Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme

  • J Crohns Colitis. 2020 Sep 16;14(9):1202-1213. doi: 10.1093/ecco-jcc/jjaa049.
William J Sandborn  1 ,  Deanna D Nguyen  2 ,  David T Beattie  2 ,  Patrick Brassil  2 ,  Whitney Krey  2 ,  Jacky Woo  2 ,  Eva Situ  2 ,  Reuben Sana  2 ,  Erik Sandvik  2 ,  M Teresa Pulido-Rios  2 ,  Raj Bhandari  3 ,  Jonathan A Leighton  4 ,  Ravi Ganeshappa  5 ,  David L Boyle  6 ,  Brihad Abhyankar  7 ,  Melanie A Kleinschek  2 ,  Richard A Graham  2 ,  Julian Panes  8
Affiliations
  • 1. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
  • 2. Theravance Biopharma US, Inc., South San Francisco, CA, USA.
  • 3. Delta Research Partners, Monroe, LA, USA.
  • 4. Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
  • 5. Pinnacle Clinical Research, San Antonio, TX, USA.
  • 6. Biomarker Laboratory, University of California San Diego, La Jolla, CA, USA.
  • 7. Theravance Biopharma Ireland Limited, Dublin, Ireland.
  • 8. Department of Gastroenterology, Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
PMID: 32161949 DOI: 10.1093/ecco-jcc/jjaa049
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].

Keywords
JAK inhibitor; Ulcerative colitis; gut-selective.
Products