GSK2586184, a JAK1 selective inhibitor, in two patients with ulcerative colitis

Abstract

Tofacitinib, a non-selective Janus kinase (JAK) inhibitor, is effective in inducing clinical and endoscopic remission in patients with active ulcerative colitis (UC). Tofacitinib inhibits cytokine signalling through blockade of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Adverse events including neutropenia and anaemia resulting from JAK2 inhibition have been observed in actively treated patients. By selectively targeting JAK1, such adverse events could be expected to be avoided. This open label study was designed to enrol 15 patients with UC, however the trial was discontinued after two inclusions due to safety concerns with the agent in a parallel trial for systemic lupus erythematosus. GSK2586184 was administered in two patients with moderate-to-severe UC. The JAK1 selective inhibitor GSK2586184 was well tolerated and induced clinical and endoscopic response in two patients with moderate-to-severe UC. In addition, treatment with GSK2586184 decreased histology scores and faecal calprotectin levels at early withdrawal.

Keywords: drugs: gastrointestinal system; inflammatory bowel disease.

Conflict of interest statement

Competing interests: LCSDV has received research funding from GlaxoSmithKline. VJL and KJH are employees of GlaxoSmithKline. GRD’H has served as speaker, consultant and principal investigator for Abbott/Abbvie, AM Pharma, Centocor/Jansen Biologics, Engene, Photopill, Setpoint, Novonordisk, MSD, UCB, Takeda, TEVA, Millenium, Boerhinger Ingelheim, Elan, Ferring, DrFALK Pharma, Shire, Cosmo, AstraZeneca, GlaxoSmithKLine and PDL.

© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

(A) The Total Mayo score, ranging from 0 to 12 points, decreased in both patients after treatment with GSK2586184 (B) The Mayo individual sub-scores, stool frequency (0–4), rectal bleeding (0–4), physician's global assessment (0–4) and the Mayo endoscopic sub-score (0–3) decreased in both patients after treatment with GSK2586184. (C) The (UCEIS) (0-11) decreased in both patients after treatment. (D) Endoscopy images of patients 1 and 2, treated with decreased in both patients after treatment with GSK2586184 for 7 and 2 weeks, respectively. (E) Serum concentrations of GSK2586184 measured in patient 1 at baseline, at day 14 pre- and post-dose and at day 28 post-dose. UCEIS, Ulcerative Colitis Index of Severity.

Figure 2

(A) Faecal calprotectin levels decreased in both patients after treatment with GSK2586184. (B) Serum CRP primarily decreased in patient 2 after treatment with GSK2586184. In patient 1, CRP concentrations were low at baseline, the increase was caused by a nasopharyngitis. (C) The Geboes score, ranging from 0 to 5, decreased in biopsies both patients after treatment with GSK258618. (D) IBDQ scores, ranging from 32 to 224 points, improved after treatment with GSK2586184.