Psoriasis, a chronic, immune-mediated disease dependent upon the interleukin (IL)-23/Th17 pathway, is thought to be initiated through plasmacytoid dendritic cell activation and induction of Type I interferons (IFNs). BMS-986165, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, blocks signal transduction of IL-23, IL-12, and Type I IFNs in cellular assays. Its selectivity for TYK2 over Janus kinases 1–3 is driven by binding to the pseudokinase domain, rather than the conserved kinase domain. 

BMS-986165 was evaluated in a randomized, placebo-controlled, dose-ranging Phase 2 trial in 267 patients with moderate to severe psoriasis. In an optional substudy, 37 patients provided skin biopsies, which were assessed from non-lesional skin on Day 1 and from lesional skin on Days 1, 15, and 85 for changes in the IL-23, IL-12, and Type I IFN pathways by QRT-PCR, RNA sequencing, and immunohistochemistry.

All BMS-986165 dose groups except 3mg every other day (QOD) achieved superiority vs placebo in the proportion of patients achieving Psoriasis Area and Severity Index 75 after 12 weeks of treatment (primary endpoint): 3mg QOD 9.1%, 3mg daily (QD) 38.6%, 3mg twice daily (BID) 68.9%, 6mg BID 66.7%, and 12mg QD 75.0%, vs placebo 6.7%. A total of 3072 differentially expressed genes (DEGs) were identified between lesion vs non-lesion biopsies at Day 1. DEG analysis identified 1786–2387 genes that significantly changed at Day 85 in the most effective dose groups (3mg BID, 6mg BID, 12mg QD), which included significant and dose-dependent reversal of psoriasis DEGs for keratinocyte responses to cytokines and Th1, Th17 TNF, and IL-22 pathways. Th1 and Th17 gene sets were also significantly reduced. Transcriptomic analysis showed BMS-986165 was associated with decreases in IL-23/Th17 and IFN pathway markers.

BMS-986165 has promising efficacy in psoriasis and a distinct selectivity and transcription signature profile warranting further investigation.

A Selective Tyrosine Kinase 2 Inhibitor, BMS-986165, Decreases the Transcriptional Signature of Th17, Interleukin-12, and Interferon Pathways in Skin of Psoriasis: Results From a Phase 2 Trial