Bridging preclinical and clinical efficacy of SIK2/SIK3 inhibition in inflammatory bowel disease through integrated murine, patient-derived models, and phase 2a trial-based analyses.

Translational attrition remains a major obstacle in inflammatory bowel disease (IBD) drug development due to limited concordance between conventional preclinical models and patient responses. In this study we aimed to evaluate the activity of the selective salt-inducible kinase 2/3 (SIK2/3) inhibitor GLPG3970 across complementary experimental platforms, including murine colitis, patient-derived intestinal organoids, and ex vivo mucosal biopsies, and compared these findings with transcriptional data from a UC-phase 2 study. Therapeutic efficacy of GLPG3970 (20 mg/kg) was assessed in the murine CD4 + CD25- T-cell transfer colitis model. Epithelial-intrinsic responses were investigated in ulcerative colitis (UC) patient-derived intestinal organoids (n = 5). In parallel, mucosal biopsies from UC (n = 10) and Crohn's disease (CD; n = 10) patients were treated ex vivo with GLPG3970 (60 µM) or tofacitinib (10 µM) for 24 h. Treatment-induced transcriptional signatures were compared with bulk RNA sequencing data from patients enrolled in a short 6-week UC-phase 2 study (GLPG3970 n = 21, placebo n = 10; NCT04577794). GLPG3970 reduced disease activity and restored goblet cell-associated mucus production in the T-cell transfer model. In patient-derived intestinal organoids, SIK2/SIK3 inhibition enhanced epithelial mucus secretion. Ex vivo exposure of IBD biopsies elicited anti-inflammatory transcriptional and proteomic responses, revealing disease- and treatment-specific signatures. Notably, GLPG3970-induced signatures in ex vivo biopsies closely aligned with treatment-responsive gene expression changes observed in the UC-phase 2 study. Integrated analyses across murine, patient-derived, and clinical trial datasets demonstrate conserved immune-epithelial responses to SIK2/SIK3 inhibition by GLPG3970. These findings support the value of patient-relevant experimental platforms to assess target engagement and therapeutic activity prior to clinical testing, strengthening translational alignment in IBD drug development.