Modulation of Disease-Associated Pathways in Hidradenitis Suppurativa by the Janus Kinase 1 Inhibitor Povorcitinib: Transcriptomic and Proteomic Analyses of Two Phase 2 Studies

Abstract

Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS.

Keywords: INCB054707; JAK1; hidradenitis suppurativa; inflammatory skin diseases; povorcitinib; proteomics; transcription.

Figure 1

Differential gene expression following treatment with povorcitinib. (a) Overlap between 15 and 30 mg povorcitinib QD for DEGs in HS lesional skin biopsies from Week 8 vs. baseline. (b) Heatmap of treatment-mediated gene expression change in lesional HS skin biopsies between Week 8 and baseline. DEG, differentially expressed gene; |FCH|, absolute fold change; HS, hidradenitis suppurativa; QD, once daily. The cutoff for significance was p < 0.05 and |FCH| >1.5.

Figure 2

Pathway enrichment analysis. (a) Pathway enrichment analysis at Week 8 of treatment with 30 mg povorcitinib QD and (b) heatmap of Week 8 DEGs from selected Hallmark signaling pathways. DEG, differentially expressed gene; FCH, fold change; FDR, false discovery rate; QD, once daily. Log2 FCH from baseline is used. HALLMARK signaling pathways were from the Molecular Signatures Database (MSigDB v7·2 [21]).

Figure 3

GSEA and enrichment plot showing signature reversal of upregulated genes in HS lesional skin after 8 weeks of treatment with 30 mg povorcitinib QD. * ES, enrichment score; FCH, fold change; FDR, false discovery rate; GSEA, gene set enrichment analysis; HS, hidradenitis suppurativa; QD, once daily. * Plot represents a case (30 mg povorcitinib QD treatment) and GSEA data based on previously described HS gene signature (HS-high) [9]. Genes displayed in heatmap are marked in yellow in the corresponding GSEA plot.

Figure 4

OASL and WIF1 gene expression in HS lesional skin biopsies over 8 weeks of treatment. (a) OASL, (b) WIF1. HS, hidradenitis suppurativa; QD, once daily.

Figure 5

Heatmap of DEPs in blood samples by treatment. (a) Week 4, (b) Week 8. DEP, differentially expressed protein; |FCH|, absolute fold change; FDR, false discovery rate; QD, once daily. The cutoff for significance was FDR < 0.05 and |FCH| > 1.5.

Figure 6

Modulation of circulating protein expression in blood samples over 8 weeks of treatment. (a) LTA, (b) SIGLEC1, (c) FLT3LG, (d) IL15, (e) TNC, and (f) CLEC7A. CLEC7A, C-type lectin domain containing 7A; |FCH|, absolute fold change; FDR, false discovery rate; FLT3LG, Fms-related receptor tyrosine kinase 3 ligand; IL, interleukin; LTA, lymphotoxin-alpha; SIGLEC1, sialic acid-binding Ig-like lectin 1; TNC, tenascin C. * FDR < 0.05. The cutoff for significance was FDR < 0.05 and |FCH| > 1.5.