Proteomic analysis of serum from brepocitinib-treated cicatricial alopecia patients reveals downregulation of key biomarkers of inflammation and fibrosis

Summary: Cicatricial alopecias (CA) are progressive scarring hair loss disorders that significantly impact patient quality of life and lack effective treatments. Given the putative role of Th1/JAK activation in CA pathogenesis, brepocitinib, a TYK2/JAK1 inhibitor, was recently evaluated in a Phase 2A, double-blind, placebo-controlled trial (NCT05076006). Patients with lichen planopilaris (LPP, n=16), frontal fibrosing alopecia (FFA, n=9), and central centrifugal cicatricial alopecia (CCCA, n=24) were randomized 3:1 to receive 45 mg brepocitinib or placebo daily for 24wks, followed by an additional 24wks of open-label brepocitinib. Serum samples collected at baseline, wk24, and wk48 were analyzed using the inflammation, cardiovascular, and neurology panel of Olink Proteomics Analysis. Differentially expressed proteins were identified based on fold changes (|FCH|>1.2, p<0.05). Proteomic analysis of serum from FFA/LPP and/or CCCA patients treated with brepocitinib revealed significant downregulation of key biomarkers associated with Th1 (CXCL9/CXCL10/CXCL11/IL2RA), T-cell activation (TNFRSF9/XCL1/CD8A/CCL19), and fibrosis (SPP1/COL1A1) at wk24, with sustained reductions through wk48 (p<0.001). No significant downregulation of the proteome was observed in the placebo at wk24. Spearman correlation analysis at wk48 demonstrated positive associations between clinical severity scores (FFASI/LPPAI/CHLG) and multiple immune-related markers, including Th1 (IL8/CCL4), Th2 (CCL17/CCL13), and Th17 (PI3/CXCL1) and negative correlation with lipid biomarkers (AMBP/CTSD) (|r|>0.5, p<0.05 for all). Brepocitinib was well tolerated and consistent with safety reported in prior studies. Overall, the reduction of inflammatory and fibrotic serum biomarker expression paralleled clinical improvement in brepocitinib-treated CA patients, further supporting its role in targeting key drivers of CA disease pathogenesis. Megan Lau¹, E Del Duca¹, J Largen¹, D Liu¹, Joel Correa da Rosa¹, Yeriel Estrada¹, B Oemar², P Mahling², E Peeva², Emma Guttman-Yassky¹ 1. Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2. Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA, United States. Translational Studies: Cell and Molecular Biology