Molecular Effects of Investigational AD Treatment Described

TOPLINE:
Temtokibart, a novel monoclonal antibody, appears to achieve clinical improvements in moderate to severe atopic dermatitis (AD) by normalizing the skin barrier and increasing hydration, according to the results of a small, 16-week, phase 2a trial.
METHODOLOGY:
Interleukin (IL)-22 expression is increased in AD and is thought to contribute to epidermal hyperplasia and impaired barrier integrity. Previous trial data have shown that temtokibart, which targets the IL-22 receptor subunit alpha-1 (IL-22RA1), achieves significant clinical improvements in patients with moderate to severe AD.
To investigate the mechanisms underlying that effect, researchers randomized 12 individuals with moderate to severe AD to receive temtokibart (450 mg every 2 weeks; eight patients) or IL-4R-alpha blocker dupilumab (300 mg every 2 weeks; four patients) for 16 weeks.
At baseline, the mean Eczema Area and Severity Index (EASI) score was > 30 in the two arms, and > 75% patients were rated as having severe disease on the Validated Investigator Global Assessment scale for AD. The mean score on the Itch Numeric Rating Scale (NRS) was approximately 7.
Skin punch biopsies and tape strips were taken at baseline and at 1, 4, and 16 weeks, and patients were followed up for another 16 weeks.
TAKEAWAY:
As expected, both groups showed comparable, clinically relevant improvements in EASI and NRS itch scores at 16 weeks; no patients experienced serious or severe adverse events.
Gene expression analysis revealed that temtokibart resulted in an increased expression of barrier-related markers, such as terminal differentiation (KRT1, KRT10) or cell adhesion (DSC1, DSG1, CLDN1) molecules, “consistent with a predominant expression of IL22RA1 by keratinocytes,” and rapid reduction in the proinflammatory S100 gene expression. This was not seen with dupilumab, which showed a decrease in type 2–associated inflammatory markers, particularly in immune cells and fibroblasts.
Temtokibart was also linked to a rapid and significant increase in skin hydration markers 2-pyrrolidone-5-carboxylic acid and urocanic acid (P < .0001).
IN PRACTICE:
The results showed that by blocking IL-22 expression in keratinocytes, temtokibart increased skin hydration and normalized the skin barrier via upregulation of natural moisturizing factors and barrier integrity genes and downregulation of S100 genes, said study presenter, Christine Bangert, MD, head of the atopic eczema outpatient clinic at the Medical University of Vienna, Vienna, Austria. “So we have this primary effect of temtokibart on the skin barrier, and probably later on, an indirect effect on the immune cells,” she concluded.
SOURCE:
Bangert presented the study results at the European Academy of Dermatology and Venereology (EADV) 2024 Congress in Amsterdam, the Netherlands, on September 26.
LIMITATIONS:
Bangert acknowledged that the study was limited by having only eight patients in the temtokibart arm and that they could not be stratified to further understand the mechanism of action in the skin.
DISCLOSURES:
LEO Pharma funded this study; one author is a company employee. Bangert disclosed being an advisor and/or having received speaker’s honoraria and/or participated in clinical trials for ALK, Almirall, AbbVie, Eli Lilly, Galderma, LEO Pharma, A. Menarini Pharma, Novartis, Pfizer, and Sanofi Genzyme.
 
Send comments and news tips to [email protected].