Development of gut-selective pan-janus kinase inhibitor TD-1473 for ulcerative colitis: A translational medicine programme

William J. Sandborn, Deanna D. Nguyen, David T. Beattie, Patrick Brassil, Whitney Krey, Jacky Woo, Eva Situ, Reuben Sana, Erik Sandvik, M. Teresa Pulido-Rios, Raj Bhandari, Jonathan A. Leighton, Ravi Ganeshappa, David L. Boyle, Brihad Abhyankar, Melanie A. Kleinschek, Richard A. Graham, Julian Panes

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background and Aims: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC. Methods: TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. Results: TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. Conclusion: Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity.

Original languageEnglish (US)
Pages (from-to)1202-1213
Number of pages12
JournalJournal of Crohn's and Colitis
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2020

Keywords

  • Gut-selective
  • JAK inhibitor
  • Ulcerative colitis

ASJC Scopus subject areas

  • Gastroenterology

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