P133 In vitro pharmacological profile of GLPG3667 suggests differentiation from the TYK2 inhibitors deucravacitinib and TAK-279 at their clinical dose regimens

Abstract

Abstract Background 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 disease, 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, TAK-279 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), 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). 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 (population PK model for GLPG3667, published PK metrics such as Cavg for the other compounds) 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 TAK-279 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-12 pathways, similar to the expected inhibition for deucravacitinib at its clinical dose regimens, without a measurable impact on TYK2-independent pathways. TAK-279 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), while inhibition was observed with deucravacitinib and TAK-279 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.