Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo

ABSTRACT

Background

Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated.

Objective

This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with non-segmental vitiligo (NSV).

Methods

65 adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n=14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n=13), 100/50 mg (n=12), 50 mg (n=11), 30 mg (n=8), or 10 mg (n=6). Skin (lesional and nonlesional) biopsies were taken at baseline, 4, and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular/cellular biomarkers were evaluated by RNA-seq/RT-qPCR/proteomics/flow cytometry.

Results

Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared with baseline and/or placebo. Significant reductions were seen in CD3⁺/CD8⁺ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50-mg ritlecitinib groups (both P<0.05). There was significant, dose-dependent downregulation in T-cell activation/NK/cytotoxic/regulatory markers in lesional skin (IL-2/IL2-RA/IL-15/CCR7/CD5/ CRTAM/NCR1/XCL1/KIR3DL1/FASLG/KLRD; P<0.05). Th1 and Th2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P<0.05). Changes in immune biomarkers correlated with clinical response.

Conclusion

Ritlecitinib significantly downregulated pro-inflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.