Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme. (11th March 2020)

• Record Type: Journal Article
• Authors: Sandborn, William J; Nguyen, Deanna D; Beattie, David T; Brassil, Patrick; Krey, Whitney; Woo, Jacky; Situ, Eva; Sana, Reuben; Sandvik, Erik; Pulido-Rios, M Teresa; Bhandari, Raj; Leighton, Jonathan A; Ganeshappa, Ravi; Boyle, David L; Abhyankar, Brihad; Kleinschek, Melanie A; Graham, Richard A; Panes, Julian
• Is Part Of: Journal of Crohn's and colitis. Volume 14:Number 9(2020)
• Page Start: 1202
• Page End: 1213
• Publication Date: 2020-03-11
• Subjects: Ulcerative colitis -- gut-selective -- JAK inhibitor; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjaa049
• Languages: English
• ISSNs: 1873-9946

Abstract

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. [Clinicaltrials.gov NCT02657122, NCT02818686]