the jak1 selective inhibitor filgotinib regulates both

© Copyright 2016 Galapagos NV© Copyright 2017 Galapagos NV

The JAK1 Selective Inhibitor Filgotinib Regulates Both Enthesitis and Colon Inflammation in a Mouse Model of Psoriatic Arthritis

Catherine Robin-Jagerschmidt, Roland Blanqué, Florence Marsais, Maté Ongenaert, Alain Monjardet, Angélina Cauvin, Corinne Saccomani, Christelle David, Didier Merciris, Emilie Chanudet, Monica Borgonovi, Liên Lepescheux, Marielle Auberval, Sonia Dupont, Philippe Clément-Lacroix, René Galien

Galapagos SASU, Romainville, France

Methods

Overexpression of IL-23 was induced by hydrodynamic delivery of mIL23 enhancedEpisomal Expression Vector (SBI) to male B10.RIII mice1. Evolution of paw and fingerinflammation 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 fortranscriptomic analysis. Using immunohistochemistry, infiltration of immune inflammatorycells and pSTAT3 positive cells, were analysed in Achilles tendon enthesis, subcutaneousarea and skin. Colon was also collected for histology and gene expression analysis.

Conclusions• Sustained IL-23 overexpression in mice mimics main features of psoriatic arthritis: inflammation, enthesitis, dactylitis, psoriasis as

reported1

• Filgotinib reduced signs and symptoms of pathology:

Decreased paw swelling, enthesitis and dactylitis

Decreased infiltration of proinflammatory cells in enthesis, subcutaneous and cutaneous areas

Decreased epidermis thickness

Decreased pSTAT3 expression in both cutaneous and subcutaneous areas

Decreased expression of IL-23-induced genes in colon and fingers

• Phase 2 study with filgotinib in PsA patients is ongoing

Introduction

Because of their pleiotropic role in cytokine signalling, Janus Kinases (JAKs) are key playersin 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 withfilgotinib (GLPG0634, GS-6034) displaying efficacy and safety in several phase 2 studies inrheumatoid arthritis (RA) patients. Psoriatic arthritis (PsA) is a heterogeneous chronicinflammatory disease characterized by the association of skeletal involvement and extra-skeletal symptoms such as psoriasis and Inflammatory Bowel Disease (IBD) with commonfindings including enthesitis and dactylitis. Current treatments include anti-TNFa, anti-IL-17and 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 gaininsight in the potential of a JAK1-selective inhibitor in PsA, we evaluated filgotinib efficacy ina mouse model of PsA induced by the overexpression of IL-23.

Disclosures: all authors are employees of Galapagos SASU

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Figure 2: Filgotinib blocks disease progression in a therapeutic model of PsA. A: Clinical score (mean ± SEM) taking into account finger and paw swelling

B: Hallmarks of the disease in mouse: a, c, e: Sham animals; b: psoriasis; d: inflammation; f: dactylitis

Figure 1: Therapeutic study design

Figure 3: Filgotinib partially reverses the IL-23-induced gene expression in the colon (A – C) and the fingers (D – F). A & D: heat map of the 50 most differentially expressed genes induced by IL-23 and impacted by filgotinib. B & E: volcano plot of filgotinib effects on IL-23-induced genes. C & F: inverse correlation between IL-23 and filgotinib effects

Figure 3: Filgotinib reduced neutrophil infiltration in Achilles enthesis (left) and decreased STAT3 induction in the skin (right). AT: Achilles tendon; C: calcaneus bone (left). E: epidermis; D: dermis; HF: hair follicle (right).

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ReferencesREFERENCE: 1Sherlock et al. (2012), Nat Med. 18:1069-76