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Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine
William J Sandborn1, Deanna D Nguyen2, David T Beattie2
1Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
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].
Insights
A new gut-selective pan-Janus kinase inhibitor, TD-1473, shows promise for ulcerative colitis treatment. It achieves high concentrations in the gut with low systemic exposure, demonstrating potential for reduced disease activity.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Systemic Janus kinase (JAK) inhibitors are effective for ulcerative colitis (UC) but associated with toxicities.
- TD-1473 is an oral, gut-selective pan-JAK inhibitor developed to mitigate systemic toxicities.
- Preclinical and clinical studies evaluated TD-1473's translation from in vitro characterization to Phase 1b efficacy in UC patients.
Purpose of the Study:
- To assess the preclinical and clinical profile of TD-1473, a gut-selective pan-JAK inhibitor.
- To evaluate the safety, pharmacokinetics, and efficacy of TD-1473 in healthy subjects and patients with ulcerative colitis.
Main Methods:
- In vitro evaluation of TD-1473's JAK inhibition potency.
- Pharmacokinetic and safety assessments in mice and healthy human subjects.
- A 28-day Phase 1b study in UC patients randomized to TD-1473 (20, 80, or 270 mg once daily) or placebo, assessing safety, plasma/colonic concentrations, and efficacy endpoints.
Main Results:
- TD-1473 demonstrated potent in vitro pan-JAK inhibition.
- In mice, oral TD-1473 achieved high colonic concentrations with low plasma exposure, reducing colitis activity without affecting blood cell counts.
- In humans, TD-1473 showed low plasma exposure, was well-tolerated, and achieved biologically active colonic concentrations, with trends toward reduced UC disease activity.
Conclusions:
- Gut-selective pan-JAK inhibition with TD-1473 leads to high intestinal drug exposure relative to plasma.
- TD-1473 demonstrates local target engagement in the colon.
- The study indicates trends toward reduced ulcerative colitis disease activity, supporting further investigation.
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