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P601 The efficacy of GSK2586184, a novel selective Janus kinase1 inhibitor, in patients with moderate to severely active ulcerative colitis

L. De Vries*1, 2, F. van Leeuwen-Hilbers2, C. Verseijden2, J. Duarte2, K. Hicks3, J. Patel3, V. Ludbrook3, W. De Jonge2, G. D’Haens1

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


Tofacitinib, a non-selective Janus Kinase (JAK) inhibitor, has demonstrated efficacy in ulcerative colitis (UC) patients. By selectively targeting JAK1, adverse effects resulting from JAK2 inhibition can be avoided. The objective of this study (funded by GSK) was to investigate the safety and tolerability of the selective JAK1 inhibitor GSK2586184 in patients with moderate-to-severe UC.


GSK2586184 was administered 400 mg b.i.d. in 2 patients for 7 and 2 weeks respectively. This trial was discontinued following the assessment that emerging safety data across the development program did not support the benefit–risk ratio of continuing ongoing clinical studies. Clinical and endoscopic response and remission was assessed using the total Mayo score; mucosal healing was defined as an endoscopic sub-score of 0 or 1. Reduction in the UCEIS was also assessed. Safety and tolerability were determined by routine laboratory tests, physical examination, and adverse event (AE) reporting. In addition, 8 sigmoid biopsies were collected at baseline (BL) and early withdrawal (EW) endoscopy for: flow cytometry to determine T-cell populations; and PCR array and QPCR on inflammatory cytokines; and IHC on percentages of T-cell and macrophage markers quantified in Image J.


GSK2586184 was well tolerated and no serious adverse events or drug related adverse events were reported. Faecal calprotectin levels decreased from 485 and 1006 µg/g at BL to resp. 120 and 172 µg/g at EW. The Total Mayo score decreased from 7 and 11 points to resp. 3 points in both patients at EW sigmoidoscopy; the endoscopic sub-score decreased from 2 and 3 points to 1 point in both patients. UCEIS at screening decreased from 6 and 7 to resp. 5 and 6 points at EW. Flow cytometry on biopsies at BL showed a decrease in proportions of Th1 in comparison to the EW percentages (10.2% and 13.7% to resp. 9.81% and 5.21%). In biopsies, GSK2586184 inhibited relative expression of interferon gamma inducible genes such as MX1, OAS1, IL12RB1, Ido1, Kynu at EW, in comparison to reference genes. In the PCR array, GSK2586184 down regulated 64 resp. 72 out of 84 cytokines (expressed in log2 fold change) such as CXC13(-10.34; -147.03), CCR2 (-1.26; -11.47), IL21(-6.32; -15.67), TNF(-1.51; -3.16) and interferon gamma (-2.75; -23.43). IHC showed that CD68 (% of stained surface area) only decreased in the first patient (7weeks) from 1.32% at BL to 0.46% at EW. The CD3 percentage only decreased in the second patient from 4.32% at BL to 2.05% at EW.


GSK2586184 was well tolerated by the 2 patients in this study. This study demonstrated efficacy of GSK2586184 in the treatment of moderate-to-severe UC in these 2 subjects, as well as efficacy in decreasing biopsy inflammation.