Pan-Janus kinase inhibitor TD-1473

Oral TD-1473 is a gut-selective pan-Janus kinase (JAK) inhibitor. In a double-blind, placebo-controlled, multicentre, phase 1b study, oral TD-1473 results in low systemic exposure and high concentration in gut tissue at doses up to 270 mg [1]. Signals for clinical, endoscopic, histological, and biomarker activity were observed in subjects with moderately to severely active ulcerative colitis after 4 weeks of treatment with TD-1473 at all 3 doses (i.e. 20 mg, 80 mg, and 270 mg).

The 40 enrolled subjects received placebo (n=9), TD-1473 20 mg (n=10), 80 mg (n=10), or 270 mg (n=11) once daily for 28 days. Trends were observed of higher rates of clinical response, endoscopic healing, and improvement by ≥1 point in rectal bleeding and endoscopy subscores with TD-1473 relative to placebo. Serum C-reactive protein decreased relative to placebo at all dose levels. Faecal calprotectin decreased in subjects treated with 80 mg and 270 mg. Four weeks of treatment with TD-1473 at 20 mg and 270 mg was associated with dose-related reductions in Robarts’ Histologic Index (RHI), along with colonic levels of phospho-STAT1 and phospho-STAT3 proteins, which reached statistical significance in the 270 mg group. RNA-sequencing analysis suggested that TD-1473 has a local effect on the ulcerative colitis-transcriptomics signature.

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   1. Sandborn W, et al. ECCO 2019, DOP53.

Posted on 9 May, 20198 April, 2024