Development of gut-selective pan-Janus kinase inhibitor TD-1473 for ulcerative colitis: A translational medicine program.
2020
BACKGROUND AND AIMS: Oral systemic pan-Janus kinase (JAK) inhibition is effective for ulcerative colitis (UC) but 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 the 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 signaling. 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 histologic 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).
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