An article from the Incyte Corporation (Wilmington DE) describes how multiomic analysis of data from two phase II clinical trials reveals how the Janus Kinase 1 Inhibitor, Povorcitinib, modulates disease-associated pathways in the treatment of the inflammatory skin condition, Hidradenitis Suppurativa (HS). The pathophysiology of HS is complex and not fully understood, creating challenges in selecting treatment approaches. Targeting the JAK pathway in HS was investigated because the JAK/STAT signal transduction pathways are responsible for the production of numerous pro-inflammatory mediators thought to contribute to the pathology of the disease. In the trials under study, samples were taken longitudinally from patients given differing doses of drug, with skin lesional samples taken for localized RNAseq analysis and serum used for proteomic analysis with a total of twelve Olink® Target 96 panels.
Transcriptomics of skin lesions showed that the number of differentially expressed genes was the greatest in the 30 mg dose group, which was consistent with the published efficacy results, and pathway analysis indicated enrichment of JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Overall povorcitinib downregulated multiple HS and inflammatory signaling marker transcripts, reversing gene expression previously associated with HS lesional skin.
The Olink analysis identified 33 differentially expressed proteins of interest (6 upregulated and 27 downregulated) for each treatment at Weeks 4 and 8. Modulation of these proteins was dose-dependent both at Week 4 and 8 and the data suggested a rapid onset of response, as these changes were generally observed as early as Week 4 and maintained over time. In line with previous data, IL2RA was significantly reduced by Week 4 following treatment with the highest two doses used, with a more moderate effect seen at the lower doses. Similar patterns were seen for LTA and SIGLEC1, whereas levels of FLT3LG increased after the higher dose treatments. When comparing to the lesional RNAseq data, changes in serum CCL18, CLEC4D, GZMB, LAIR2, SH2D1A, and TNFRSF6B protein in response to the drug mirrored the transcriptomics, while the reductions in serum CXCL10, GZMH, IL12B, IL2RA, and TNFSF11 correlated with differential expression of these genes in HS lesions compared to healthy skin.
The multiomic data therefore provided important data related to the drug mode of action, response time and dosing. Particular significance was seen in the peak protein changes occurring as early as week 4, indicating rapid onset of action for the drug, which was also seen in the clinical responses during the efficacy assessments in the trials.
Liu H, Santos L, Smith S, et al. Modulation of Disease-Associated Pathways in Hidradenitis Suppurativa by the Janus Kinase 1 Inhibitor Povorcitinib: Transcriptomic and Proteomic Analyses of Two Phase 2 Studies. (2023) International Journal of Molecular Sciences, DOI: 10.3390/ijms24087185
Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4
Liu et al. (2023)
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