1. Development of gut-selective pan-Janus kinase inhibitor TD-1473 for ulcerative colitis: A translational medicine program
- Author
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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, and Panes, Julian
- Subjects
Inflammatory Bowel Disease ,Clinical Research ,Autoimmune Disease ,Digestive Diseases ,Clinical Trials and Supportive Activities ,5.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Oral and gastrointestinal ,Administration ,Oral ,Adult ,Animals ,Biomarkers ,Pharmacological ,Blood Cell Count ,Colitis ,Ulcerative ,Dose-Response Relationship ,Immunologic ,Healthy Volunteers ,Humans ,Intestinal Mucosa ,Janus Kinase Inhibitors ,Male ,Mice ,Severity of Illness Index ,Tissue Distribution ,Translational Research ,Biomedical ,Treatment Outcome ,Ulcerative colitis ,gut-selective ,JAK inhibitor ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
Background and aimsOral 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.MethodsTD-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.ResultsTD-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.ConclusionGut-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].
- Published
- 2020