Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme
| Autor: | Raj Bhandari, M. Teresa Pulido-Rios, David T Beattie, Reuben Sana, Brihad Abhyankar, Jonathan A. Leighton, Jacky Woo, Richard Graham, Eva Situ, Ravi Ganeshappa, Erik Sandvik, Melanie A. Kleinschek, Whitney Krey, David L. Boyle, Deanna D Nguyen, Julián Panés, William J. Sandborn, Patrick Brassil |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Biomedical Administration Oral Ulcerative Pharmacology Severity of Illness Index Oral and gastrointestinal Biomarkers Pharmacological Translational Research Biomedical Mice Eccojc/1040 0302 clinical medicine Immunologic Medicine Tissue Distribution Intestinal Mucosa Janus kinase inhibitor Gastroenterology General Medicine Colitis Ulcerative colitis Healthy Volunteers Treatment Outcome JAK inhibitor 5.1 Pharmaceuticals 6.1 Pharmaceuticals Administration 030211 gastroenterology & hepatology Development of treatments and therapeutic interventions Oral Adult gut-selective Clinical Trials and Supportive Activities Clinical Sciences Dose-Response Relationship Immunologic Placebo Autoimmune Disease Dose-Response Relationship 03 medical and health sciences Pharmacokinetics Clinical Research Translational Research Animals Humans Janus Kinase Inhibitors Potency AcademicSubjects/MED00260 Tofacitinib Gastroenterology & Hepatology business.industry Pharmacological Inflammatory Bowel Disease Evaluation of treatments and therapeutic interventions Histology Original Articles medicine.disease Eccojc/1000 Blood Cell Count Editor's Choice 030104 developmental biology Colitis Ulcerative Digestive Diseases business Biomarkers |
| Zdroj: | Journal of Crohn's & Colitis Journal of Crohn's & colitis, vol 14, iss 9 |
| ISSN: | 1876-4479 1873-9946 |
| DOI: | 10.1093/ecco-jcc/jjaa049 |
| Popis: | 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] |
| Databáze: | OpenAIRE |
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