Background/Purpose: Tyrosine kinase 2 (TYK2), a Janus kinase (JAK) family member, is attracting a lot of interest as a new target to treat patients with autoimmune and inflammatory diseases, including inflammatory bowel diseases, and several inhibitors are currently in clinical development. In vitro pharmacological profiling of TYK2 inhibitors has been employed to evaluate potency and selectivity; however, such data are best viewed in relation to clinical exposure levels. We compared expected levels of inhibition of TYK2-dependent and -independent pathways for deucravacitinib, zasocitinib and GLPG3667 at their respective clinical dose regimens and demonstrate that relevant differences exist between these compounds.

Methods: Potency of the TYK2 inhibitors was compared for TYK2-dependent pathways (IFNα, IL-12, IL-23), TYK2-independent pathways (IL-6, IL-2, GM-CSF) and the anti-inflammatory IL-10 pathway in in vitro human whole blood assays using STAT phosphorylation (flow cytometry) and cytokine release (ELISA) measures. Sigmoidal Emax models were fitted to the concentration–inhibition data from healthy donors to estimate IC50, Emax and Hill slope for each assay and compound. The obtained relationships were subsequently coupled to the clinical pharmacokinetic (PK) profiles of the compounds (such as Cavg, Cmax and Ct from population PK model for GLPG3667 and published PK metrics for deucravacitinib and zasocitinib) to estimate the level of inhibition of the various pathways at clinically relevant dose regimens.

Results: Human whole blood assays performed for various JAK pathways demonstrated that all TYK2 inhibitors display selectivity for TYK2 over the JAK1–3 family members, with zasocitinib being the most selective. At exposure levels associated with its clinical dose of 150 mg once daily, GLPG3667 showed inhibition of the IFNα, and IL-23 pathways, comparable to the expected inhibition for deucravacitinib at its clinical dose regimens, without a measurable impact on TYK2-independent pathways. Inhibition of the IL-12 pathway was more pronounced for GLPG3667 than for deucravacitinib. Zasocitinib showed the most sustained inhibition of TYK2-dependent pathways. GLPG3667 showed no measurable inhibition of IL-10-mediated signalling up to the highest concentration tested (~10-fold above clinical concentrations) in monocytes, CD4+ T cells and CD19+ B cells, while strong inhibition was observed with deucravacitinib and overall zasocitinib at concentrations corresponding to the respective clinical dose regimens.

Conclusion: At concentrations corresponding to its highest anticipated clinical dose, GLPG3667 shows selective inhibition of TYK2-mediated signalling, with a level of inhibition similar to deucravacitinib clinical dose regimens. While GLPG3667 did not show any impact on IL-10-mediated signalling, inhibition of this anti-inflammatory pathway is expected for the allosteric TYK2 inhibitors at their clinical exposure levels.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-vitro-pharmacological-profile-of-glpg3667-suggests-differentiation-from-the-tyk2-inhibitors-deucravacitinib-and-zasocitinib-at-their-clinical-dose-regimens/