also observed as the number of patients continuing in the study after end of treatment becomes very small.

Dupilumab, the first monoclonal antibody approved for the treatment of moderate-to-severe AD in adults in 2017, has been revolutionary in the treatment of several important atopic/allergic Th2-driven conditions including AD [37, 38]. Eblasakimab is the first monoclonal antibody in the clinic that selectively blocks the inflammation-specific IL-13Rα1 subunit of the type 2 receptor complex, rather than targeting IL-4Rα like dupilumab, and has now demonstrated comparable potential for patients with respect to the clinical benefit and reduction in serum biomarkers of AD [19, 20]. In the current study, rapid reductions in serum TARC levels were apparent and significant as early as week 1 in patients treated with eblasakimab, similar to those reported in dupilumab studies [14].

While this study has demonstrated the effect of eblasakimab on improving markers of disease severity, some study limitations are noted. First, the small sample size limits the power of the study and the generalizability of the findings. The study was powered for changes in EASI scores from baseline to Week 8, and not for changes in biomarker response. However, the similarity in findings between the OC set and the data with LOCF imputations demonstrates the robustness of the results. Direct linear correlations were not carried out between EASI/IGA scores and biomarker levels due to the small sample size in the study. This will be highly relevant for future studies with larger sample sizes and known effective treatment doses. Secondly, it was observed that patients in the eblasakimab 400-mg group had the greatest reduction in serum biomarker levels from baseline. This was possibly due to comparatively higher baseline serum levels of the biomarkers in the 400-mg group, smaller sample size in the 400-mg group compared with the 600-mg group, and higher confidence intervals in the 400-mg group, suggesting a high degree of variability in the findings. Thirdly, even though patients uniformly responded to treatment with eblasakimab with reductions in biomarker levels, the patient population was ethnically diverse, potentially introducing other characteristics that may influence patient response to treatment of this highly heterogenous disease. Furthermore, while there was no strong differentiation in the dose response between the eblasakimab 400-mg and 600-mg groups, patients who received the 200-mg dose experienced a limited clinical response. This is possibly because the proof-of-concept approach to the study design is not equipped to detect dose-related differences in biomarker response. A larger study with appropriate design and sample sizes would be required to determine the difference in efficacy between the 400-mg and 600-mg doses. While the results in this study provide some experimental mechanistic insights for eblasakimab in AD, not much is currently known about how to apply these learnings in clinical practice. Various biomarkers have been reported in AD studies often as exploratory aims, as there are no validated or established predictive biomarkers in AD. Further investigations will be required to confirm clinical benefit and demonstrate dynamic and robust effects on serum biomarker levels during and after treatment.