Background/Purpose:

Because of their pleotropic role in cytokine signaling, Janus Kinases (JAKs) are key players in inflammatory diseases. Among the 4 members of the JAK family (JAK1, JAK2, JAK3, TYK2), JAK1 has been demonstrated as a validated target in inflammatory diseases with filgotinib (GLPG0634, GS-6034) displaying efficacy and safety in several phase 2 studies in rheumatoid arthritis (RA) patients. Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease characterized by the association of skeletal involvement and extra-skeletal symptoms such as psoriasis and Inflammatory Bowel Disease (IBD) with common findings including enthesitis and dactylitis. Current treatments include anti-TNFa, anti-IL-17 and anti-IL-12/IL-23 antibodies with varying success rates. The involvement of several pro-inflammatory cytokines suggests that therapies targeting JAKs may be effective. To gain insight in the potential of a JAK1-selective inhibitor in PsA, we evaluated filgotinib efficacy in a mouse model of PsA induced by the overexpression of IL-23.

Methods:

Overexpression of IL-23 was induced by hydrodynamic delivery of mIl23 enhanced Episomal Expression Vector (SBI) to male B10.RIII mice¹. Evolution of paw and finger inflammation was assessed by clinical scoring as well as by in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system). Enthesis, colon and fingers were collected for transcriptomic analysis. Using immunohistochemistry, infiltration of immune inflammatory cells and  pSTAT3 positive cells, were analyzed in Achilles’ enthesis, subcutaneous area and skin. Colon was also collected for histology and gene expression analysis.

Results:

High levels of IL-23 were maintained during the time-course of the study and were correlated with severity of finger and paw swelling and asscociated with inflammation of enthesis and finger as observed in PsA patients. Only moderate inflammation of the colon was observed. Filgotinib significantly improved clinical scoring and tended to prevent neutrophil/granulocyte infiltration in paw (notably at earlier time points) while strongly decreasing immune cell infiltration in the skin. Transcriptomic analysis of enthesis, fingers and colon showed that filgotinib reversed the effect of IL-23 for a consistent number of genes. Notably, expression of some upregulated inflammatory genes in enthesis and/or fingers (CCL20, CXCL1, IL‑22, MMP9 and TNFa) as well as the target-related gene Mx2 were reduced. Filgotinib also significantly counteracted pSTAT3 induction in the subcutaneous area and in the epidermis (mainly concentrated in proliferating keratinocytes) further demonstrating target engagement in the diseased tissue.

Conclusion:

In a mouse model of PsA, filgotinib improved global clinical score and decreased signs of inflammation in hindlimbs. Target engagement both in hindlimbs and colon was also demonstrated. These data support the evaluation of filgotinib in patients with PsA.

References:

1- Sherlock et al. 2012 Nature Med 7:1069–1076