Rilzabrutinib attenuates inflammatory biomarkers in moderate-to-severe atopic dermatitis: A tape-strip proteomic analysis

Summary: Rilzabrutinib, a selective oral Bruton’s tyrosine kinase (BTK) inhibitor, was investigated in a placebo-controlled phase-2b trial (EudraCT: 2021-001704-15) in adult patients with moderate-to-severe atopic dermatitis (AD). We used a minimally invasive, tape-stripping approach, to evaluate the effect of Rilzabrutinib on the cutaneous proteomic profile of AD. We performed Olink Proteomic analysis on tape-strip skin samples from 24 AD patients treated with Rilzabrutinib BID (n=5), Rilzabrutinib TID (n=10) and placebo (n=9). Tape-strips were obtained from lesional (LS) and non-lesional (NL) skin at baseline and week 16. Differentially expressed proteins/DEPs were defined as fold changes/|FCH|>1.3, and p-value<0.05. At week 16, the LS proteome of patients receiving rilzabrutinib TID showed 100% improvement from baseline towards a NL profile compared to 40% in the placebo respectively (p<0.001), whereas no significant improvement was observed in the BID group. Rilzabrutinib TID also showed significant downregulation of key markers belonging to innate immunity (TNF/IL6/IL18), Th1 (CCL3/CXCL10/CXCL11/CXCL9/IL12B/CCL4), Th2 (CCL7/IL10), and Th17 (CCL20/CXCL1/ IL17A/S100A12/TGFB1), in LS skin at Week 16 (p<0.05), while no significant downregulation was observed in placebo. In rilzabrutinib-treated patients, changes in protein biomarker expression in LS skin were correlated with reductions in clinical severity scores indicating a relationship between specific modulation in key proteins and disease severity. BSA, EASI, and IGA improvements showed positive correlations with Th1 (TNF/CXCL10/CXCL11), Th2 (CCL7/IL33), and T-cell activation (CD38/CCL8) related markers (<i>r</i>>0.75, p<0.05). We showed significant modulation of the proteomic skin profile of patients treated with rilzabrutinib TID, highlighting its therapeutic potential in managing AD. Ester Del Duca¹, Megan Lau¹, Joel Correa da Rosa¹, Yeriel Estrada¹, Lydie Baret-Cormel², Leda Mannent², Cintia Palu², Nils Ternes², Vincent Mikol², Emma Guttman-Yassky¹ 1. Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2. R&D, Sanofi, Paris, France. Clinical Research: Interventional Research