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P020 The efficacy of tofacitinib and a selective Janus kinase 1 inhibitor in dextran sulphate sodium colitis models

L. De Vries*1, 2, F. van Leeuwen-Hilbers2, P. van Hamersveld2, V. Ludbrook3, G. D’Haens1, W. De Jonge2

1Academic Medical Centre (AMC), Gastroenterology & Hepatology, Amsterdam, Netherlands, 2Academic Medical Centre (AMC), Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands, 3GlaxoSmithKline, Immuno-Inflammation Therapy Area, Stevenage, United Kingdom

Background

Nonselective Janus kinase (JAK) inhibitors such as tofacitinib have shown efficacy in treatment of ulcerative colitis. Side effects unrelated to direct immune suppression, such as anaemia and neutropenia because of inhibition of JAK2, challenge the clinical application of tofacitinib. A recently developed selective JAK1 inhibitor (JAK1i, GSK2586186) may act more selectively on relevant cytokine receptors such as IL2R, IL6R, and IFNR. The aim of this study was to investigate the potency of JAK1i vs tofacitinib (CP-690,550-10, Pfizer) in acute and chronic DSS colitis models.

Methods

In acute DSS experiments C57/Bl6 mice (8–12 weeks) were given 2% DSS in drinking water, combined with daily oral gavage of JAK1i or tofacitinib 3, 10, or 30 mg/kg until sacrifice at day 7. In chronic DSS experiments, 2% DSS was given for 5 days, followed by a recovery period. Next, JAK1i or tofacitinib 1, 3, or 10 mg/kg were dosed every other day by oral gavage, starting at day 7 until sacrifice at day 14. Clinical scores, such as colon weight-length ratio, diarrhoea score, and biomarkers for inflammation, were assessed. In addition, histology and endoscopy scoring was performed. Animal experiments were performed according to the guidelines of our Ethical Animal Research Committee.

Results

In acute DSS colitis, treatment with 3, 10, and 30 mg/kg JAK1i or tofacitinib did not protect mice from weight loss in comparison with DSS-treated animals. JAK1i and tofacitinib 3, 10, or 30 mg/kg did not improve clinical, histology, and endoscopy scores at day 7. Cytokine secretion (IL6, TNFα, IL10, and IFNγ measured in colon homogenates was not affected, although 10 mg/kg JAK1i increased CXCL10 secretion (p = 0.0020).

In chronic DSS experiments, treatment with 1, 3, or 10 mg/kg JAK1i or tofacitinib did not affect body weight recovery between day 7 and 14, compared with mice receiving DSS alone. However, in mice receiving tofacitinib, a decreasing trend in mean endoscopy colitis severity scores were observed at the highest dose of 10 mg/kg, in comparison with mice receiving DSS alone (2.75 vs 1.143, p = 0.317), whereas JAK1i had no effect up to 30 mg/kg. Cytokine secretion (IL6, TNFα, IL10, and IFNγ) measured in colon homogenates was not affected by JAK1i or tofacitinib.

Conclusion

In vivo, 3, 10, or 30 mg/kg JAK1i and tofacitinib did not protect mice from acute DSS colitis. Tofacitinib but not JAK1i ameliorated some aspects of the course of a chronic DSS colitis at the highest dose given. By contrast, data on a different selective JAK1 inhibitor molecule GLPG0634 reported efficacy in a mouse DSS-induced colitis model., In our study, tofacitinib as well as GSK2586186, has limited effect on the course of DSS colitis in mice.

References:

[1] Merciris D, Delachaume C, De Vriendt V, et al. GLPG0634, the first selective JAK1 inhibitor, shows strong activity in the mouse DSS-colitis model. ECCO 2014; Poster presentations: Basic Science.