Can SIK3 inhibition become the Holy Grail for autoimmune diseases?

The investigational salt-inducible kinase 3 (SIK3) inhibitor O3R-5671 may have the potential to transform the treatment paradigm for various autoimmune diseases, including ulcerative colitis (UC) and Crohn’s disease (CD). Although the agent has only recently entered the clinical phase, the initial results are encouraging.

“The SIK3 inhibitor O3R-5671 acts on tumour necrosis factor-alpha (TNF-α), interleukin (IL)-12, and IL-23, creating a potential therapeutic option for multiple autoimmune diseases, including psoriasis, UC, and CD”, said Dr Fabrice Kolb (Onco3R Therapeutics, Belgium). “The drug inhibits multiple cytokines, is administered orally, avoids the formation of anti-drug antibodies, and has shown favourable pre-clinical safety data.” Dr Kolb explained that this selective SIK3 inhibitor is more selective than the previously investigated dual SIK2/SIK3 inhibitor GLPG3970 [1].

“In a psoriasis mouse model, we observed reductions in ear thickness by 57-72% at day 5 across various O3R-5671 doses, comparable to the effects seen with tyrosine kinase (TYK)2 inhibition,” said Dr Kolb. The investigational SIK3 inhibitor also dose-dependently reduced disease score in a T-cell transfer mouse model of colitis. “The results were on par with those of IL-23 inhibitors in the same model,” he added.

O3R-5671 is a potential best-in-class SIK3 inhibitor that displayed encouraging pre-clinical activity and safety. “The first clinical dose cohort has been completed, showing a favourable and predictable pharmacokinetic profile,” Dr Kolb noted. “A second cohort is currently ongoing, further exploring the therapeutic value of this novel mode-of-action in autoimmune diseases.”

1. Kolb F, et al. Discovery of a novel, selective SIK3 inhibitor for the treatment of ulcerative colitis, Crohn’s disease and other autoimmune diseases. LB08, Hot off the press: IBD treatment, UEG Week, 4-7 October 2025, Berlin, Germany.

Medical writing support was provided by Robert van den Heuvel.
Copyright ©2025 Medicom Medical Publishers



Posted on 6 October 20256 October 2025