New Phase 2a Data Support Oral ATI-2138 as Treatment for Atopic Dermatitis

Treatment of atopic dermatitis with ATI-2138 has been linked with clinical measure improvements and reductions in patients’ molecular markers of inflammation and fibrosis in skin and plasma, according to new findings.1

These late-breaking findings, supporting the potential of oral ATI-2138 as a new treatment for clinical and molecular reversal of patients’ atopic dermatitis, were presented at the European Academy of Dermatology and Venereology (EADV) 2025 Congress in Paris, France. They were presented by trial investigator Jessica Beaziz-Tordjman, MD, of the Department of Dermatology at the Icahn School of Medicine in New York.

In their introduction, Beaziz-Tordjman et al described atopic dermatitis as a chronic inflammatory skin conditon known to continue to markedly diminish patients' quality of life, even with recent progress in drugs targeting the Th2 pathway. They added that ATI-2138, an oral small-molecule inhibitor of ITK and JAK3, was evaluated in an open-label, single-arm clinical trial (NCT06585202) in individuals living with moderate-to-severe atopic dermatitis.

In this molecular sub-study designed by the investigators, they explored treatment-related biomarker shifts and their relationship with clinical outcomes. Collection of biopsies, skin tape strips, and plasma samples was done from both lesional and non-lesional regions with 9 patients from baseline through the 12-week mark. They performed transcriptomic profiling via RNA sequencing and RT-PCR on skin samples.

Beaziz-Tordjman and coauthors' proteomic analysis involved 369 plasma analytes and was conducted through the Olink high-throughput platform. They also assessed any observed associations between biomarker shifts and clinical indices—including patients' Eczema Area and Severity Index (EASI), body surface area (BSA), and Peak Pruritus Numerical Rating Scale (PP-NRS)

Patients showed, by week 4, substantial clinical improvements.1 The investigative team highlighted reductions in BSA by 63.9%, in EASI scores by 77.3%, and in PP-NRS by 44.8%. Such score improvements were statistically significant (all P< .05). Additionally, these 4-week scores were maintained through Week 12. RNA-Seq analyses demonstrated decreases in inflammatory mediators across a variety of pathways among patients.

These included Th1 (CXCL9, IL12RB2, OASL), Th2 (CCL24), and innate immunity (IL6). Suppression of markers of fibrosis and hyperplasia, such as COL1A1 and ADAMTS14, was also observed. Additional confirmation of downregulation of IL13, S100A9, DEFB4, CXCL9, MMP12, and CCL13, was observed through RT-PCR in biopsies. In addition, the team found that inhibition of the ITK pathway among subjects was evident, given the significant T cell proliferation reductions and differentiation marker reductions (CD4, CD5, IL6R, IL13, IL4R) observed in biopsy and/or tape-strip samples.

Beaziz-Tordjman and colleagues' plasma proteomic profiling findings also demonstrated that the treatment had several systemic anti-inflammatory effects, including significant down-regulation of Th1 (IL2), Th2 (IL4, IL33), and Th17 (CXCL1, PI3, TGFB1) pathways among study subjects. Reductions in pro-inflammatory genes were noted in

In their correlation analyses, Beaziz-Tordjman et al reported that pro-inflammatory gene reductions (TSLP, CCL21, CXCL12) and fibrosis-linked markers (ELN, SPON1, LUM) aligned positively with patients' EASI, BSA, and/or PP-NRS improvements (all P< 0.05). Conversely, the restoration of epidermal barrier–related genes (KRT77, LPO, KRT23, ELOVL5) demonstrated negative correlations with patients' clinical severity scores. This would indicate improved barrier function with treatment, the team highlighted.

Overall, ATI-2138 use was linked by the investigative team to robust clinical improvements among patients with atopic dermatitis, alongside notable reductions in the molecular markers of inflammation and fibrosis in both skin and plasma.

References

1. Beaziz-Tordjman J, Del Duca E, Guttman-Yassky E, et al. Molecular and Clinical Effects of Oral ATI-2138, an ITK/JAK3 inhibitor, in Moderate-to-Severe Atopic Dermatitis: Sub-study of a Phase 2a Open-Label, Single-Arm Trial. Presented at the 2025 European Academy of Dermatology and Venereology (EADV) Congress, Sept 17-20, 2025.

2. Kaul A, Hope H, Monahan J, et al. Characterization of the dual ITK/JAK3 small molecule covalent inhibitor ATI-2138. J Pharmacol Exp Ther. 2025 Feb;392(2):100054. doi: 10.1016/j.jpet.2024.100054. Epub 2024 Dec 9. PMID: 40023606.