TY - JOUR
T1 - Development of gut-selective pan-janus kinase inhibitor TD-1473 for ulcerative colitis
T2 - A translational medicine programme
AU - Sandborn, William J.
AU - Nguyen, Deanna D.
AU - Beattie, David T.
AU - Brassil, Patrick
AU - Krey, Whitney
AU - Woo, Jacky
AU - Situ, Eva
AU - Sana, Reuben
AU - Sandvik, Erik
AU - Pulido-Rios, M. Teresa
AU - Bhandari, Raj
AU - Leighton, Jonathan A.
AU - Ganeshappa, Ravi
AU - Boyle, David L.
AU - Abhyankar, Brihad
AU - Kleinschek, Melanie A.
AU - Graham, Richard A.
AU - Panes, Julian
N1 - Publisher Copyright:
© The Author(s) 2020.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - Gut-selective
KW - JAK inhibitor
KW - Ulcerative colitis
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UR - http://www.scopus.com/inward/citedby.url?scp=85091127382&partnerID=8YFLogxK
U2 - 10.1093/ecco-jcc/jjaa049
DO - 10.1093/ecco-jcc/jjaa049
M3 - Article
C2 - 32161949
AN - SCOPUS:85091127382
SN - 1873-9946
VL - 14
SP - 1202
EP - 1213
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 9
ER -