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Objectives Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin condition with no approved targeted treatments. Afimetoran – a first-in-class, once daily oral, selective, equipotent, small-molecule inhibitor of TLR7/8 – was safe and well tolerated in patients with CLE in a phase 1b trial ( NCT04493541). Here, we describe clinical disease activity and systemic and local biomarkers associated with response to afimetoran.Methods Exploratory CLASI-50 response (50% improvement in CLASI from baseline) was determined at week (Wk) 16 for 12 patients who completed treatment and Wk 12 for 1 discontinued patient. Transcriptomics and flow cytometry were performed on whole blood (WB) collected at baseline and Wk 16. WB transcriptomics from 13 age-, race-, and gender-matched normal healthy volunteers (NHVs) were also analyzed. FFPE skin punch biopsies from lesion and non-lesion areas at baseline and Wk 16 were used for transcriptomics. Longitudinal changes in the CLASI-A scores were analyzed using a mixed-effect model of repeated measures. Gene set variation analysis (GSVA) was performed to assess transcriptional signature enrichment.Results Among 13 randomized patients (afimetoran, n = 8; placebo, n = 5), 5 patients receiving afimetoran (62.5%) achieved a CLASI-50 response (responders, Rs) and none with placebo. A more potent and sustained reduction in CLASI-A scores was observed in Rs vs non-responders (NRs, < CLASI-50) or placebo over time ( figure 1). GSVA enrichment analysis of WB transcriptome revealed robust PD activity of afimetoran through its impact on TLR7/8 and IFN pathways, as well as on immune cells including activated dendritic cells (DCs) and monocytes and B-cell subsets in Rs and NRs (figure 2). This decreased presence of subsets of DCs and monocytes in afimetoran-treated patients was further demonstrated by WB flow cytometry. Although PD effects were seen in the lesional skin of both Rs and NRs, the reduction in the immune cells signature scores was more pronounced in Rs.Abstract PO:02:027 Figure 1Mean changes from baseline in CLASI-A scores for Rs versus NRs and placebo-treated subjectsAbstract PO:02:027 Figure 2WB transcriptional signature enrichment scores at baseline versus Wk 16Conclusions In patients with CLE, afimetoran-treated patients that achieved CLASI-50 showed a distinct profile from NRs, based on the magnitude and duration of clinical improvements, robust PD effects in blood and lesional skin, and the reduced presence of activated DCs and monocytes in the lesional skin.