Brepocitinib improves inflammation and fibrosis in cicatricial alopecias through transcriptomic changes

Summary: Cicatricial alopecias (CA) are scarring hair loss disorders characterized by inflammation and progressive scalp fibrosis. In a recent phase 2 trial (NCT05076006), brepocitinib, a dual TYK2/JAK1 inhibitor, demonstrated clinical improvement in CA patients. In order to better characterize the potential molecular targets of brepocitinib in CA, transcriptomic analysis using RNA sequencing was conducted on scalp samples obtained from the same trial. Patients with frontal fibrosing alopecia/lichen planopilaris (FFA/LPP, <i>n</i>=22) and central centrifugal cicatricial alopecia (CCCA, <i>n</i>=22) were randomized to receive brepocitinib 45 mg daily or placebo for 24 weeks, followed by placebo cross-over, open-label treatment with brepocitinib for an additional 24 weeks. Biopsies were collected from nonlesional and lesional scalp at baseline, and from lesional scalp at week 24 and week 48. RNA sequencing was performed, with differential gene expression identified using fold-change/|FCH|>1.5 and false-discovery-rate/FDR<0.05 thresholds. At week 24, brepocitinib significantly downregulated markers of Th1 (MX1, CXCR3, IL2RA, OASL, CCR2, TNF, IRF1, CXCL9/10/11, STAT1, CCR5), Th2 (IL10, CCL13, OX40, IL7R), Th17/22 (IL32, IL6R, S100A7/8) and fibrosis (CXCR3, IL2RA, IL7R, CCL2, CCR2, TNF) pathways in lesional scalp from FFA/LPP and/or CCCA patients. These effects persisted at week 48, with stronger modulation observed in the FFA/LPP group. Notably, clinical scores (FFASI/LPPAI/CHLG) correlated positively with JAK/STAT-related markers and fibrosis markers (COL12A1, COL8A2, ITGB1BP1, COL5A3, JAKMIP3) (r>0.7; p<0.05). Brepocitinib was well tolerated and consistent with safety reported in other clinical studies. Taken together, brepocitinib significantly reduced markers of inflammation and fibrosis in the lesional scalp of FFA/LPP and CCCA patients, supporting its potential as a therapeutic option in CA patients. J Largen¹, Megan Lau¹, E Del Duca¹, Joel Correa da Rosa¹, J Pulsinelli¹, 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