Background/Purpose: Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates the signaling from type 1 interferon (IFN), interleukin (IL)-12/IL-23 and the IL-10 family of cytokines. Genetic analyses have indicated an association between TYK2 variants and risk of inflammatory diseases. In addition, clinical data obtained with ustekinumab suggest that compounds that inhibit TYK2 could be potential treatments for inflammatory diseases, notably through inhibition of IL-12 and IL-23 signaling. We describe here GLPG3667, a potent and selective TYK2 inhibitor that is in development as a treatment for inflammatory and autoimmune diseases.

Methods: Potency and selectivity of GLPG3667 on TYK2 was addressed using radioactive and fluorescent biochemical assays. Peripheral blood mononuclear cells (PBMC) and human whole blood assays for various Janus kinase (JAK)-dependent pathways were performed to address GLPG3667 potency and selectivity, using flow cytometry or enzyme-linked immunosorbent assay. GLPG3667 pharmacological activity was demonstrated in a psoriasis mouse model driven by IL-23 (a cytokine that signals through JAK2/TYK2). In healthy human volunteers (HV), pharmacodynamic activity of GLPG3667 was demonstrated by measuring signal transducer and activator of transcription (STAT) phosphorylation using flow cytometry analysis on the IFNα pathway and selectivity described through analysis of IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) pathways. Biological effects of GLPG3667 in humans were assessed using transcriptomic analysis of blood cells after in vivo IFNα (1 million IU of IntronA) challenge in healthy HV.

Results: Biochemical assays showed that GLPG3667 displayed nanomolar potency on TYK2 with a selectivity over other JAK kinases >3-fold. In human PBMC, GLPG3667 showed comparable potency on the IFNα and IL-23 pathways (around 50 nM). Selectivity for TYK2 on the IFNα pathway was >14-fold and >19-fold toward the IL-2 and GM-CSF pathways in human PBMC and whole blood, respectively. Dermal ear inflammation in a mouse model of psoriasis driven by IL-23 was prevented by GLPG3667 with a minimal effective dose of 3 mg/kg given orally once daily. This effect was associated with a decrease in neutrophil infiltration and STAT3 phosphorylation at sites of inflammation. In healthy HV, GLPG3667 completely inhibited IFNα-induced STAT1 and STAT3 phosphorylation but did not impact IL-2- and GM-CSF-induced STAT5 phosphorylation. After in vivo IFNα challenge, GLPG3667 blocked the induced expression of IFN-response genes.

Conclusion: The TYK2 inhibitor GLPG3667 demonstrated selectivity toward the three other JAK family members in several biochemical, cellular and human whole blood assays ex vivo and in vivo during a Phase 1 study (NCT04097938) in healthy HV. Pharmacological effects of GLPG3667 were demonstrated in a mouse model of psoriasis driven by IL-23 and in healthy HV challenged with IFNα. GLPG3667 is in development for the treatment of moderate to severe psoriasis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacological-characterization-of-glpg3667-a-selective-tyk2-inhibitor-for-treatment-of-inflammatory-diseases/