Background/Purpose: ESK-001 is a potent, highly selective, oral, allosteric small molecule inhibitor of TYK2 currently being investigated in adults with active SLE in the LUMUS trial. The recent ESK-001 STRIDE trial achieved high rates of clinical response in moderate to severe psoriasis in a dose-dependent manner, with the highest at the top 40 mg BID dose. The STRIDE study undertook transcriptomic analyses in blood and skin to characterize ESK-001’s ability to down regulate cytokine pathways such as type I interferons that signal through TYK2 and are thought to be central to SLE/CLE pathogenesis.

Methods: Public Expression Data: Data from the following series accessions from Gene Expression Omnibus (GEO) were used for analysis: GSE109248, GSE110169, GSE112087, and GSE154851. For GSE109248, GSE110169 and GSE154851, normalized microarray values were analyzed using the limma package in R. For GSE112087, raw RNA-seq count tables were analyzed with DESeq2.

STRIDE Psoriasis Trial Data: RNA-sequencing (RNA-seq) of whole blood and skin was conducted at multiple time points during the 12-week dosing period and after a 4-week washout period. Skin punch biopsies were collected at baseline and week 12. Reads were aligned to the genome and transcriptome using STAR, and transcripts were quantified with Salmon. Gene level counts were normalized with the DESeq2 package. Type 1 IFN scores were calculated by taking median expression of HERC5, RSAD2, IFI27, and IFIT1 (Northcott et al 2022) for the Dxterity type 1 IFN score and IFI44, IFI44L, 1IFIT3, LY6E, and MX1 (Brkic et al 2013) for the Brkic IFN signature.

Results: Analysis of SLE case-control gene expression data substantiated two definitions of Type 1 IFN response. STRIDE blood and skin RNA-seq analyses show that ESK-001 administration suppresses expression of these two type 1 IFN scores in a dose-dependent manner. Additionally, we found expression of a novel blood PD biomarker to also be dose-dependent and fully suppressed by ESK-001 administration. Further analysis of four public gene expression datasets of SLE blood and CLE skin shows that expression of the novel TYK2 biomarker is highly elevated in patients vs control.

Conclusion: ESK-001 is a selective TYK2 inhibitor that demonstrates dose-dependent suppression of key pathways that are dysregulated in SLE. Blood RNA-seq shows maximal inhibition of of pathways believed to be central to the pathophysiology of SLE such as type 1 IFN gene expression signatures at the ESK-001 40 mg BID dose. Type 1 IFN was also suppressed in the skin at the top 40mg BID dose. Analysis of public gene expression datasets of SLE blood and CLE skin shows significant enrichment of type 1 IFN signature genes and our novel PD biomarker in SLE compared to controls. These findings support the dose range (including 40 mg BID dose) in the ongoing SLE Ph2b LUMUS study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/esk-001-an-allosteric-tyk2-inhibitor-maximally-suppresses-type-1-interferon-a-therapeutic-pathway-central-to-sle-and-cle/